Search results for: renal malignancy

Authors: Sean Yao Zu Kong, Khong Yik Chew

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Introduction: We described a case report of the successful use of advanced surgical techniques in a patient with recurrent breast cancer who underwent a wide resection including the hemi-sternum, clavicle, multiple ribs, and a lobe of the lung due to tumor involvement. This extensive resection exposed critical structures, requiring a creative approach to reconstruction. To address this complex chest wall reconstruction, a free fibula flap and a 4-zone rectus abdominis musculocutaneous flap were successfully utilized. The use of a free vascularized bone flap allowed for rapid osteointegration and resistance against osteoradionecrosis after adjuvant radiation, while a four-zone tram flap allowed for reconstruction of both the chest wall and breast mound. Although limited recipient vessels made free flaps challenging, the free fibula flap served as both a bony reconstruction and vascular conduit, supercharged with the distal peroneal artery and veins of the peroneal artery from the fibula graft. Our approach highlights the potential of advanced surgical techniques to improve outcomes in complex cases of chest wall reconstruction in patients with recurrent breast cancer, which is becoming increasingly relevant as breast cancer incidence rates increases. Case presentation: This report describes a successful reconstruction of a patient with recurrent breast cancer who required extensive resection, including the anterior chest wall, clavicle, and sternoclavicular joint. Challenges arose due to the loss of accessory muscles and the non-rigid rib cage, which could lead to compromised ventilation and instability. A free fibula osteocutaneous flap and a four-zone TRAM flap with vascular supercharging were utilized to achieve long-term stability and function. The patient has since fully recovered, and during the review, both flaps remained viable, and chest mound reconstruction was satisfactory. A planned nipple/areolar reconstruction was offered pending the patient’s decision after adjuvant radiotherapy. Conclusion: In conclusion, this case report highlights the successful use of innovative surgical techniques in addressing a complex case of recurrent breast cancer requiring extensive resection and radical reconstruction. Our approach, utilized a combination of a free fibula flap and a 4-zone rectus abdominis musculocutaneous flap, demonstrates the potential for advanced techniques in chest wall reconstruction to minimize complications and ensure long-term stability and function. As the incidence of breast cancer continues to rise, it is crucial that healthcare professionals explore and utilize innovative techniques to improve patient outcomes and quality of life.

Keywords: free fibula flap, rectus abdominis musculocutaneous flap, post-adjuvant radiotherapy, reconstructive surgery, malignancy

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Authors: Tais Basaco, Stefanie Pektor, Josue A. Moreno, Matthias Miederer, Andreas Türler

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Radiopharmaceuticals based in monoclonal anti-body (mAb) via chemical linkers have become a potential tool in nuclear medicine because of their specificity and the large variability and availability of therapeutic radiometals. It is important to identify the conjugation sites and number of attached chelator to mAb to obtain radioimmunoconjugates with required immunoreactivity and radiostability. Girentuximab antibody (G250) is a potential candidate for radioimmunotherapy of clear cell carcinomas (RCCs) because it is reactive with CAIX antigen, a transmembrane glycoprotein overexpressed on the cell surface of most ( > 90%) (RCCs). G250 was conjugated with the bifunctional chelating agent DOTA (1,4,7,10-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid) via a benzyl-thiocyano group as a linker (p-SCN-Bn-DOTA). DOTA-G250 conjugates were analyzed by size exclusion chromatography (SE-HPLC) and by electrophoresis (SDS-PAGE). The potential site-specific conjugation was identified by liquid chromatography–mass spectrometry (LC/MS-MS) and the number of linkers per molecule of mAb was calculated using the molecular weight (MW) measured by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The average number obtained in the conjugates in non-reduced conditions was between 8-10 molecules of DOTA per molecule of mAb. The average number obtained in the conjugates in reduced conditions was between 1-2 and 3-4 molecules of DOTA per molecule of mAb in the light chain (LC) and heavy chain (HC) respectively. Potential DOTA modification sites of the chelator were identified in lysine residues. The biological activity of the conjugates was evaluated by flow cytometry (FACS) using CAIX negative (SKRC-18) and CAIX positive (SKRC-52). The DOTA-G250 conjugates were labelled with 177Lu with a radiochemical yield > 95% reaching specific activities of 12 MBq/µg. The stability in vitro of different types of radioconstructs was analyzed in human serum albumin (HSA). The radiostability of 177Lu-DOTA-G250 at high specific activity was increased by addition of sodium ascorbate after the labelling. The immunoreactivity was evaluated in vitro and in vivo. Binding to CAIX positive cells (SK-RC-52) at different specific activities was higher for conjugates with less DOTA content. Protein dose was optimized in mice with subcutaneously growing SK-RC-52 tumors using different amounts of 177Lu- DOTA-G250.

Keywords: mass spectrometry, monoclonal antibody, radiopharmaceuticals, radioimmunotheray, renal cancer

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Authors: Michael Vieth, Aric Schadler, Hubert Ballard, J. A. Bauer, Pratibha Thakkar

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Introduction: Congenital diaphragmatic hernia (CDH) is a condition characterized by the herniation of abdominal contents into the thoracic cavity requiring postnatal surgical repair. Previous literature suggests improved CDH outcomes at high-volume regional referral centers compared to low-volume centers. The purpose of this study was to examine CDH outcomes at Kentucky Children’s Hospital (KCH), a low-volume center, compared to the Congenital Diaphragmatic Hernia Study Group (CDHSG). Methods: A retrospective chart review was performed at KCH from 2007-2019 for neonates with CDH, and then subdivided into two cohorts: those requiring ECMO therapy and those not requiring ECMO therapy. Basic demographic data and measures of mortality and morbidity including ventilator days and length of stay were compared to the CDHSG. Measures of morbidity for the ECMO cohort including duration of ECMO, clinical bleeding, intracranial hemorrhage, sepsis, need for continuous renal replacement therapy (CRRT), need for sildenafil at discharge, timing of surgical repair, and total ventilator days were collected. Statistical analysis was performed using IBM SPSS Statistics version 28. One-sample t-tests and one-sample Wilcoxon Signed Rank test were utilized as appropriate.Results: There were a total of 27 neonatal patients with CDH at KCH from 2007-2019; 9 of the 27 required ECMO therapy. The birth weight and gestational age were similar between KCH and the CDHSG (2.99 kg vs 2.92 kg, p =0.655; 37.0 weeks vs 37.4 weeks, p =0.51). About half of the patients were inborn in both cohorts (52% vs 56%, p =0.676). KCH cohort had significantly more Caucasian patients (96% vs 55%, p=<0.001). Unadjusted mortality was similar in both groups (KCH 70% vs CDHSG 72%, p =0.857). Using ECMO utilization (KCH 78% vs CDHSG 52%, p =0.118) and need for surgical repair (KCH 95% vs CDHSG 85%, p =0.060) as proxy for severity, both groups’ mortality were comparable. No significant difference was noted for pulmonary outcomes such as average ventilator days (KCH 43.2 vs. CDHSG 17.3, p =0.078) and home oxygen dependency (KCH 44% vs. CDHSG 24%, p =0.108). Average length of hospital stay for patients treated at KCH was similar to CDHSG (64.4 vs 49.2, p=1.000). Conclusion: Our study demonstrates that outcome in CDH patients is independent of center’s case volume status. Management of CDH with a standardized approach in a low-volume center can yield similar outcomes. This data supports the treatment of patients with CDH at low-volume centers as opposed to transferring to higher-volume centers.

Keywords: ECMO, case volume, congenital diaphragmatic hernia, congenital diaphragmatic hernia study group, neonate

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Authors: Cassey Younghans

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Background: Current health care trends demonstrate that there is an increasing number of patients being hospitalized with complex comorbidities. These complex needs require advanced therapies, and treatment goals often focus on doing everything possible to prolong life rather than focusing on the individual patient’s quality of life which is the goal of palliative care efforts. Patients benefit from palliative care in the early stages of the illness rather than after the disease progressed or the state of acuity has advanced. The clinical problem identified was that palliative care was not being implemented early enough in the disease process with patients who had complex medical conditions and who would benefit from the philosophy and skills of palliative care professionals. Purpose: The purpose of this quality improvement study was to increase the number of palliative care screenings and consults completed on adults after being admitted to one Non-ICU and Non-COVID hospital unit. Methods: A retrospective chart review assessing for possible missed opportunities to introduce palliation was performed for patients with six primary diagnoses, including heart failure, liver failure, end stage renal disease, chronic obstructive pulmonary disease, cerebrovascular accident, and cancer in a population of adults over the ago of 19 on one medical-surgical unit over a three-month period prior to the intervention. An educational session with the nurses on the benefits of palliative care was conducted by the researcher, and a screening tool was implemented. The expected outcome was to have an increase in early palliative care consultation with patients with complex comorbid conditions and a decrease in missed opportunities for the implementation of palliative care. Another retrospective chart review was completed following completion of the three month piloting of the tool. Results: During the retrospective chart review, 46 patients were admitted to the medical-surgical floor with the primary diagnoses identified in the inclusion criteria. Six patients had palliative care consults completed during that time. Twenty-two palliative care screening tools were completed during the intervention period. Of those, 15 of the patients scored a 7 or higher, suggesting that a palliative care consultation was warranted. The final retrospective chart review identified that 4 palliative consults were implemented during that time of the 31 patients who were admitted over the three month time frame. Conclusion: Educating nurses and implementing a palliative care screening upon admission can be of great value in providing early identification of patients who might benefit from palliative care. Recommendations – It is recommended that this screening tool should be used to help identify the patents of whom would benefit from a palliative care consult, and nurses would be able to initiated a palliative care consultation themselves.

