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Dev Kumar Shah,1 Suneel Piryani,2 Rano Mal Piryani,3 Mohammad Nazrul Islam,1 Rajesh Kumar Jha,4 Gopendra Prasad Deo51Department of Physiology; 2Department of Community Medicine & Public Health; 3Internal & Pulmonary Medicine and Medical Education; 4Department of Pharmacology; 5Department of Anesthesiology, Chitwan Medical College, Bharatpur, Chitwan, NepalBackground: The educational environment of an institution affects learning and has a significant role in determining students’ academic achievement. The objective of the study was to determine the undergraduate medical students’ perception about educational environment in clinical years of study utilizing Dundee Ready Education Environment Measure (DREEM) questionnaire.Methods: A descriptive cross-sectional questionnaire-based study was conducted among fourth and fifth-year medical students toward the end of their 2016 academic year in Chitwan Medical College, Bharatpur, Nepal. The 50-item DREEM questionnaire was used to collect the data. The items were scored based on a 5-point Likert scale. The data were analyzed using SPSS version 20. Scores obtained were expressed as mean±SD.Results: The mean total DREEM score was 122/200. The mean score for Students’ Perceptions of Learning, Students’ Perceptions of Teachers, Students’ Academic Self-Perceptions, Students’ Perceptions of Atmosphere, and Students’ Social Self-Perceptions were 29.8/48, 25.9/44, 20.3/32, 28.6/48, and 17.27/28, respectively. This shows the environment for learning was satisfactory. There were nine problem areas with a mean score of ≤2. There was no significant difference observed in educational environment subscales scores according to enrollment year, gender, or funding source for education.Conclusion: The overall student’s perception of the educational environment was satisfactory. Nevertheless, the study revealed some problematic areas in the learning environment which require remedial measures to make the environment more conducive for learning to satisfy the students and achieve a far better outcome.Keywords: DREEM, educational environment, medical students, Nepal, perception

Ram Lochan Yadav,1 Rano Mal Piryani,2 Gopendra Prasad Deo,3 Dev Kumar Shah,1 Laxmi Kumari Yadav,4 Md Nazrul Islam1 1Department of Physiology, Chitwan Medical College, Bharatpur, Nepal; 2Department of Internal Medicine and Health Professional Educational Research Center (HPERC), Chitwan Medical College, Bharatpur, Nepal; 3Department of Anaesthesiology and Critical Care, Chitwan Medical College, Bharatpur, Nepal; 4Department of Microbiology, Chitwan Medical College, Bharatpur, Nepal Background: Problem-based learning (PBL) was introduced into Basic Medical Sciences early in the 1980s at Tribhuvan University (TU), Nepal, followed by other universities where didactic lecture method was still followed as the main teaching strategy. Despite gaining its popularity worldwide as integrated teaching learning method, PBL is not given importance in Nepal. This study aimed to assess the attitude and perceptions of undergraduate medical students regarding learning outcomes of PBL and to know their views about role and qualities of effective tutors for its successful implementation.Methods: This descriptive study was based on a self-administered questionnaire. The first part of the questionnaire measured students’ perception and attitude toward benefits of PBL and the second part measured students’ perception about role of PBL tutor. Bachelor of Medicine and Bachelor of Surgery (MBBS) first year (2014/2015 academic year) students at Chitwan Medical College, TU, were asked to express their opinions about the importance of learning outcomes by rating each statement on a five-point Likert scale and the responses were combined into three categorical variables: “agree” (strongly agree plus agree), “neutral”, and “disagree” (strongly disagree plus disagree). Data were analyzed using SPSS version 21.0.Results: Approximately 85.5% participants agreed that PBL is an interesting method of teaching learning. Most of them (86.7%) accepted that PBL is an interactive and a mutual learning method and improves self-directed learning (83.2%). Although 78% had recommended it better than lecture, many (54.2%) pointed it out as a time-consuming method. The participants were also highly rated (80.5%) to the statement - the tutor’s role in enhancing the constructive active learning and maintaining good intra-personal behavior.Conclusion: Student’s attitude toward PBL was positive. They highly appreciated the roles of a tutor as facilitators and motivators for proper activities in PBL session. PBL sessions were considered effective in improving students professional knowledge and refining problem-solving and self-directed learning skills along with enriching teamwork experience. Keywords: PBL, student’s perception, role of tutor, teaching learning method