Keywords: palliative care, screening, early, palliative care consult

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Authors: Vandana Mohan, Ashwani Koul

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Aim: To evaluate the potential of Aqueous Tinospora cordifolia stem extract (Aq.Tc) and Arabinogalactan (AG) on pulmonary carcinogenesis and associated tumor markers. Background: Lung cancer is one of the most frequent malignancy with high mortality rate due to limitation of early detection resulting in low cure rates. Current research effort focuses on identifying some blood-based biomarkers like CEA, ctDNA and LDH which may have potential to detect cancer at an early stage, evaluation of therapeutic response and its recurrence. Medicinal plants and their active components have been widely investigated for their anticancer potentials. Aqueous preparation of T. Cordifolia extract is enriched in the polysaccharide fraction i.e., AG when compared with other types of extract. Moreover, reports are available of polysaccharide fraction of T. Cordifolia in in vitro lung cancer models which showed profound anti-metastatic activity against these cell lines. However, not much has been explored about its effect in in vivo lung cancer models and the underlying mechanism involved. Experimental Design: Mice were randomly segregated into six groups. Group I animals served as control. Group II animals were administered with Aq. Tc extract (200 mg/kg b.w.) p.o.on the alternate days. Group III animals were fed with AG (7.5 mg/kg b.w.) p.o. on the alternate days (thrice a week). Group IV animals were installed with Benzo(a)pyrene (50 mg/kg b.w.), i.p. twice within an interval of two weeks. Group V animals received Aq. Tc extract as in group II along with it B(a)P was installed after two weeks of Aq. Tc administration following the same protocol as for group IV. Group VI animals received AG as in group III along with it B(a)P was installed after two weeks of AG administration. Results: Administration of B(a)P to mice resulted in increased tumor incidence, multiplicity and pulmonary somatic index with concomitant increase in serum/plasma markers like CEA, ctDNA, LDH and TNF-α.Aq.Tc and AG supplementation significantly attenuated these alterations at different stages of tumorigenesis thereby showing potent anti-cancer effect in lung cancer. A pronounced decrease in serum/plasma markers were observed in animals treated with Aq.Tc as compared to those fed with AG. Also, extensive hyperproliferation of alveolar epithelium was prominent in B(a)P induced lung tumors. However, treatment of Aq.Tc and AG to lung tumor bearing mice exhibited reduced alveolar damage evident from decreased number of hyperchromatic irregular nuclei. A direct correlation between the concentration of tumor markers and the intensity of lung cancer was observed in animals bearing cancer co-treated with Aq.Tc and AG. Conclusion: These findings substantiate the chemopreventive potential of Aq.Tc and AG against lung tumorigenesis. Interestingly, Aq.Tc was found to be more effective in modulating the cancer as reflected by various observations which may be attributed to the synergism offered by various components of Aq.Tc. Further studies are in progress to understand the underlined mechanism in inhibiting lung tumorigenesis by Aq.Tc and AG.

Keywords: Arabinogalactan, Benzo(a)pyrene B(a)P, carcinoembryonic antigen (CEA), circulating tumor DNA (ctDNA), lactate dehydrogenase (LDH), Tinospora cordifolia

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Authors: Jaci Marie Mastrandrea, Rosario Haro

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Background: The National Comprehensive Cancer Network (NCCN) recommends that healthcare institutions have established processes for integrating palliative care (PC) into cancer treatment and that all cancer patients be screened for PC needs upon initial diagnosis as well as throughout the entire continuum of care (National Comprehensive Cancer Network, 2021). Early PC screening and intervention is directly associated with improved patient outcomes. The Sky Lakes Cancer Treatment Center (SLCTC) is an institution that has access to PC services yet does not have protocols in place for identifying patients with palliative needs or a standardized referral process. The aim of this quality improvement project was to improve early access to PC services by establishing a standardized screening and referral process for outpatient oncology patients. Method: The sample population included all adult patients with an oncology diagnosis who presented to the SLCTC for treatment during the project timeline. The “Palliative and Supportive Needs Assessment'' (PSNA) screening tool was developed from validated, evidence-based PC referral criteria. The tool was initially implemented using paper forms, and data was collected over a period of eight weeks. Patients were screened by nurses on the SLCTC oncology treatment team. Nurses responsible for screening patients received an educational inservice prior to implementation. Patients with a PSNA score of three or higher received an educational handout on the topic of PC and education about PC and symptom management. A score of five or higher indicates that PC referral is strongly recommended, and the patient’s EHR is flagged for the oncology provider to review orders for PC referral. The PSNA tool was approved by Sky Lakes administration for full integration into Epic-Beacon. The project lead collaborated with the Sky Lakes’ information systems team and representatives from Epic on the tool’s aesthetic and functionality within the Epic system. SLCTC nurses and physicians were educated on how to document the PSNA within Epic and where to view results. Results: Prior to the implementation of the PSNA screening tool, the SLCTC had zero referrals to PC in the past year, excluding referrals to hospice. Data was collected from the completed screening assessments of 100 patients under active treatment at the SLCTC. Seventy-three percent of patients met criteria for PC referral with a score greater than or equal to three. Of those patients who met referral criteria, 53.4% (39 patients) were referred for a palliative and supportive care consultation. Patients that were not referred to PC upon meeting criteria were flagged in EPIC for re-screening within one to three months. Patients with lung cancer, chronic hematologic malignancies, breast cancer, and gastrointestinal malignancy most frequently met the criteria for PC referral and scored highest overall on the scale of 0-12. Conclusion: The implementation of a standardized PC screening tool at the SLCTC significantly increased awareness of PC needs among cancer patients in the outpatient setting. Additionally, data derived from this quality improvement project supports the national recommendation for PC to be an integral component of cancer treatment across the entire continuum of care.

Keywords: oncology, palliative and supportive care, symptom management, outpatient oncology, palliative screening tool

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Authors: Carmiña L. Vargas-Zapata, María A. Conde-Sarmiento, Maria Consuelo Maestre-Vargas

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Calcium is an essential element for good growth and development of the organism, and its requirement is increased at school age. Low socio-economic populations of developing countries such as Colombia may have food deficiency of this mineral in schoolchildren that could be reflected in calcium biochemical indicators, bone alterations and anthropometric indicators. The objective of this investigation was to evaluate some calcium biochemical indicators in a group of schoolchildren of low socioeconomic level from Barranquilla city and to correlate with body mass index. 60 schoolchildren aged 7 to 15 years were selected from Jesus’s Heart Educational Institution in Barranquilla-Atlántico, apparently healthy, without suffering from infectious or gastrointestinal diseases, without habits of drinking alcohol or smoking another hallucinogenic substance and without taking supplementation with calcium in the last six months or another substance that compromises bone metabolism. The research was approved by the ethics committee at Universidad del Atlántico. The selected children were invited to donate a blood and urine sample in a fasting time of 12 hours, the serum was separated by centrifugation and frozen at ˗20 ℃ until analyzed and the same was done with the urine sample. On the day of the biological collections, the weight and height of the students were measured to determine the nutritional status by BMI using the WHO tables. Calcium concentrations in serum and urine (SCa, UCa), alkaline phosphatase activity total and of bone origin (SAPT, SBAP) and urinary creatinine (UCr) were determined by spectrophotometric methods using commercial kits. Osteocalcin and Cross-linked N-telopeptides of type I collagen (NTx-1) in serum were measured with an enzyme-linked inmunosorbent assay. For statistical analysis the Statgraphics software Centurium XVII was used. 63% (n = 38) and 37% (n = 22) of the participants were male and female, respectively. 78% (n = 47), 5% (n = 3) and 17% (n = 10) had a normal, malnutrition and high nutritional status, respectively. The averages of evaluated indicators levels were (mean ± SD): 9.50 ± 1.06 mg/dL for SCa; 181.3 ± 64.3 U/L for SAPT, 143.8 ± 73.9 U/L for SBAP; 9.0 ± 3.48 ng/mL for osteocalcin and 101.3 ± 12.8 ng/mL for NTx-1. UCa level was 12.8 ± 7.7 mg/dL that adjusted with creatinine ranged from 0.005 to 0.395 mg/mg. Considering serum calcium values, approximately 7% of school children were hypocalcemic, 16% hypercalcemic and 77% normocalcemic. The indicators evaluated did not correlate with the BMI. Low values ​​were observed in calcium urinary excretion and high in NTx-1, suggesting that mechanisms such as increase in renal retention of calcium and in bone remodeling may be contributing to calcium homeostasis.

Keywords: calcium, calcium biochemical, indicators, school children, low socioeconomic status

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Authors: Meitham Amereh, Mohsen Akbari, Ben Nadler

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Cancer has been recognized as one of the most challenging problems in biology and medicine. Aggressive tumors are a lethal type of cancers characterized by high genomic instability, rapid progression, invasiveness, and therapeutic resistance. Their behavior involves complicated molecular biology and consequential dynamics. Although tremendous effort has been devoted to developing therapeutic approaches, there is still a huge need for new insights into the dark aspects of tumors. As one of the key requirements in better understanding the complex behavior of tumors, mathematical modeling and continuum physics, in particular, play a pivotal role. Mathematical modeling can provide a quantitative prediction on biological processes and help interpret complicated physiological interactions in tumors microenvironment. The pathophysiology of aggressive tumors is strongly affected by the extracellular cues such as stresses produced by mechanical forces between the tumor and the host tissue. During the tumor progression, the growing mass displaces the surrounding extracellular matrix (ECM), and due to the level of tissue stiffness, stress accumulates inside the tumor. The produced stress can influence the tumor by breaking adherent junctions. During this process, the tumor stops the rapid proliferation and begins to remodel its shape to preserve the homeostatic equilibrium state. To reach this, the tumor, in turn, upregulates epithelial to mesenchymal transit-inducing transcription factors (EMT-TFs). These EMT-TFs are involved in various signaling cascades, which are often associated with tumor invasiveness and malignancy. In this work, we modeled the tumor as a growing hyperplastic mass and investigated the effects of mechanical stress from surrounding ECM on tumor invasion. The invasion is modeled as volume-preserving inelastic evolution. In this framework, principal balance laws are considered for tumor mass, linear momentum, and diffusion of nutrients. Also, mechanical interactions between the tumor and ECM is modeled using Ciarlet constitutive strain energy function, and dissipation inequality is utilized to model the volumetric growth rate. System parameters, such as rate of nutrient uptake and cell proliferation, are obtained experimentally. To validate the model, human Glioblastoma multiforme (hGBM) tumor spheroids were incorporated inside Matrigel/Alginate composite hydrogel and was injected into a microfluidic chip to mimic the tumor’s natural microenvironment. The invasion structure was analyzed by imaging the spheroid over time. Also, the expression of transcriptional factors involved in invasion was measured by immune-staining the tumor. The volumetric growth, stress distribution, and inelastic evolution of tumors were predicted by the model. Results showed that the level of invasion is in direct correlation with the level of predicted stress within the tumor. Moreover, the invasion length measured by fluorescent imaging was shown to be related to the inelastic evolution of tumors obtained by the model.