Dev Kumar Shah, Ram Lochan Yadav, Deepak Sharma, Prakash Kumar Yadav, Niraj Khatri Sapkota, Rajesh Kumar Jha, Md Nazrul Islam Department of Physiology, Chitwan Medical College, Bharatpur, Chitwan, Nepal Background: Many factors shape the quality of learning. The intrinsically motivated students adopt a deep approach to learning, while students who fear failure in assessments adopt a surface approach to learning. In the area of health science education in Nepal, there is still a lack of studies on learning approach that can be used to transform the students to become better learners and improve the effectiveness of teaching. Therefore, we aimed to explore the learning approaches among medical, dental, and nursing students of Chitwan Medical College, Nepal using Biggs’s Revised Two-Factor Study Process Questionnaire (R-SPQ-2F) after testing its reliability. Methods: R-SPQ-2F containing 20 items represented two main scales of learning approaches, deep and surface, with four subscales: deep motive, deep strategy, surface motive, and surface strategy. Each subscale had five items and each item was rated on a 5-point Likert scale. The data were analyzed using Student’s t-test and analysis of variance. Reliability of the administered questionnaire was checked using Cronbach’s alpha. Results: The Cronbach’s alpha value (0.6) for 20 items of R-SPQ-2F was found to be acceptable for its use. The participants predominantly had a deep approach to learning regardless of their age and sex (deep: 32.62±6.33 versus surface: 25.14±6.81, P

Rajesh K Jha,1 Keshab R Paudel,1 Dev K Shah,2 Ajit K Sah,1 Sangharshila Basnet,1 Phoolgen Sah,1 Sandeep Adhikari1 1Department of Pharmacology, 2Department of Physiology, Chitwan Medical College, Bharatpur, Nepal Introduction: The selection of a discipline for future specialization may be an important factor for the medical students' future career, and it is influenced by multiple factors. The interest of students in the early stages can be improved in subjects related to public health or of academic importance, as per need. Methods: A questionnaire-based study was conducted among 265 first- and second-year medical students of Chitwan Medical College, Nepal to find out their subject of preference for postgraduation and the factors affecting their selection along with their interesting basic science subject. Only the responses from 232 completely filled questionnaires were analyzed. Results: The preference of the students for clinical surgical (50.9%), clinical medical (45.3%), and basic medical (3.9%) sciences for postgraduation were in descending order. The most preferred specialty among male students was clinical surgical sciences (56.3%), and among female students, it was clinical medical sciences (53.6%). Although all the students responded to their preferred specialty, only 178 students specified the subject of their interest. General surgery (23.4%), pediatrics (23.4%), and anatomy (2.4%) were the most favored subjects for postgraduation among clinical surgical, clinical medical, and basic medical sciences specialties, respectively. More common reasons for selection of specific subject for future career were found to be: personal interests, good income, intellectual challenge, and others. Conclusion: Many students preferred clinical surgical sciences for their future specialization. Among the reasons for the selection of the specialty for postgraduation, no significant reason could be elicited from the present study. Keywords: career, surgical, medical, specialization

Study Question: Do higher leptin levels and lower adiponectin levels predict subsequent development of endometriosis?Summary Answer: Plasma leptin and adiponectin levels were not associated with laparoscopically confirmed endometriosis when collected prior to disease diagnosis.What Is Known Already: Case-control studies have identified altered levels of the inflammatory adipokines leptin and adiponectin in women with endometriosis, but it remains unclear whether inflammation results in endometriosis or whether the presence of endometriosis creates an inflammatory state.Study Design, Size, Duration: Nested, matched, case-control study within the prospective Nurses' Health Study II (NHS II) cohort. Blood samples were collected between 1996 and 1999 from 29 611 female nurses within the cohort. Women who reported endometriosis before blood collection were excluded.Participants/materials, Setting, Methods: Plasma leptin and adiponectin levels were assayed by ELISA. Three hundred and fifty cases of laparoscopically confirmed endometriosis were matched 1:2 with 694 controls of comparable race, age, infertility history, menopausal status and time of blood draw. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression models adjusting for matching factors and BMI.Main Results and the Role Of Chance: After adjusting for BMI, there were no statistically significant associations between endometriosis and leptin [RR = 1.2; 95% CI = 0.7-2.0; P-value, test for linear trend (P(trend)) = 0.72], adiponectin (RR = 0.8; 95% CI = 0.5-1.2; P(trend) = 0.48) or the leptin to adiponectin ratio (RR = 0.8; 95% CI = 0.4-1.4; P(trend) = 0.14) when comparing the upper with the lower quartile. Results were unaltered when analyses were stratified by BMI or restricted to cases diagnosed ≥ 4 years after blood draw. To evaluate statistical significance and limit the role of chance to the gold standard of 5%, we present 95% CIs about the RRs, and for P-values calculated for linear tests of trend and tests of heterogeneity, we have set the α-level to be 0.05 (i.e. <0.05 is considered to be statistically significant).Limitations and Reasons For Caution: A limitation of this study is the inability to differentiate the time of endometriosis 'diagnosis' from the time of disease 'onset' due to the impossibility in identifying a precise time point at which the disease process was first initiated at a molecular or cellular level. Additional limitations include lack of information regarding stage of endometriosis and the possibility of asymptomatic disease in the control population.Wider Implications Of the Findings: The mean age at diagnosis of endometriosis in the study population is 41.7, ≈ 10 years older than the mean age of diagnosis in the general population. While this may limit the generalizability of the results, there is no reason to suspect that the association between adipokines and endometriosis risk should differ at a younger age of diagnosis in an adult population. [ABSTRACT FROM AUTHOR]

Meckel's diverticulum is the most common congenital malformation of gastrointestinal tract. It can cause complications in the form of ulceration, haemorrhage, intussusception, intestinal obstruction, perforation and, very rarely, vesicodiverticular fistulae and tumours. These complications, especially bleeding, are more common in the paediatric age group than in adults; however it is not uncommon to miss the diagnosis of Meckel's diverticulum in adults. Here, we reviewed the literature regarding the complications of this forgotten clinical entity in adults with potential diagnostic difficulties and management strategies. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) have become a vital class of therapeutics in oncology because of their ability to selectively deliver potent drug molecules to tumor cells. However, ADC-associated toxicities cause high failure rates in the clinic and hinder their full potential. Due to the complex structure and pharmacokinetics of ADCs, it is challenging to identify the drivers of their toxicities. Here, quantitative analysis was performed to correlate the incidence of clinical adverse events (AEs) with nine different commonly measured exposure parameters collected from study-level summary data. We considered ADC analytes for different classes of ADCs, to identify ADC analytes that are strongly associated with the AEs for ADCs. Published clinical exposure and safety data for any grade and grade ≥3 AEs from 40 publications across six ADCs and three payloads were collected and analyzed. Exposure-AE relationships were quantified using logit models, and the strength of the correlations and rank order were determined. The analysis suggests that deruxtecan ADC-related toxicities correlated most strongly with the exposure of the free payload; monomethyl auristatin E (MMAE) ADC-related toxicities correlated with the free MMAE area under the curve; and pyrrolobenzodiazepine ADC-related toxicities correlated with no specific analyte but the dose. These findings agree with the published literature and support the notion that AE profiles are often shared by ADCs that deliver the same cytotoxic payload. The exposure-AE relationships presented here, together with identification of the most informative ADC analytes, may facilitate more focused mechanistic studies on the drivers of clinical AEs and could support dosing decisions during clinical development of ADCs., (© 2024, The American College of Clinical Pharmacology.)