Keywords: cancer, invasion, mathematical modeling, microfluidic chip, tumor spheroids

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Authors: Ramanpreet, Gursatej Gandhi

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Background: Dependence on electromagnetic radiations involved in communication and information technologies has incredibly increased in the personal and professional world. Among the numerous radiations, sources are fixed site transmitters, mobile phone base stations, and power lines beside indoor devices like cordless phones, WiFi, Bluetooth, TV, radio, microwave ovens, etc. Rather there is the continuous emittance of radiofrequency radiations (RFR) even to those not using the devices from mobile phone base stations. The consistent and widespread usage of wireless devices has build-up electromagnetic fields everywhere. In fact, the radiofrequency electromagnetic field (RF-EMF) has insidiously become a part of the environment and like any contaminant may pose to be health-hazardous requiring assessment. Materials and Methods: In the present study, cytogenetic damage was assessed using the Buccal Micronucleus Cytome (BMCyt) assay as a function of radiation exposure after Institutional Ethics Committee clearance of the study and written voluntary informed consent from the participants. On a pre-designed questionnaire, general information lifestyle patterns (diet, physical activity, smoking, drinking, use of mobile phones, internet, Wi-Fi usage, etc.) genetic, reproductive (pedigrees) and medical histories were recorded. For this, 24 hour-personal exposimeter measurements (PEM) were recorded for unrelated 60 healthy adults (40 cases residing in the vicinity of mobile phone base stations since their installation and 20 controls residing in areas with no base stations). The personal exposimeter collects information from all the sources generating EMF (TETRA, GSM, UMTS, DECT, and WLAN) as total RF-EMF uplink and downlink. Findings: The cases (n=40; 23-90 years) and the controls (n=20; 19-65 years) matched for alcohol drinking, smoking habits, and mobile and cordless phone usage. The PEM in cases (149.28 ± 8.98 mV/m) revealed significantly higher (p=0.000) electric field strength compared to the recorded value (80.40 ± 0.30 mV/m) in controls. The GSM 900 uplink (p=0.000), GSM 1800 downlink (p=0.000),UMTS (both uplink; p=0.013 and downlink; p=0.001) and DECT (p=0.000) electric field strength were significantly elevated in the cases as compared to controls. The electric field strength in the cases was significantly from GSM1800 (52.26 ± 4.49mV/m) followed by GSM900 (45.69 ± 4.98mV/m), UMTS (25.03 ± 3.33mV/m), DECT (18.02 ± 2.14mV/m) and was least from WLAN (8.26 ± 2.35mV/m). The higher significantly (p=0.000) increased exposure to the cases was from GSM (97.96 ± 6.97mV/m) in comparison to UMTS, DECT, and WLAN. The frequencies of micronuclei (1.86X, p=0.007), nuclear buds (2.95X, p=0.002) and cell death parameter (condensed chromatin cells) were significantly (1.75X, p=0.007) elevated in cases compared to that in controls probably as a function of radiofrequency radiation exposure. Conclusion: In the absence of other exposure(s), any cytogenetic damage if unrepaired is a cause of concern as it can cause malignancy. Larger sample size with the clinical assessment will prove more insightful of such an effect.

Keywords: Buccal micronucleus cytome assay, cytogenetic damage, electric field strength, personal exposimeter

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Authors: Faris Alkhalil, Rana Bitar, Amer Azaz, Hisham Natour, Noora Almeraikhi, Mohamad Miqdady

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Background: Children with liver transplantation are achieving very good survival and so there is now a need to concentrate on achieving good health in these patients and preventing disease. Immunosuppressive medications have side effects that need to be monitored and if possible avoided. Glucocorticoids and calcineurin inhibitors are detrimental to bone and mineral homeostasis in addition steroids can also affect linear growth. Steroid sparing regimes in renal transplant children has shown to improve children’s height. Aim: We aim to review the growth and bone health of children post liver transplant by measuring bone mineral density (BMD) using dual energy X-ray absorptiometry (DEXA) scan and assessing if there is a clear link between poor growth and impaired bone health and use of long term steroids. Subjects and Methods: This is a single centre retrospective Cohort study, we reviewed the medical notes of children (0-16 years) who underwent a liver transplantation between November 2000 to November 2016 and currently being followed at our centre. Results: 39 patients were identified (25 males and 14 females), the median transplant age was 2 years (range 9 months - 16 years), and the median follow up was 6 years. Four patients received a combined transplant, 2 kidney and liver transplant and 2 received a liver and small bowel transplant. The indications for transplant included, Biliary Atresia (31%), Acute Liver failure (18%), Progressive Familial Intrahepatic Cholestasis (15%), transplantable metabolic disease (10%), TPN related liver disease (8%), Primary Hyperoxaluria (5%), Hepatocellular carcinoma (3%) and other causes (10%). 36 patients (95%) were on a calcineurin inhibitor (34 patients were on Tacrolimus and 2 on Cyclosporin). The other three patients were on Sirolimus. Low dose long-term steroids was used in 21% of the patients. A considerable proportion of the patients had poor growth. 15% were below the 3rd centile for weight for age and 21% were below the 3rd centile for height for age. Most of our patients with poor growth were not on long term steroids. 49% of patients had a DEXA scan post transplantation. 21% of these children had low bone mineral density, one patient had met osteoporosis criteria with a vertebral fracture. Most of our patients with impaired bone health were not on long term steroids. 20% of the patients who did not undergo a DEXA scan developed long bone fractures and 50% of them were on long term steroid use which may suggest impaired bone health in these patients. Summary and Conclusion: The incidence of impaired bone health, although studied in limited number of patients; was high. Early recognition and treatment should be instituted to avoid fractures and improve bone health. Many of the patients were below the 3rd centile for weight and height however there was no clear relationship between steroid use and impaired bone health, reduced weight and reduced linear height.

Keywords: bone, growth, pediatric, liver, transplantation

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Authors: Neha Batra Bali, Monika Tomar, Vinay Gupta

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A reagentless biosensor for detection of urea based on ZnO-CuO composite thin film is presented in following work. Biosensors have immense potential for varied applications ranging from environmental to clinical testing, health care, and cell analysis. Immense growth in the field of biosensors is due to the huge requirement in today’s world to develop techniques which are both cost effective and accurate for prevention of disease manifestation. The human body comprises of numerous biomolecules which in their optimum levels are essential for functioning. However mismanaged levels of these biomolecules result in major health issues. Urea is one of the key biomolecules of interest. Its estimation is of paramount significance not only for healthcare sector but also from environmental perspectives. If level of urea in human blood/serum is abnormal, i.e., above or below physiological range (15-40mg/dl)), it may lead to diseases like renal failure, hepatic failure, nephritic syndrome, cachexia, urinary tract obstruction, dehydration, shock, burns and gastrointestinal, etc. Various metal nanoparticles, conducting polymer, metal oxide thin films, etc. have been exploited to act as matrix to immobilize urease to fabricate urea biosensor. Amongst them, Zinc Oxide (ZnO), a semiconductor metal oxide with a wide band gap is of immense interest as an efficient matrix in biosensors by virtue of its natural abundance, biocompatibility, good electron communication feature and high isoelectric point (9.5). In spite of being such an attractive candidate, ZnO does not possess a redox couple of its own which necessitates the use of electroactive mediators for electron transfer between the enzyme and the electrode, thereby causing hindrance in realization of integrated and implantable biosensor. In the present work, an effort has been made to fabricate a matrix based on ZnO-CuO composite prepared by pulsed laser deposition (PLD) technique in order to incorporate redox properties in ZnO matrix and to utilize the same for reagentless biosensing applications. The prepared bioelectrode Urs/(ZnO-CuO)/ITO/glass exhibits high sensitivity (70µAmM⁻¹cm⁻²) for detection of urea (5-200 mg/dl) with high stability (shelf life ˃ 10 weeks) and good selectivity (interference ˂ 4%). The enhanced sensing response obtained for composite matrix is attributed to the efficient electron exchange between ZnO-CuO matrix and immobilized enzymes, and subsequently fast transfer of generated electrons to the electrode via matrix. The response is encouraging for fabricating reagentless urea biosensor based on ZnO-CuO matrix.

Keywords: biosensor, reagentless, urea, ZnO-CuO composite

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Authors: Niklas Ravn-Boess, Nainita Bhowmick, Takamitsu Hattori, Shohei Koide, Christopher Park, Dimitris Placantonakis

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Background: Glioblastoma (GBM) is the most common and deadly primary brain malignancy in adults. Tumor propagation, brain invasion, and resistance to therapy critically depend on GBM stem-like cells (GSCs); however, the mechanisms that regulate GSC self-renewal are incompletely understood. Given the aggressiveness and poor prognosis of GBM, it is imperative to find biomarkers that could also translate into novel drug targets. Along these lines, we have identified a cell surface antigen, CD97 (ADGRE5), an adhesion G protein-coupled receptor (GPCR), that is expressed on GBM cells but is absent from non-neoplastic brain tissue. CD97 has been shown to promote invasiveness, angiogenesis, and migration in several human cancers, but its frequency of expression and functional role in regulating GBM growth and survival, and its potential as a therapeutic target has not been investigated. Design: We assessed CD97 mRNA and protein expression in patient derived GBM samples and cell lines using publicly available RNA-sequencing datasets and flow cytometry, respectively. To assess CD97 function, we generated shRNA lentiviral constructs that target a sequence in the CD97 extracellular domain (ECD). A scrambled shRNA (scr) with no predicted targets in the genome was used as a control. We evaluated CD97 shRNA lentivirally transduced GBM cells for Ki67, Annexin V, and DAPI. We also tested CD97 KD cells for their ability to self-renew using clonogenic tumorsphere formation assays. Further, we utilized synthetic Abs (sAbs) generated against the ECD of CD97 to test for potential antitumor effects using patient-derived GBM cell lines. Results: CD97 mRNA expression was expressed at high levels in all GBM samples available in the TCGA cohort. We found high levels of surface CD97 protein expression in 6/6 patient-derived GBM cell cultures, but not human neural stem cells. Flow cytometry confirmed downregulation of CD97 in CD97 shRNA lentivirally transduced cells. CD97 KD induced a significant reduction in cell growth in 3 independent GBM cell lines representing mesenchymal and proneural subtypes, which was accompanied by reduced (~20%) Ki67 staining and increased (~30%) apoptosis. Incubation of GBM cells with sAbs (20 ug/ ml) against the ECD of CD97 for 3 days induced GSC differentiation, as determined by the expression of GFAP and Tubulin. Using three unique GBM patient derived cultures, we found that CD97 KD attenuated the ability of GBM cells to initiate sphere formation by over 300 fold, consistent with an impairment in GSC self-renewal. Conclusion: Loss of CD97 expression in patient-derived GBM cells markedly decreases proliferation, induces cell death, and reduces tumorsphere formation. sAbs against the ECD of CD97 reduce tumorsphere formation, recapitulating the phenotype of CD97 KD, suggesting that sAbs that inhibit CD97 function exhibit anti-tumor activity. Collectively, these findings indicate that CD97 is necessary for the proliferation and survival of human GBM cells and identify CD97 as a promising therapeutically targetable vulnerability in GBM.