Objective: To assess whether the provision of fertility treatment for patients with polycystic ovary syndrome (PCOS) varies by patient and physician-level demographic characteristics., Design: Retrospective cohort study., Setting: University health system., Patient(s): Patients seeking care for PCOS and infertility from 2007-2021., Intervention(s): Patient age, body mass index, race, ethnicity, estimated household income, primary insurance payor, provider sex, and provider medical specialty., Main Outcome Measure(s): Prescriptions for fertility treatment, including clomiphene citrate (CC), letrozole, and injectable gonadotropins. Differences in patient and physician demographics between patients who did as well as did not receive a prescription were identified with univariable analysis. Multilevel mixed-effects logistic regression was performed to determine associations between patient and physician demographics and prescription receipt., Result(s): A total of 3,435 patients with PCOS and infertility were identified, with a mean age of 31.1 ± 5.7 years. Of the 68.8% of patients who received a prescription, 47.8% of prescriptions were CC, 38.6% were letrozole, and 13.7% were injectable gonadotropins. There were lower odds of prescription receipt for Black patients compared with White patients (adjusted odds ratio [aOR], 0.75; 95% confidence interval [CI], 0.61-0.93), those with estimated household income below the federal poverty level compared with those above the national median (aOR, 0.71; 95% CI, 0.46-0.97), and those with public compared with commercial insurance (aOR, 0.53; 95% CI, 0.40-0.71). These disparities persisted in a subanalysis of patients prescribed oral medications only with lower odds of prescription receipt for Black compared with White patients (aOR, 0.74; 95% CI, 0.57-0.95), those with estimated household income below the federal poverty level compared with above the national median (aOR, 0.93; 95% CI, 0.87-0.98), and those with public compared with commercial insurance (aOR, 0.57; 95% CI, 0.42-0.76). Black patients waited, on average, 153.3 days longer than White patients, from the initial visit to the prescription receipt. Patients had lower odds of receiving any prescription from family medicine physicians (aOR, 0.36; 95% CI, 0.24-0.52) and general internal medicine physicians (aOR, 0.55; 95% CI, 0.42-0.73) compared with reproductive endocrinologists., Conclusion(s): Racial and socioeconomic disparities exist in the provision of infertility treatments for patients with PCOS. Fewer primary care physicians engaged in first-line fertility treatment, indicating an opportunity for physician education to improve access to fertility care., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: This phase 1 (NCT04396717) open-label, multicenter study, evaluated Pritumumab, a IgG1 monoclonal antibody, in patients with gliomas and brain metastases. The primary objective was to evaluate the safety and/or tolerability and to identify a recommended phase 2 dose (RP2D) of Pritumumab., Methods: Adult patients with recurrent gliomas or brain metastases were enrolled in the dose cohort that was open at the time of their consent. Study treatment consisted of pritumumab administered intravenously weekly on days 1, 8, 15, and 22 in 28-day cycles. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated., Results: Fifteen patients received Pritumumab in the recurrent setting. Pritumumab was well tolerated, with no serious adverse events related to Pritumumab reported. The most common drug-related toxicities were constipation and fatigue. There were no dose-limiting toxicities observed, and a maximum tolerable dose was not reached. Thus, the maximum feasible dose and recommended phase 2 dose of Pritumumab was established at 16.2 mg/kg weekly. Out of eleven patients evaluated for efficacy, one patient (9.1%) demonstrated partial response based on response assessment in neuro-oncology criteria, and disease stabilization was seen in 3 patients (27.3%)., Conclusions: Pritumumab was well tolerated with no DLTs observed up to 16.2 mg/kg weekly. Further studies are warranted to determine clinical benefit in patients., Competing Interests: S.K. reports research funding to institution from AADI, Aivita Biomedical, Inc., Bavarian Nordic, Bayer, Biocept, Blue Earth Diagnostics, Caris MPI, CNS Pharmaceuticals, EpicentRx, Incyte, Lilly, Oblato, Orbus Therapeutics, and Stemedica Cell Technologies; reports stock or other ownership interests in xCures; reports receiving honoraria from Jubilant Biosys and Pyramid Biosciences; and is a consultant/advisory board member for Curtana Pharmaceuticals, Nascent Biotech, Biocept, iCAD, and xCures; JC reports research funding to institution from Nascent Biotech. IB reports consulting fees and stock options from Nascent Biotech. S.C. is employed by Nascent Biotech. All other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Objective: This study aimed to investigate the effect of molecular size on the pulmonary pharmacokinetics (PK) of proteins following systemic and local administration in wild-type mice. Methods: A non-cross-reactive antibody trastuzumab, and F(ab')2, Fab, and scFv fragments of this antibody were used for the investigation. Proteins were injected intravenously or via intratracheal instillation, and PK was measured in plasma, lungs, trachea, bronchi, and bronchoalveolar lavage (BAL) using ELISA. Concentrations in BAL were urea normalized. Results: Following systemic administration, the biodistribution coefficient (BC) for lungs, trachea, bronchi, and BAL was 11%, 11%, 15%, and 2% for the antibody; 15%, 7%, 13%, and 8% for F(ab')2; 25%, 17%, 28%, and 46% for Fab; and 14%, 1%, 2%, and 50% for scFv. The antibody exposure in BAL was ~50-fold lower than plasma and ~5-7-fold lower than lung tissues. A tissue-dependent BC vs. molecular size relationship was observed, where distribution in tissues was the highest for Fab (50 kDa), and scFv demonstrated the highest distribution in the BAL. PK data generated following local administration were quite variable; however, local dosing resulted in BAL exposures that were 10-100-fold higher than those achieved after systemic dosing for all proteins. The BAL antibody concentrations were 100-1000-fold higher than plasma concentrations initially, which normalized by day 14. For most proteins, local dosing resulted in higher lung concentrations than trachea and bronchi, opposite to what was observed after systemic dosing. Conclusions: The PK data presented here provide an unprecedented quantitative insight into the effect of molecular size on the pulmonary disposition of proteins following systemic and local administration.

Study Objective: To compare the prevalence and accrual of 30-day postoperative complications by operative time for open myomectomy (OM) and minimally invasive myomectomy (MIM)., Design: Retrospective cohort study SETTING: Hospitals participating in the National Surgical Quality Improvement Program database from January 2015 to December 2021., Patients: Female patients aged ≥18 years undergoing OM or MIM., Interventions: Patients were categorized into OM and MIM cohorts. Covariates associated with operative time and composite complications were identified using general linear model and chi-square or Fisher's exact test as appropriate. Adjusted spline regression was performed as a test of linearity between operative time and composite complications. Adjusted risk ratios of 30-day postoperative individual, minor, major, and composite complications by 60-minute operative time increments were estimated using Poisson regression with robust error variance., Measurements and Main Results: Of 27 728 patients, 11 071 underwent MIM and 16 657 underwent OM. Mean operative times (SD) were 164.6 (82.0) for MIM and 129.2 (67.0) for OM. Raw composite complication rates were 5.5% for MIM and 15.8% for OM. Adjusted spline regression demonstrated linearity between operative time and relative risk of composite postoperative complications for both MIM and OM. MIM had higher adjusted relative risk (aRR, 95% CI) compared to OM of blood transfusion (1.55, 1.45-1.64 versus 1.29, 1.25-1.34), overall minor complications (1.13, 1.03-1.23 versus 1.01, 0.92-1.10), and overall major complications (1.43, 1.35-1.51 versus 1.27, 1.12-1.32). Operative time had greater impact on risk of composite complications for MIM than OM, reaching aRR 2.0 at 296 minutes versus 461 minutes for OM., Conclusion: OM has a higher overall rate of composite, minor, and major complications compared to MIM. While operative time is independently and linearly associated with postoperative complications with myomectomy regardless of approach, optimizing surgical efficiency for MIM may be more critical than for OM., (Copyright © 2024 AAGL. Published by Elsevier Inc. All rights reserved.)

Objective: To estimate the prevalence of the Vice Chair of Education (VCE) role in obstetrics and gynecology (OBGYN) departments and to describe the demographics, responsibilities, resource allocation, and challenges faced by individuals in this role., Design: A 2-part survey was developed with the Association of Professors of Gynecology and Obstetrics (APGO) Member Engagement Workgroup., Setting: National survey., Participants: Part 1 was sent to OBGYN department chairs to identify departments with a VCE and to assess characteristics of departments without 1. Part 2 was sent directly to VCEs to assess characteristics of the department and the individual VCE, including demographics, academic appointments, leadership and educational experience, responsibilities, and institutional support. Chi-squared tests were used to compare departments with and without VCE., Results: 196 of 256 OBGYN chairs (76.5%) responded to part 1 of the survey, and 71 of 86 VCEs (82.5%) responded to part 2 of the survey. The prevalence of the VCE role was 43.9%. Departments with a VCE had larger numbers of faculty, residents, and medical students, and were more likely to identify as university-affiliated (all p < 0.001). A majority of VCEs identified as women (82.1%), associate professors (55.0%), and academic specialists (51%), with 62.3% serving as the inaugural VCE in their department. Approximately half of VCEs have a defined job description, and only 35.8% controlled an educational budget. Two-thirds (65.7%) of VCEs received full-time equivalent (FTE) support for the role, with 37.1% receiving 0.2 FTE., Conclusions: The VCE role remains relatively new in OBGYN. Optimizing success of individuals in this role requires increased job clarity, adequate support, and ongoing opportunities for career development., (Copyright © 2024 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: To identify independent predictors of a successful match to reproductive endocrinology and infertility (REI) fellowships, and to develop and internally validate a prediction model for REI match results., Design: Retrospective cohort study., Setting: University-based institution., Participants: Reproductive endocrinology and infertility fellowship applications sent to the University of Pennsylvania from 2019 to 2023 (excluding 2020), which represented nearly all REI applicants nationally according to National Resident Matching Program data., Intervention(s): Demographics, education, training, and academic achievements., Main Outcome Measure(s): Match result, confirmed through online search and communication with program administrators. Univariate analyses identified variables associated with match, which were then included in multivariable models to identify independent predictors. Bootstrapping was used to assess model discrimination and calibration. The final model was integrated into a web-based tool., Result(s): Of 286 applications (99.0% of REI applications to the National Resident Matching Program), 199 (69.6%) resulted in a successful match. In univariate analyses, variables associated with match were younger age, attendance at an allopathic US medical school, United States Medical Licensing Examination (USMLE) and Council on Resident Education in Obstetrics and Gynecology scores, residency rank, residency affiliation with a fellowship, research experiences, first-author publications, abstracts/articles in progress, and poster presentations. In the adjusted model, independent predictors of match included residency affiliation with an REI