Keywords: adhesion GPCR, CD97, GBM stem cell, glioblastoma

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Authors: John T. Leman, James Gibson, Peter J. Bonitatibus

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There have been no potential clinically translatable developments of intravenous CT contrast materials over decades, and iodinated contrast agents (ICA) remain the only FDA-approved media for CT. Small molecule ICA used to highlight vascular anatomy have weak CT signals in large-to-obese patients due to their rapid redistribution from plasma into interstitial fluid, thereby diluting their intravascular concentration, and because of a mismatch of iodine’s K-edge and the high kVp settings needed to image this patient population. The use of ICA is also contraindicated in a growing population of renally impaired patients who are hypersensitive to these contrast agents; a transformative intravenous contrast agent with improved capabilities is urgently needed. Tantalum oxide nanoparticles (TaO NPs) with zwitterionic siloxane polymer coatings have high potential as clinically translatable general-purpose CT contrast agents because of (1) substantially improved imaging efficacy compared to ICA in swine/phantoms emulating medium-sized and larger adult abdomens and superior thoracic vascular contrast enhancement of thoracic arteries and veins in rabbit, (2) promising biological safety profiles showing near-complete renal clearance and low tissue retention at 3x anticipated clinical dose (ACD), and (3) clinically acceptable physiochemical parameters as concentrated bulk solutions(250-300 mgTa/mL). Here, we review requirements for general-purpose intravenous CT contrast agents in terms of patient safety, X-ray attenuating properties and contrast-producing capabilities, and physicochemical and pharmacokinetic properties. We report the current status of a TaO NP-based contrast agent, including chemical process technology developments and results of newly defined scaled-up processes for NP synthesis and purification, yielding reproducible formulations with appropriate size and concentration specifications. We discuss recent results of recent pre-clinical in vitro immunology, non-GLP high dose tolerability in rats (10x ACD), non-GLP long-term biodistribution in rats at 3x ACD, and non-GLP repeat dose in rats at ACD. We also include a discussion of NP characterization, in particular size-stability testing results under accelerated conditions (37C), and insights into TaO NP purity, surface structure, and bonding of the zwitterionic siloxane polymer coating by multinuclear (1H, 13C, 29Si) and multidimensional (2D) solution NMR spectroscopy.

Keywords: nanoparticle, imaging, diagnostic, process technology, nanoparticle characterization

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Authors: Mariam Khaled, Noha Farag, Ghada Mohamed Abdel Salam, Khaled Abu-Aisha, Mohamed El-Azizi

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Gastric and colorectal cancers are among the most frequent causes of cancer-associated mortalities in Africa. They have been considered as a global public health concern, as nearly one million new cases are reported per year. IL-1β is a pro-inflammatory cytokine-produced by activated macrophages and monocytes- and a member of the IL-1 family. The inactive IL-1β precursor is cleaved and activated by caspase-1 enzyme, which itself is activated by the assembly of intracellular structures defined as NLRP3 (Nod Like receptor P3) inflammasomes. Activated IL-1β stimulates the Interleukin-1 receptor type-1 (IL-1R1), which is responsible for the initiation of a signal transduction pathway leading to cell proliferation. It has been proven that the IL-1β gene is a highly polymorphic gene in which single nucleotide polymorphisms (SNPs) may affect its expression. It has been previously reported that SNPs including base transitions between C and T at positions, -511 (C-T; dbSNP: rs16944) and -31 (C-T; dbSNP: rs1143627), from the transcriptional start site, contribute to the pathogenesis of gastric and colorectal cancers by affecting IL-1β levels. Altered production of IL-1β due to such polymorphisms is suspected to stimulate an amplified inflammatory response and promote Epithelial Mesenchymal Transition leading to malignancy. Allele frequency distribution of the IL-1β-31 and -511 SNPs, in different populations, and their correlation to the incidence of gastric and colorectal cancers, has been intriguing to researchers worldwide. The current study aims to investigate allele distributions of the IL-1β SNPs among gastric and colorectal cancers Egyptian patients. In order to achieve to that, 89 Biopsy and surgical specimens from the antrum and corpus mucosa of chronic gastritis subjects and gastric and colorectal carcinoma patients was collected for DNA extraction followed by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). The amplified PCR products of IL-1β-31C > T and IL-1β-511T > C were digested by incubation with the restriction endonuclease enzymes ALu1 and Ava1. Statistical analysis was carried out to determine the allele frequency distribution in the three studied groups. Also, the effect of the IL-1β -31 and -511 SNPs on nuclear factor binding was analyzed using Fluorescence Electrophoretic Mobility Shift Assay (EMSA), preceded by nuclear factor extraction from gastric and colorectal tissue samples and LPS stimulated monocytes. The results of this study showed that a significantly higher percentage of Egyptian gastric cancer patients have a homozygous CC genotype at the IL-1β-31 position and a heterozygous TC genotype at the IL-1β-511 position. Moreover, a significantly higher percentage of the colorectal cancer patients have a homozygous CC genotype at the IL-1β-31 and -511 positions as compared to the control group. In addition, the EMSA results showed that IL-1β-31C/T and IL-1β-511T/C SNPs do not affect nuclear factor binding. Results of this study suggest that the IL-1β-31 C/T and IL-1β-511 T/C may be correlated to the incidence of gastric cancer in Egyptian patients; however, similar findings couldn’t be proven in the colorectal cancer patients group for the IL-1β-511 T/C SNP. This is the first study to investigate IL-1β -31 and -511 SNPs in the Egyptian population.

Keywords: colorectal cancer, Egyptian patients, gastric cancer, interleukin-1β, single nucleotide polymorphisms

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Authors: Ngwa Lodence Njwe

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This study investigated the response of hemodialysis patients to an established nutrition therapy guide accompanied by a 7-day menu plan administered for a month. End Stage Renal Disease (ESRD), also known as End Stage Kidney Disease (ESKD), is a non-communicable disease primarily caused by hypertension and diabetes, posing significant challenges in both developed and developing nations. Hemodialysis is a key treatment for these patients. In this experimental study, 100 hemodialysis patients from Douala General Hospital in Cameroon participated. A questionnaire was used to collect data on sociodemographic and anthropometric characteristics, health status, and dietary intake, while medical records provided biomedical data. The levels of the biochemical parameters (Phosphorus, calcium and hemoglobin) were determined before and one month after the distribution of the nutrition education guide and the use of a 7-day menu plan. The Phosphorus and Calcium levels were measured using an LTCC03 semi-automatic chemistry analyzer. Blood was collected from each patient into a test tube, allowed to clot and centrifuged. 50µl of the serum was aspirated by the analyzer for Ca and P level analysis, and results were read from the display. The hemoglobin level was measured using the URIT–12 hemoglobin Meter. The blood sample was collected by hand prick and placed in a strip, and the results were read from the screen. The means of the biochemical parameters were then computed. The most prevalent age group was 40-49 years, with males constituting 70% and females 30% of respondents. Among these patients, 80% were hypertensive, 3% had both hypertension and diabetes, 9% were hypertensive, diabetic, and obese, and 1% suffered from hypertension and heart failure. Analysis of anthropometric parameters revealed a high prevalence of underweight, overweight, and obesity, highlighting the urgent need for targeted nutrition interventions to modify cooking methods, enhance food choices, and increase dietary variety for improved quality of life. Before the nutrition therapy guide was implemented, average calcium levels were 73.05 mg/L for males and 89.44 mg/L for females; post-implementation, these values increased to 77.55 mg/L and 91.44 mg/L, respectively. Conversely, average phosphorus levels decreased from 42.05 mg/L for males and 43.55 mg/L for females to 41.05 mg/L and 39.3 mg/L, respectively, after the intervention. Additionally, average hemoglobin levels increased from 8.35 g/dL for males and 8.5 g/dL for females to 9.2 g/dL and 8.95 g/dL, respectively. The findings confirm that the nutrition therapy guide and the 7-day menu significantly impacted the biomedical parameters of hemodialysis patients, underscoring the need for ongoing nutrition education and counseling for this population.

Keywords: end stage kidney disease, nutrition therapy guide, nutritional status, anthropometric parameters, food frequency, biomedical data

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Authors: Thao Nguyen, Maximiliano Hyon, Sany Rajagukguk, Anna Melkonyan

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Introduction: Type 2 Diabetes is a well-established risk factor for severe SARS-CoV-2 infection. Uncontrolled hyperglycemia in patients with established or newly diagnosed diabetes is associated with poor outcomes, including increased mortality and hospital length of stay. Objectives: Our study aims to compare three different glycemic management strategies and their association with clinical outcomes in patients hospitalized for moderate to severe SARS-CoV-2 infection. Identifying optimal glycemic management strategies will improve the quality of patient care and improve their outcomes. Method: This is a retrospective observational study on patients hospitalized at Adventist Health White Memorial with severe SARS-CoV-2 infection from 11/1/2020 to 02/28/2021. The following inclusion criteria were used: positive SARS-CoV-2 PCR test, age >18 yrs old, diabetes or random glucose >200 mg/dL on admission, oxygen requirement >4L/min, and treatment with glucocorticoids. Our exclusion criteria included: ICU admission within 24 hours, discharge within five days, death within five days, and pregnancy. The patients were divided into three glycemic management groups: Group 1, managed solely by the Primary Team, Group 2, by Pharmacy; and Group 3, by Endocrinologist. Primary outcomes were average glucose on Day 5, change in glucose between Days 3 and 5, and average insulin dose on Day 5 among groups. Secondary outcomes would be upgraded to ICU, inpatient mortality, and hospital length of stay. For statistics, we used IBM® SPSS, version 28, 2022. Results: Most studied patients were Hispanic, older than 60, and obese (BMI >30). It was the first CV-19 surge with the Delta variant in an unvaccinated population. Mortality was markedly high (> 40%) with longer LOS (> 13 days) and a high ICU transfer rate (18%). Most patients had markedly elevated inflammatory markers (CRP, Ferritin, and D-Dimer). These, in combination with glucocorticoids, resulted in severe hyperglycemia that was difficult to control. Average glucose on Day 5 was not significantly different between groups primary vs. pharmacy vs. endocrine (220.5 ± 63.4 vs. 240.9 ± 71.1 vs. 208.6 ± 61.7 ; P = 0.105). Change in glucose from days 3 to 5 was not significantly different between groups but trended towards favoring the endocrinologist group (-26.6±73.6 vs. 3.8±69.5 vs. -32.2±84.1; P= 0.052). TDD insulin was not significantly different between groups but trended towards higher TDD for the endocrinologist group (34.6 ± 26.1 vs. 35.2 ± 26.4 vs. 50.5 ± 50.9; P=0.054). The endocrinologist group used significantly more preprandial insulin compared to other groups (91.7% vs. 39.1% vs. 65.9% ; P < 0.001). The pharmacy used more basal insulin than other groups (95.1% vs. 79.5% vs. 79.2; P = 0.047). There were no differences among groups in the clinical outcomes: LOS, ICU upgrade, or mortality. Multivariate regression analysis controlled for age, sex, BMI, HbA1c level, renal function, liver function, CRP, d-dimer, and ferritin showed no difference in outcomes among groups. Conclusion: Given high-risk factors in our population, despite efforts from the glycemic management teams, it’s unsurprising no differences in clinical outcomes in mortality and length of stay.

Keywords: glycemic management, strategies, hospitalized, SARS-CoV-2, outcomes

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Authors: Yang Yang, Luciana Magalhães Rebelo Alencar, Martha Sahylí Ortega Pijeira, Beatriz da Silva Batista, Alefe Roger Silva França, Erick Rafael Dias Rates, Ruana Cardoso Lima, Sara Gemini-Piperni, Ralph Santos-Oliveira

Abstract:

Radium-²²³ dichloride ([²²³Rₐ]RₐCl₂) is an alpha particle-emitting radiopharmaceutical currently approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. [²²³Rₐ]RₐCl₂ is bone-seeking calcium mimetic that bonds into the newly formed bone stroma, especially osteoblastic or sclerotic metastases, killing the tumor cells by inducing DNA breaks in a potent and localized manner. Nonetheless, the successful therapy of osteosarcoma as primary bone tumors is still a challenge. Nanomicelles are colloidal nanosystems widely used in drug development to improve blood circulation time, bioavailability, and specificity of therapeutic agents, among other applications. In addition, the enhanced permeability and retention effect of the nanosystems, and the renal excretion of the nanomicelles reported in most cases so far, are very attractive to achieve selective and increased accumulation in tumor site as well as to increase the safety of [²²³Rₐ]RₐCl₂ in the clinical routine. In the present work, [²²³Rₐ]RₐCl₂ nanomicelles were produced, characterized, in vitro evaluated, and compared with pure [²²³Rₐ]RₐCl2 solution using SAOS2 osteosarcoma cells. The [²²³Rₐ]RₐCl₂ nanomicelles were prepared using the amphiphilic copolymer Pluronic F127. The dynamic light scattering analysis of freshly produced [²²³Rₐ]RₐCl₂ nanomicelles demonstrated a mean size of 129.4 nm with a polydispersity index (PDI) of 0.303. After one week stored in the refrigerator, the mean size of the [²²³Rₐ]RₐCl₂ nanomicelles increased to 169.4 with a PDI of 0.381. Atomic force microscopy analysis of [223Rₐ]RₐCl₂ nanomicelles exhibited spherical structures whose heights reach 1 µm, suggesting the filling of 127-Pluronic nanomicelles with [²²³Rₐ]RₐCl₂. The viability assay with [²²³Rₐ]RₐCl₂ nanomicelles displayed a dose-dependent response as it was observed using pure [²²³Rₐ]RₐCl2. However, at the same dose, [²²³Rₐ]RₐCl₂ nanomicelles were 20% higher efficient in killing SAOS2 cells when compared with pure [²²³Rₐ]RₐCl₂. These findings demonstrated the effectiveness of the nanosystem validating the application of nanotechnology in targeted alpha therapy with [²²³Ra]RₐCl₂. In addition, the [²²³Rₐ]RaCl₂nanomicelles may be decorated and incorporated with a great variety of agents and compounds (e.g., monoclonal antibodies, aptamers, peptides) to overcome the limited use of [²²³Ra]RₐCl₂.

Keywords: nanomicelles, osteosarcoma, radium dichloride, targeted alpha therapy

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Authors: Angelis P. Barlampas

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Introduction: The term phantom lung mass describes the ovoid collection of fluid within the interlobular fissure, which initially creates the impression of a mass. The problem of correct differential diagnosis is great, especially in plain radiography. A case is presented with three nodular pulmonary foci, the shape, location, and density of which, as well as the presence of chronic loculated pleural effusions, suggest the presence of multiple phantom tumors of the lung. Purpose: The aim of this paper is to draw the attention of non-experienced and non-specialized physicians to the existence of benign findings that mimic pathological conditions and vice versa. The careful study of a radiological examination and the comparison with previous exams or further control protect against quick wrong conclusions. Methods: A hospitalized patient underwent a non-contrast CT scan of the chest as part of the general control of her situation. Results: Computed tomography revealed pleural effusions, some of them loculated, increased cardiothoracic index, as well as the presence of three nodular foci, one in the left lung and two in the right with a maximum density of up to 18 Hounsfield units and a mean diameter of approximately five centimeters. Two of them are located in the characteristical anatomical position of the major interlobular fissure. The third one is located in the area of the right lower lobe’s posterior basal part, and it presents the same characteristics as the previous ones and is likely to be a loculated fluid collection, within an auxiliary interlobular fissure or a cyst, in the context of the patient's more general pleural entrapments and loculations. The differential diagnosis of nodular foci based on their imaging characteristics includes the following: a) rare metastatic foci with low density (liposarcoma, mucous tumors of the digestive or genital system, necrotic metastatic foci, metastatic renal cancer, etc.), b) necrotic multiple primary lung tumor locations (squamous epithelial cancer, etc. ), c) hamartomas of the lung, d) fibrotic tumors of the interlobular fissures, e) lipoid pneumonia, f) fluid concentrations within the interlobular fissures, g) lipoma of the lung, h) myelolipomas of the lung. Conclusions: The collection of fluid within the interlobular fissure of the lung can give the false impression of a lung mass, particularly on plain chest radiography. In the case of computed tomography, the ability to measure the density of a lesion, combined with the provided high anatomical details of the location and characteristics of the lesion, can lead relatively easily to the correct diagnosis. In cases of doubt or image artifacts, comparison with previous or subsequent examinations can resolve any disagreements, while in rare cases, intravenous contrast may be necessary.

Keywords: phantom mass, chest CT, pleural effusion, cancer

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Authors: Sandra Smieszek, Jonathan Haines

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Introduction: Numerous research efforts have focused on searching for ‘longevity genes’. However, attempting to decipher the genetic component of the longevous phenotype have resulted in limited success and the mechanisms governing longevity remain to be explained. We conducted a genome-wide homozygosity analysis (GWHA) of the founder population of the Amish community in central Ohio. While genome-wide association studies using unrelated individuals have revealed many interesting longevity associated variants, these variants are typically of small effect and cannot explain the observed patterns of heritability for this complex trait. The Amish provide a large cohort of extended kinships allowing for in depth analysis via family-based approach excellent population due to its. Heritability of longevity increases with age with significant genetic contribution being seen in individuals living beyond 60 years of age. In our present analysis we show that the heritability of longevity is estimated to be increasing with age particularly on the paternal side. Methods: The present analysis integrated both phenotypic and genotypic data and led to the discovery of a series of variants, distinct for stratified populations across ages and distinct for paternal and maternal cohorts. Specifically 5437 subjects were analyzed and a subset of 893 successfully genotyped individuals was used to assess CHIP heritability. We have conducted the homozygosity analysis to examine if homozygosity is associated with increased risk of living beyond 90. We analyzed AMISH cohort genotyped for 614,957 SNPs. Results: We delineated 10 significant regions of homozygosity (ROH) specific for the age group of interest (>90). Of particular interest was ROH on chromosome 13, P < 0.0001. The lead SNPs rs7318486 and rs9645914 point to COL4A2 and our lead SNP. COL25A1 encodes one of the six subunits of type IV collagen, the C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities. The second region of interest points to IRS2. Furthermore we built a classifier using the obtained SNPs from the significant ROH region with 0.945 AUC giving ability to discriminate between those living beyond to 90 years of age and beyond. Conclusion: In conclusion our results suggest that a history of longevity does indeed contribute to increasing the odds of individual longevity. Preliminary results are consistent with conjecture that heritability of longevity is substantial when we start looking at oldest fifth and smaller percentiles of survival specifically in males. We will validate all the candidate variants in independent cohorts of centenarians, to test whether they are robustly associated with human longevity. The identified regions of interest via ROH analysis could be of profound importance for the understanding of genetic underpinnings of longevity.