fellowship (adjusted odds ratio [aOR], 5.43; 2.02-14.64), residency rank (aOR, 1.77; 1.25-2.50), USMLE score (aOR, 1.05; 1.02-1.08), at least one first-author publication (aOR, 2.32; 1.08-4.96), projects in progress (aOR, 1.26; 1.02-1.55), and poster presentations (aOR, 1.07; 1.00-1.15). Attendance at an international medical school was a negative predictor (aOR, 0.32; 0.11-0.88). The model achieved an area under the curve of 0.883, with 88.5% sensitivity and 65.8% specificity. A refined model without USMLE scores maintained strong performance (C-statistic, 0.85; 0.81-0.91; calibration slope, 0.91; 0.72-1.24)., Conclusion(s): Affiliation with an REI fellowship, residency reputation, and research output strongly predicted match success. Gender, race, and ethnicity were not major predictors, yet underrepresentation of certain racial and ethnic groups limited the power to detect potential differences. Our prediction model correctly classified >75% of candidates' match results. These findings may help candidates optimize applications and estimate chances of a successful match into REI fellowship, as well as assist programs in critically reviewing their selection criteria for fellowship match., Competing Interests: Declaration of Interests L.A.H. has nothing to disclose. J.A. has nothing to disclose. M.A.M. has nothing to disclose. C.E.M. has nothing to disclose. D.K.S has nothing to disclose., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

There has been increasing debate around how or if race and ethnicity should be used in medical research-including the conceptualization of race as a biological entity, a social construct, or a proxy for racism. The objectives of this narrative review are to identify and synthesize reported racial and ethnic inequalities in obstetrics and gynecology (ob/gyn) and develop informed recommendations for racial and ethnic inequity research in ob/gyn. A reproducible search of the 8 highest impact ob/gyn journals was conducted. Articles published between January 1, 2010 and June 30, 2023 containing keywords related to racial and ethnic disparities, bias, prejudice, inequalities, and inequities were included (n=318). Data were abstracted and summarized into 4 themes: 1) access to care, 2) adherence to national guidelines, 3) clinical outcomes, and 4) clinical trial diversity. Research related to each theme was organized topically under the headings i) obstetrics, ii) reproductive medicine, iii) gynecologic cancer, and iv) other. Additionally, interactive tables were developed. These include data on study timeline, population, location, and results for every article. The tables enable readers to filter by journal, publication year, race and ethnicity, and topic. Numerous studies identified adverse reproductive outcomes among racial and ethnic minorities as compared to white patients, which persist despite adjusting for differential access to care, socioeconomic or lifestyle factors, and clinical characteristics. These include higher maternal morbidity and mortality among Black and Hispanic/Latinx patients; reduced success during fertility treatments for Black, Hispanic/Latinx, and Asian patients; and lower survival rates and lower likelihood of receiving guideline concordant care for gynecological cancers for non-White patients. We conclude that many racial and ethnic inequities in ob/gyn cannot be fully attributed to patient characteristics or access to care. Research focused on explaining these disparities based on biological differences incorrectly reinforces the notion of race as a biological trait. More research that deconstructs race and assesses efficacy of interventions to reduce these disparities is needed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of this work was to develop a population physiologically based pharmacokinetic (popPBPK) model to characterize the variability in the clinical PK of monoclonal antibodies (mAbs) following intravenous (IV) and subcutaneous (SC) administration. An extensive literature search was conducted and clinical PK data for FDA-approved as well as non-approved mAbs were collected. Training and validation datasets of 44 and 9 mAbs exhibiting linear pharmacokinetics were used for model development. The variability in antibody PK was captured by accounting for different rate constants of pinocytosis (CL up ) and intracellular degradation (k deg ) for different mAbs. Typical values for CL up and k deg and their respective inter-antibody variabilities (ωClup, ωKdeg) were estimated to be 0.32 L/h/L and 26.1 h-1 (73% and 46%). Varied absorption profiles following SC dosing were characterized by incorporating inter-antibody variability in local degradation (k SC ) and rate of lymphatic uptake (S&#95;Lu) of mAbs. Estimates for typical k SC and S&#95;Lu values, and ωKsc,ωS&#95;Lu, were found to be 0.0015 h-1 and 0.54 (193%, and 49%). FDA-approved mAbs showed less local degradation (0.0014 h-1 vs. 0.0038 h-1) compared with other clinically tested mAbs, whereas no substantial differences in physiological processes involved in disposition were observed. To evaluate the generalizability of estimated PK parameters and model validation, the final popPBPK model was used to simulate the range of expected PK for mAbs following SC administration of nine different mAbs that were not used for model-building purposes. The predicted PK of all nine mAbs was within the expected range specified a priori . Thus, the popPBPK model presented here may serve as a tool to predict the clinical PK of mAbs with linear disposition before administering them to humans. The model may also support preclinical-to-clinical translation and 'first-in-human' dose determination for mAbs.

Aims: This study aims to develop a generalized pharmacokinetic (PK) model for monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) that can simultaneously capture the PK of multiple ADC analytes commonly measured in the clinic., Methods: A comprehensive literature review was conducted to collect PK data on MMAE-based ADCs from clinical trials. From each study, PK profiles of total antibody, the ADC, conjugated MMAE, and unconjugated MMAE, were extracted. These data were pooled and dose-normalized to evaluate the generalizability of PK across various ADCs and dose levels. Upon confirming PK generalizability, a generalized PK model for MMAE-based ADCs was developed using the entire dataset. Furthermore, exposure metrics ( C max and AUC) reported across the range of doses were combined to establish linear relationships between dose and exposure metrics for MMAE-based ADCs., Results: A total of 109 PK profiles from 18 distinct MMAE-based ADCs were gathered. The dose-normalized PK profiles supported the generalizability of PK for MMAE-based ADCs. A generalized PK model was developed, which enabled capturing the PK data for 4 ADC analytes across all collected MMAE-based ADCs. A linear relationship between dose and PK exposure metrics was established, enabling the prediction of typical exposure values across different doses for MMAE-based ADCs., Conclusions: This study comprehensively analysed clinical PK data from different valine-citrulline (vc)-MMAE-based ADCs. The generalized PK model developed here serves as an important tool for a priori prediction of the PK for multiple ADC analytes in clinical settings and lays the foundation for establishing generalized exposure-response and exposure-toxicity correlations for MMAE-based ADCs., (© 2024 British Pharmacological Society.)

Background: Effective seizure detection is important however, clinical signs of seizure activity may be subtle in neonates. This study aimed to systematically investigate SpO 2 and respiratory pattern changes associated with EEG seizures in term-born neonates., Method: An observational study in term neonates at risk of seizures admitted to a single tertiary level neonatal intensive care unit. Synchronised high-resolution physiological data (ECG, pulse oximetry, respiration) and EEG/amplitude-integrated EEG (aEEG) monitoring were recorded. Sections of traces with evidence of clear EEG seizure activity were compared with physiological data recorded at the same time., Results: 22/44 (50%) neonates who had aEEG monitoring were noted to have electrographic seizures. Physiologic download measurements were available for 11 of these neonates. In nine of these, an acute drop in oxygen saturation (SpO 2 ) of at least 5% was noted in at least one seizure. Accompanying apnoeas were noted in three neonates., Conclusion: Acute decreases in SpO 2 were seen in term neonates associated with seizures and these were not always accompanied by an apnoeic episode. Physiologic download in association with EEG monitoring may assist in improving seizure detection. Unexplained drops in SpO 2 could indicate further investigation for possible seizures in at-risk neonates., Impact: A decrease in blood oxygen saturation (SpO 2 ) associated with EEG seizures can occur in term infants with HIE or perinatal stroke. Drops in SpO 2 associated with EEG seizures in term infants with HIE or stroke may occur in the absence of apnoeas. Unexplained acute falls in SpO 2 in sick neonates may suggest possible seizures. Drops in SpO 2 associated with seizures in term infants can occur over less than 3 minutes. Physiological monitoring alongside EEG monitoring could help to improve seizure detection., (© 2024. The Author(s).)