Keywords: regions of homozygosity, longevity, SNP, Amish

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Authors: Shiamaa Eltantawy, Gihan Sobhy, Alif Alaam

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Wilson disease, or hepatolenticular degeneration, is an autosomal recessive disease that results in excess copper buildup in the body. It primarily affects the liver and basal ganglia of the brain, but it can affect other organ systems. Musculoskeletal abnormalities, including premature osteoarthritis, skeletal deformity, and pathological bone fractures, can occasionally be found in WD patients with a hepatic or neurologic type. The aim was to assess the prevalence of osteoporosis and osteopenia in Wilson’s disease patients. This case-control study was conducted on ninety children recruited from the inpatient ward and outpatient clinic of the Paediatric Hepatology, Gastroenterology, and Nutrition department of the National Liver Institute at Menofia University, aged from 1 to 18 years. Males were 49, and females were 41. Children were divided into three groups: (Group I) consisted of thirty patients with WD; (Group II) consisted of thirty patients with chronic liver disease other than WD; (Group III) consisted of thirty age- and sex-matched healthy The exclusion criteria were patients with hyperparathyroidism, hyperthyroidism, renal failure, Cushing's syndrome, and patients on certain drugs such as chemotherapy, anticonvulsants, or steroids. All patients were subjected to the following: 1- Full history-taking and clinical examination. 2-Laboratory investigations: (FBC,ALT,AST,serum albumin, total protein, total serum bilirubin,direct bilirubin,alkaline phosphatase, prothrombin time, serum critine,parathyroid hormone, serum calcium, serum phosphrus). 3-Bone mineral density (BMD, gm/cm2) values were measured by dual-energy X-ray absorptiometry (DEXA). The results revealed that there was a highly statistically significant difference between the three groups regarding the DEXA scan, and there was no statistically significant difference between groups I and II, but the WD group had the lowest bone mineral density. The WD group had a large number of cases of osteopenia and osteoporosis, but there was no statistically significant difference with the group II mean, while a high statistically significant difference was found when compared to group III. In the WD group, there were 20 patients with osteopenia, 4 patients with osteoporosis, and 6 patients who were normal. The percentages were 66.7%, 13.3%, and 20%, respectively. Therefore, the largest number of cases in the WD group had osteopenia. There was no statistically significant difference found between WD patients on different treatment regimens regarding DEXA scan results (Z-Score). There was no statistically significant difference found between patients in the WD group (normal, osteopenic, or osteoporotic) regarding phosphorus (mg/dL), but there was a highly statistically significant difference found between them regarding ionised Ca (mmol/L). Therefore, there was a decrease in bone mineral density when the Ca level was decreased. In summary, Wilson disease is associated with bone demineralization. The largest number of cases in the WD group in our study had osteopenia (66.7%). Different treatment regimens (zinc monotherapy, Artamin, and zinc) as well as different laboratory parameters have no effect on bone mineralization in WD cases. Decreased ionised Ca is associated with low BMD in WD patients. Children with WD should be investigated for BMD.

Keywords: wilson disease, Bone mineral density, liver disease, osteoporosis

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Authors: Karolina Wieczorek, Zofia Przypaśniak

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Climate change is a rapidly growing threat to global health, and part of the responsibility to combat it lies within the healthcare sector itself, including adequate education of future medical professionals. To mitigate the consequences, the General Medical Council (GMC) has equipped medical schools with a list of outcomes regarding sustainability teaching. Students are expected to analyze the impact of the healthcare sector’s emissions on climate change. The delivery of the related teaching content is, however, often inadequate and insufficient time is devoted for exploration of the topics. Teaching curricula lack in-depth exploration of the learning objectives. This study aims to assess the extent and characteristics of climate change and sustainability subjects teaching in the curriculum of a chosen UK medical school (Barts and The London School of Medicine and Dentistry). It compares the data to the national average scores from the Climate Change and Sustainability Teaching (C.A.S.T.) in Medical Education Audit to draw conclusions about teaching on a regional level. This is a single-center audit of the timetabled sessions of teaching in the medical course. The study looked at the academic year 2020/2021 which included a review of all non-elective, core curriculum teaching materials including tutorials, lectures, written resources, and assignments in all five years of the undergraduate and graduate degrees, focusing only on mandatory teaching attended by all students (excluding elective modules). The topics covered were crosschecked with GMC Outcomes for graduates: “Educating for Sustainable Healthcare – Priority Learning Outcomes” as gold standard to look for coverage of the outcomes and gaps in teaching. Quantitative data was collected in form of time allocated for teaching as proxy of time spent per individual outcomes. The data was collected independently by two students (KW and ZP) who have received prior training and assessed two separate data sets to increase interrater reliability. In terms of coverage of learning outcomes, 12 out of 13 were taught (with the national average being 9.7). The school ranked sixth in the UK for time spent per topic and second in terms of overall coverage, meaning the school has a broad range of topics taught with some being explored in more detail than others. For the first outcome 4 out of 4 objectives covered (average 3.5) with 47 minutes spent per outcome (average 84 min), for the second objective 5 out of 5 covered (average 3.5) with 46 minutes spent (average 20), for the third 3 out of 4 (average 2.5) with 10 mins pent (average 19 min). A disproportionately large amount of time is spent delivering teaching regarding air pollution (respiratory illnesses), which resulted in the topic of sustainability in other specialties being excluded from teaching (musculoskeletal, ophthalmology, pediatrics, renal). Conclusions: Currently, there is no coherent strategy on national teaching of climate change topics and as a result an unstandardized amount of time spent on teaching and coverage of objectives can be observed.

Keywords: audit, climate change, sustainability, education

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Authors: Surachart Koyadun

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Introduction: Plasmodium knowlesi (P. knowlesi) malaria is a zoonotic disease that is classified as type 5 of human malaria. Commonly found in macaques (Macaca fascicularis) and (Macaca nemestrina), P. knowlesi is capable of resulting in both uncomplicated and severe malaria in humans. Situation of P. knowlesi malaria in Phang-Nga province for the past 3 years from 2020 – 2022 revealed no case report in 2020, however, a total of 14 cases had been reported in 2021 - 2022. This research aimed to 1) study the epidemiology of P. knowlesi, 2) examine the clinical manifestations of P. knowlesi patients, 3) analyze the ecology and entomology of P. knowlesi, and 4) analyze the diagnosis and treatment of P. knowlesi. Method: This research was a retrospective descriptive study/case report. The study was conducted in 14 patients with P. knowlesi malaria between 2021 and 2022 in 4 districts of Phang-Nga Province, Thailand including Thapput, Kapong, Takuapa and Khuraburi. Results: The study subjects of P. knowlesi malaria were all males. Most of them were working age groups as farmers and worked in forest or plantation areas. All had no history of blood transfusions. Most of the patients did not use mosquito nets and had a history of camping in the forest prior to the onset of fever. An analysis of all 14 sources of infection unveiled the area is home to macaques, and that area has detected Anopheles mosquito, which is the carrier of the disease. Majority of them got sick in the dry season of Thailand (December-April). The main symptoms brought to the hospital were fever, chills, headache, body aches. Laboratory findings on the first day of diagnosis were as follows: The white blood cell count was found within the normal range. In the proportion of white blood cells, eosinophils were found to be slightly higher than normal. Slight anemia was found on early examination. The platelet count was found to be below normal in all cases. Severely low platelet count (2,000 cells/mm3) was found in severe cases with multiple complications. No patient was found dead but 85.7% of complications were found, with acute renal failure being the most common. Patients with delayed diagnosis and treatment of malaria (inaccurate diagnosis or late access to the hospital) had the highest severity and complications than those who had seen the doctor since the first 3-4 days of illness or the screening of symptoms and risk history by the malaria clinic staff at vector-borne disease control unit. Conclusion and Recommendation: P. knowlesi malaria is an emerging infectious disease transmitted from animals to humans. There are challenges in epidemiology, entomology, ecology for effective surveillance, prevention and control. Early diagnosis and treatment would reduce complications and prevent death.

Keywords: malaria, plasmodium knowlesi, epidemiology, ecology, entomology, diagnosis, treatment

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Authors: Hansraj Bookun, Rachel Xuan, Angela Tan, Kejia Wang, Animesh Singla, David Kim, Christopher Loupos, Jim Iliopoulos

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Introduction: Complex endovascular aortic aneursymal repairs with fenestrated and branched endografts require customised devices to exclude the pathology while reducing morbidity and mortality, which was historically associated with open repair of complex aneurysms. Such endovascular procedures have predominantly been performed in a large volume dedicated tertiary centres. We present here our nine year multidisciplinary experience with this technology in an Australian tertiary centre. Method: This was a cross-sectional, single-centre observational study of 670 patients who had undergone complex endovascular aortic aneurysmal repairs with conventional endografts, fenestrated endografts, and iliac-branched devices from January 2010 to July 2019. Descriptive statistics were used to characterise our sample with regards to demographic and perioperative variables. Homogeneity of the sample was tested using multivariant regression, which did not identify any statistically significant confounding variables. Results: 670 patients of mean age 74, were included (592 males) and the comorbid burden was as follows: ischemic heart disease (55%), diabetes (18%), hypertension (90%), stage four or greater kidney impairment (8%) and current or ex-smoking (78%). The main indications for surgery were elective aneurysms (86%), symptomatic aneurysms (5%), and rupture aneurysms (5%). 106 patients (16%) underwent fenestrated or branched endograft repairs. The mean length of stay was 7.6 days. 2 patients experienced reactionary bleeds, 11 patients had access wound complications (6 lymph fistulae, 5 haematoms), 11 patients had cardiac complications (5 arrhythmias, 3 acute myocadial infarctions, 3 exacerbation of congestive cardiac failure), 10 patients had respiratory complications, 8 patients had renal impairment, 4 patients had gastrointestinal complications, 2 patients suffered from paraplegia, 1 major stroke, 1 minor stroke, and 1 acute brain syndrome. There were 4 vascular occlusions requiring further arterial surgery, 4 type I endoleaks, 4 type II endoleaks, 3 episodes of thromboembolism, and 2 patients who required further arterial operations in the setting of patient vessels. There were 9 unplanned returns to the theatre. Discussion: Our numbers of 10 years suggest that we are not a dedicated high volume centre focusing on aortic repairs. However, we have achieved significantly low complication rates. This can be attributed to our multidisciplinary approach with the intraoperative involvement of skilled interventional radiologists and vascular surgeons as well as postoperative protocols with particular attention to spinal cord protection. Additionally, we have a ratified perioperative pathway that involves multidisciplinary team discussions of patient-related factors and lesion-centered characteristics, which allows for holistic, patient-centered care.

Keywords: aneurysm, aortic, endovascular, fenestrated

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Authors: Rajeswari Raguraman, Sowmya Parameswaran, Krishnakumar Subramanian, Jagat Kanwar, Rupinder Kanwar

Abstract:

Background: Tumor microenvironment has been implicated in several cancers to regulate cell growth, invasion and metastasis culminating in outcome of therapy. Tumor stroma consists of multiple cell types that are in constant cross-talk with the tumor cells to favour a pro-tumorigenic environment. Not much is known about the existence of tumor microenvironment in the pediatric intraocular malignancy, Retinoblastoma (RB). In the present study, we aim to understand the multiple stromal cellular subtypes and tumor stromal interactions expressed in RB tumors. Materials and Methods: Immunohistochemistry for stromal cell markers CD31, CD68, alpha-smooth muscle (α-SMA), vimentin and glial fibrillary acidic protein (GFAP) was performed on formalin fixed paraffin embedded tissues sections of RB (n=12). The differential expression of stromal target molecules; fibroblast activation protein (FAP), tenascin-C (TNC), osteopontin (SPP1), bone marrow stromal antigen 2 (BST2), stromal derived factor 2 and 4 (SDF2 and SDF4) in primary RB tumors (n=20) and normal retina (n=5) was studied by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blotting. The differential expression was correlated with the histopathological features of RB. The interaction between RB cell lines (Weri-Rb-1, NCC-RbC-51) and Bone marrow stromal cells (BMSC) was also studied using direct co-culture and indirect co-culture methods. The functional effect of the co-culture methods on the RB cells was evaluated by invasion and proliferation assays. Global gene expression was studied by using Affymetrix 3’ IVT microarray. Pathway prediction was performed using KEGG and the key molecules were validated using qRT-PCR. Results: The immunohistochemistry revealed the presence of several stromal cell types such as endothelial cells (CD31+;Vim+/-); macrophages (CD68+;Vim+/-); Fibroblasts (Vim+; CD31-;CD68- );myofibroblasts (α-SMA+/ Vim+) and invading retinal astrocytes/ differentiated retinal glia (GFAP+; Vim+). A characteristic distribution of these stromal cell types was observed in the tumor microenvironment, with endothelial cells predominantly seen in blood vessels and macrophages near actively proliferating tumor or necrotic areas. Retinal astrocytes and glia were predominant near the optic nerve regions in invasive tumors with sparse distribution in tumor foci. Fibroblasts were widely distributed with rare evidence of myofibroblasts in the tumor. Both gene and protein expression revealed statistically significant (P<0.05) up-regulation of FAP, TNC and BST2 in primary RB tumors compared to the normal retina. Co-culture of BMSC with RB cells promoted invasion and proliferation of RB cells in direct and indirect contact methods respectively. Direct co-culture of RB cell lines with BMSC resulted in gene expression changes in ECM-receptor interaction, focal adhesion, IL-8 and TGF-β signaling pathways associated with cancer. In contrast, various metabolic pathways such a glucose, fructose and amino acid metabolism were significantly altered under the indirect co-culture condition. Conclusion: The study suggests that the close interaction between RB cells and the stroma might be involved in RB tumor invasion and progression which is likely to be mediated by ECM-receptor interactions and secretory factors. Targeting the tumor stroma would be an attractive option for redesigning treatment strategies for RB.

Keywords: gene expression profiles, retinoblastoma, stromal cells, tumor microenvironment

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Authors: Wonil Nam, Xiang Ren, Inyoung Kim, Masoud Agah, Wei Zhou

Abstract:

Despite its ultrasensitive detection capability, surface-enhanced Raman spectroscopy (SERS) faces challenges as a quantitative biochemical analysis tool due to the significant dependence of local field intensity in hotspots on nanoscale geometric variations of plasmonic nanostructures. Therefore, despite enormous progress in plasmonic nanoengineering of high-performance SERS devices, it is still challenging to quantitatively correlate the measured SERS signals with the actual molecule concentrations at hotspots. A significant effort has been devoted to developing SERS calibration methods by introducing internal standards. It has been achieved by placing Raman tags at plasmonic hotspots. Raman tags undergo similar SERS enhancement at the same hotspots, and ratiometric SERS signals for analytes of interest can be generated with reduced dependence on geometrical variations. However, using Raman tags still faces challenges for real-world applications, including spatial competition between the analyte and tags in hotspots, spectral interference, laser-induced degradation/desorption due to plasmon-enhanced photochemical/photothermal effects. We show that electronic Raman scattering (ERS) signals from metallic nanostructures at hotspots can serve as the internal calibration standard to enable quantitative SERS analysis and improve biostatistical analysis. We perform SERS with Au-SiO₂ multilayered metal-insulator-metal nano laminated plasmonic nanostructures. Since the ERS signal is proportional to the volume density of electron-hole occupation in hotspots, the ERS signals exponentially increase when the wavenumber is approaching the zero value. By a long-pass filter, generally used in backscattered SERS configurations, to chop the ERS background continuum, we can observe an ERS pseudo-peak, IERS. Both ERS and SERS processes experience the |E|⁴ local enhancements during the excitation and inelastic scattering transitions. We calibrated IMRS of 10 μM Rhodamine 6G in solution by IERS. The results show that ERS calibration generates a new analytical value, ISERS/IERS, insensitive to variations from different hotspots and thus can quantitatively reflect the molecular concentration information. Given the calibration capability of ERS signals, we performed label-free SERS analysis of living biological systems using four different breast normal and cancer cell lines cultured on nano-laminated SERS devices. 2D Raman mapping over 100 μm × 100 μm, containing several cells, was conducted. The SERS spectra were subsequently analyzed by multivariate analysis using partial least square discriminant analysis. Remarkably, after ERS calibration, MCF-10A and MCF-7 cells are further separated while the two triple-negative breast cancer cells (MDA-MB-231 and HCC-1806) are more overlapped, in good agreement with the well-known cancer categorization regarding the degree of malignancy. To assess the strength of ERS calibration, we further carried out a drug efficacy study using MDA-MB-231 and different concentrations of anti-cancer drug paclitaxel (PTX). After ERS calibration, we can more clearly segregate the control/low-dosage groups (0 and 1.5 nM), the middle-dosage group (5 nM), and the group treated with half-maximal inhibitory concentration (IC50, 15 nM). Therefore, we envision that ERS calibrated SERS can find crucial opportunities in label-free molecular profiling of complicated biological systems.

Keywords: cancer cell drug efficacy, plasmonics, surface-enhanced Raman spectroscopy (SERS), SERS calibration

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Authors: Anush Patric, M. Jadeyegowda, M. N. Ramesh, M. Ravikumar, C. R. Ajay

Abstract:

Kodagu district which is situated in Central Western Ghats regions falls in one of the hottest of hot spots of biodiversity which is recognised by UNESCO. The district has one of the highest densities of community managed sacred forests in the world with rich floral and faunal diversity. It is a habitat for more than ten different types of Ethnic Indigenous tribal groups commonly called ‘Girijanas’ (Soligas, Yarvas, Jenukuruba, Bettakuruba etc.), who are having the rich knowledge of medicinal value of the plants that are commonly available in the forest. The tribal men of this region are the treasure house of the traditional plant knowledge and health care practices. An ethnobotanical survey was undertaken in tribal areas of the district to collect information about some of the indigenous medicinal plant knowledge of tribal people by semi-structured interviews, ranking exercises and field observations on their native habitat in order to evaluate the potential medicinal uses of local plants. The study revealed that, the ethnobotanical information of 83 plant species belonging to 45 families, of the total 83 species documented, most plants used in the treatment were trees (11 species), shrubs (41 species), herbs (22 species) and rarely climbers (9 species) which are used in the treatment of Hyperacidity, Respiratory disorders, Snake bite Abortifacient, Anthelmintic, Paralysis, Antiseptic, Fever, Chest pain, Stomachic, Jaundice, Piles, Asthma, Malaria, Renal disorders, Malaria and many other diseases. Maximum of 6 plant species each of Acanthaceae, Apiaceae and were used for drug preparation, followed by Asclepiadaceae, Liliaceae, Fabaceae, Verbenaceae, Caesalpinaceae, Bombaceae, Papilonaceae, Solanaceae, Rubiaceae, Myrtaceae, Amaranthaceae, Asteraceae, Ascelepidaceae, Cucurbitaceae, Apocyanaceae, and Solanaceae etc. In our present study, only medicinal plants and their local medicinal uses are recorded and presented. Information was obtained by local informants having the knowledge about medicinal plants. About 23 local tribes were interviewed. For each plant, necessary information like botanical name, family of plant species, local name and uses are given. Recent trend shows a decline in the number of traditional herbal healers in the tribal areas since the younger generation is not interested to continue this tradition. Hence, there is an urgent need to record and preserve all information on plants used by different ethnic/tribal communities for various purposes before it reaches to verge of extinction. In addition, several wild medicinal plants are declining in numbers due to deforestation and forest fires. There is need for phytochemical analysis and conservation measures to be taken for conserving medicinal plant species which is far better than allopathic medicines and these do not cause any side effects as they are the natural disease healers. So, conservation strategies have to be practiced in all levels and sectors by creating awareness about the value of such medicinal plants, and it is necessary to save the disappearing plants to strengthen the document and to conserve them for future generation.

Keywords: diseases, ethnic groups, folk medicine, Kodagu, medicinal plants

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Authors: George Zhou, Yunchan Chen, Candace Chien

Abstract:

Kidney replacement therapy is the current standard of care for end-stage renal diseases. In-center or home hemodialysis remains an integral component of the therapeutic regimen. Arteriovenous fistulas (AVF) make up the vascular circuit through which blood is filtered and returned. Naturally, AVF patency determines whether adequate clearance and filtration can be achieved and directly influences clinical outcomes. Our aim was to build a deep learning model for automated AVF stenosis screening based on the sound of blood flow through the AVF. A total of 311 patients with AVF were enrolled in this study. Blood flow sounds were collected using a digital stethoscope. For each patient, blood flow sounds were collected at 6 different locations along the patient’s AVF. The 6 locations are artery, anastomosis, distal vein, middle vein, proximal vein, and venous arch. A total of 1866 sounds were collected. The blood flow sounds are labeled as “patent” (normal) or “stenotic” (abnormal). The labels are validated from concurrent ultrasound. Our dataset included 1527 “patent” and 339 “stenotic” sounds. We show that blood flow sounds vary significantly along the AVF. For example, the blood flow sound is loudest at the anastomosis site and softest at the cephalic arch. Contextualizing the sound with location metadata significantly improves classification performance. How to encode and incorporate categorical metadata is an active area of research1. Herein, we study ordinal (i.e., integer) encoding schemes. The numerical representation is concatenated to the flattened feature vector. We train a vision transformer (ViT) on spectrogram image representations of the sound and demonstrate that using scalar multiples of our integer encodings improves classification performance. Models are evaluated using a 10-fold cross-validation procedure. The baseline performance of our ViT without any location metadata achieves an AuROC and AuPRC of 0.68 ± 0.05 and 0.28 ± 0.09, respectively. Using the following encodings of Artery:0; Arch: 1; Proximal: 2; Middle: 3; Distal 4: Anastomosis: 5, the ViT achieves an AuROC and AuPRC of 0.69 ± 0.06 and 0.30 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 10; Proximal: 20; Middle: 30; Distal 40: Anastomosis: 50, the ViT achieves an AuROC and AuPRC of 0.74 ± 0.06 and 0.38 ± 0.10, respectively. Using the following encodings of Artery:0; Arch: 100; Proximal: 200; Middle: 300; Distal 400: Anastomosis: 500, the ViT achieves an AuROC and AuPRC of 0.78 ± 0.06 and 0.43 ± 0.11. respectively. Interestingly, we see that using increasing scalar multiples of our integer encoding scheme (i.e., encoding “venous arch” as 1,10,100) results in progressively improved performance. In theory, the integer values do not matter since we are optimizing the same loss function; the model can learn to increase or decrease the weights associated with location encodings and converge on the same solution. However, in the setting of limited data and computation resources, increasing the importance at initialization either leads to faster convergence or helps the model escape a local minimum.

Keywords: arteriovenous fistula, blood flow sounds, metadata encoding, deep learning

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Authors: Suliman Al-Fayoumi, Sherri Amberg, Huafeng Zhou, Jack W. Singer, James P. Dean

Abstract:

Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R. In clinical studies, pacritinib was well tolerated with clinical activity in patients with myelofibrosis. The most frequent adverse events (AEs) observed with pacritinib are gastrointestinal (diarrhea, nausea, and vomiting; mostly grade 1-2 in severity) and typically resolve within 2 weeks. A human ADME mass balance study demonstrated that pacritinib is predominantly cleared via hepatic metabolism and biliary excretion (>85% of administered dose). The major hepatic metabolite identified, M1, is not thought to materially contribute to the pharmacological activity of pacritinib. Hepatic diseases are known to impair hepatic blood flow, drug-metabolizing enzymes, and biliary transport systems and may affect drug absorption, disposition, efficacy, and toxicity. This phase 1 study evaluated the pharmacokinetics (PK) and safety of pacritinib and the M1 metabolite in study subjects with mild, moderate, or severe hepatic impairment (HI) and matched healthy subjects with normal liver function to determine if pacritinib dosage adjustments are necessary for patients with varying degrees of hepatic insufficiency. Study participants (aged 18-85 y) were enrolled into 4 groups based on their degree of HI as defined by Child-Pugh Clinical Assessment Score: mild (n=8), moderate (n=8), severe (n=4), and healthy volunteers (n=8) matched for age, BMI, and sex. Individuals with concomitant renal dysfunction or progressive liver disease were excluded. A single 400 mg dose of pacritinib was administered to all participants. Blood samples were obtained for PK evaluation predose and at multiple time points postdose through 168 h. Key PK parameters evaluated included maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration time curve (AUC) from hour zero to last measurable concentration (AUC0-t), AUC extrapolated to infinity (AUC0-∞), and apparent terminal elimination half-life (t1/2). Following treatment, pacritinib was quantifiable for all study participants at 1 h through 168 h postdose. Systemic pacritinib exposure was similar between healthy volunteers and individuals with mild HI. However, there was a significant difference between those with moderate and severe HI and healthy volunteers with respect to peak concentration (Cmax) and plasma exposure (AUC0-t, AUC0-∞). Mean Cmax decreased by 47% and 57% respectively in participants with moderate and severe HI vs matched healthy volunteers. Similarly, mean AUC0-t decreased by 36% and 45% and mean AUC0-∞ decreased by 46% and 48%, respectively in individuals with moderate and severe HI vs healthy volunteers. Mean t1/2 ranged from 51.5 to 74.9 h across all groups. The variability on exposure ranged from 17.8% to 51.8% across all groups. Systemic exposure of M1 was also significantly decreased in study participants with moderate or severe HI vs. healthy participants and individuals with mild HI. These changes were not significantly dissimilar from the inter-patient variability in these parameters observed in healthy volunteers. All AEs were grade 1-2 in severity. Diarrhea and headache were the only AEs reported in >1 participant (n=4 each). Based on these observations, it is unlikely that dosage adjustments would be warranted in patients with mild, moderate, or severe HI treated with pacritinib.

Keywords: pacritinib, myelofibrosis, hepatic impairment, pharmacokinetics

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Authors: Kuo-Kai Lin, Po-Lun Chang

Abstract:

Research Background and Purpose: Following the development of the Internet and multimedia, the Internet and information technology have become crucial avenues of modern communication and knowledge acquisition. The advantages of using mobile devices for learning include making learning borderless and accessible. Mobile learning has become a trend in disease management and health promotion in recent years. End-stage renal disease (ESRD) is an irreversible chronic disease, and patients who do not receive kidney transplants can only rely on hemodialysis or peritoneal dialysis to survive. Due to the complexities in caregiving for patients with ESRD that stem from their advanced age and other comorbidities, the patients’ incapacity of self-care leads to an increase in the need to rely on their families or primary caregivers, although whether the primary caregivers adequately understand and implement patient care is a topic of concern. Therefore, this study explored whether primary caregivers’ health care provisions can be improved through the intervention of an automatic speech intelligent system, thereby improving the objective health outcomes of patients undergoing long-term dialysis. Method: This study developed an automatic speech intelligent system with healthcare functions such as health information voice prompt, two-way feedback, real-time push notification, and health information delivery. Convenience sampling was adopted to recruit eligible patients from a hemodialysis center at a regional teaching hospital as research participants. A one-group pretest-posttest design was adopted. Descriptive and inferential statistics were calculated from the demographic information collected from questionnaires answered by patients and primary caregivers, and from a medical record review, a health care scale (recorded six months before and after the implementation of intervention measures), a subjective health assessment, and a report of objective physiological indicators. The changes in health care behaviors, subjective health status, and physiological indicators before and after the intervention of the proposed automatic speech intelligent system were then compared. Conclusion and Discussion: The preliminary automatic speech intelligent system developed in this study was tested with 20 pretest patients at the recruitment location, and their health care capacity scores improved from 59.1 to 72.8; comparisons through a nonparametric test indicated a significant difference (p < .01). The average score for their subjective health assessment rose from 2.8 to 3.3. A survey of their objective physiological indicators discovered that the compliance rate for the blood potassium level was the most significant indicator; its average compliance rate increased from 81% to 94%. The results demonstrated that this automatic speech intelligent system yielded a higher efficacy for chronic disease care than did conventional health education delivered by nurses. Therefore, future efforts will continue to increase the number of recruited patients and to refine the intelligent system. Future improvements to the intelligent system can be expected to enhance its effectiveness even further.

Keywords: automatic speech intelligent system for health care, primary caregiver, long-term hemodialysis, health care capabilities, health outcomes

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Authors: A. F. C. Nassar, D. K. Tessler, L. Okuda, C. Del Fava, D. P. Chiebao, A. H. C. N. Romaldini, A. P. Alvim, M. J. Sanchez-Vazquez, M. S. Rosa, J. C. Pompei, R. Harakava, M. C. S. Araujo, G. H. F. Marques, E. M. Pituco

Abstract:

Glanders is a zoonotic disease of Equidae caused by the bacterium Burkholderia mallei presented in acute or chronic clinical forms with inflammatory nodules in the respiratory tract, lymphangitis and caseous lymph nodes. There is not a treatment with veterinary drugs to this life-threatening disease; thus, its occurrence must be notified to official animal health services and any infected animal must be eliminated. This study aims to detect B. mallei from horses euthanized in outbreaks of glanders in Brazil, providing a better understanding of the bacterial characteristics and determine a proper protocol for isolation. The work was carried out with the collaboration of the Ministry of Agriculture and the Sao Paulo State Animal Health Department, while its procedures were approved by the Committee of Ethics in Animal Experimentation from the Instituto Biologico (CETEA n°156/2017). To the present time, 16 horses from farms with outbreaks of glanders detected by complement fixation test (CFT) serology method were analyzed. During the necropsy, samples of possibly affected organs (lymph nodes, lungs, heart, liver, spleen, kidneys and trachea) were collected for bacterial isolation, molecular tests and pathology. Isolation was performed using two enriched mediums, a potato infusion agar with 5% sheep blood, 4% glycerol and antibiotics (penicilin100U/ mL), and another with the same ingredients except the antibiotic. A PCR protocol was modified for this study using primers design to identify a region of the Flip gen of B. mallei. Thru isolation, 12.5% (2/16) animals were confirmed positive using only the enriched medium with antibiotic and confirmed by PCR: from mediastinal and submandibular lymph nodes and lungs in one animal and from mediastinal lymph node in the other. The detection of the bacterium using PCR showed positivity of 100% (16/16) horses from 144 samples of organs. Pathology macroscopic lesions observed were catarrhal nasal discharge, fetlock ulcers, emaciation, lymphangitis in limbs, suppurative lymphangitis, lymph node enlargement, star shaped liver, and spleen scars, adherence of the renal capsule, pulmonary hemorrhage, and miliary nodules. Microscopic lesions were suppurative bronchopneumonia with microabscesses and Langhans giant cells in lungs; lymph nodes with abscesses and intense lymphoid reaction; hemosiderosis and abscesses in spleen. Positive samples on PCR will be sequenced later and analyzed comparing with previous records in the literature. A throughout description of the recent acute cases of glanders occurring in Brazil and characterization of the bacterium related will contribute to advances in the knowledge of the pathogenicity, clinical symptoms, and epidemiology of this zoonotic disease. Acknowledgment: This project is sponsored by FAPESP.

Keywords: equines, bacterial isolation, zoonosis, PCR, pathology

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