Background: Fetal growth restriction (FGR) corresponds to the fetus's inability to achieve an adequate weight gain based on genetic potential and gestational age. It is an important cause of morbidity and mortality., Summary: In this review, we address the challenges of diagnosis and classification of FGR. We review how chronic fetal hypoxia impacts brain development. We describe recent advances on placental and fetal brain imaging using magnetic resonance imaging and how they offer new noninvasive means to study growth restriction in humans. We go on to review the impact of FGR on brain integrity in the neonatal period, later childhood, and adulthood and review available therapies., Key Messages: FGR consequences are not limited to the perinatal period. We hypothesize that impaired brain reserve, as defined by structure and size, may predict some concerning epidemiological data of impaired cognitive outcomes and dementia with aging in this group of patients., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and it leads to irreversible inflammation in intra-articular joints. Current treatment approaches for RA include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, and biological agents. To overcome the drug-associated toxicity of conventional therapy and transdermal tissue barrier, an injectable NSAID-loaded hydrogel system was developed and explored its efficacy., Results: The surface morphology and porosity of the hydrogels indicate that they mimic the natural ECM, which is greatly beneficial for tissue healing. Further, NSAIDs, i.e., diclofenac sodium, were loaded into the hydrogel, and the in vitro drug release pattern was found to be burst release for 24 h and subsequently sustainable release of 50% drug up to 10 days. The DPPH assay revealed that the hydrogels have good radical scavenging activity. The biocompatibility study carried out by MTT assay proved good biocompatibility and anti-inflammatory activity of the hydrogels was carried out by gene expression study in RAW 264.7 cells, which indicate the downregulation of several key inflammatory genes such as COX-2, TNF-α & 18s., Conclusion: In summary, the proposed ECM-mimetic, thermo-sensitive in situ hydrogels may be utilized for intra-articular inflammation modulation and can be beneficial by reducing the frequency of medication and providing optimum lubrication at intra-articular joints., (© 2024. The Author(s).)

Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the in vitro , ex vivo and in vivo performance of a drug, and if there exists a correlation between in vitro and in vivo , as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C). The in vitro , ex vivo and in vivo in healthy models validate the hypothesis that 4C has better reach and binding to the receptors. The results indicate that 4C offered better performance over 2C in vivo in improving the oral bioavailability of insulin (INS) by 1.1-fold (3.5-fold compared to unfunctionalized nanoparticles) in a healthy rat model. Similar observations were made in pathophysiological models; however, the effects were less prominent compared to those in healthy models. Throughout, ligand decorated nanoparticles outperformed unfunctionalized nanoparticles. Finally, a semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed using the experimental data sets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability and efficacy of insulin. The study presents a sophisticated oral delivery system for INS or hydrophilic therapeutic cargo, highlighting the significant impact on bioavailability that minor adjustments to the surface chemistry can have.

Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans. Datasets used for model development include more than 15 types of proteins: IgG (150 kDa), F(ab)2 (100 kDa), minibody (80 kDa), Fc-containing proteins (205, 200, 110, 105, 92, 84, 81, 65, or 60 kDa), albumin conjugate (85.7 kDa), albumin (67 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), dAb2 (23.5 kDa), proteins with an albumin-binding domain (26, 23.5, 22, 16, 14, or 13 kDa), nanobody (13 kDa), and other proteins (110, 65, or 60 kDa). The PBPK model incorporates: (i) molecular weight (MW)-dependent extravasation through large and small pores via diffusion and filtration, (ii) MW-dependent renal filtration, (iii) endosomal FcRn-mediated protection from catabolism for IgG and albumin-related modalities, and (iv) competition for FcRn binding from endogenous IgG and albumin. The finalized model can well characterize PK of most of these proteins, with area under the curve predicted within two-fold error. The model also provides insights into contribution of renal filtration and lysosomal degradation towards total elimination of proteins, and contribution of paracellular convection/diffusion and transcytosis towards extravasation. The PBPK model presented here represents a cross-modality, cross-species platform that can be used for development of novel biologics., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: This study aimed to examine the variation between clinician-recorded and continuously downloaded invasive blood pressure (BP)., Study Design: Prospective study where invasive BP data were downloaded every 10 seconds for the first week of life. Hourly clinician-recorded BP was recorded. Agreement between the two methods were examined., Results: A total of 1,180 BP measurements were examined from 42 preterm infants with a mean (standard deviation [SD]) gestation and birthweight of 25.7 weeks (1.4) and 802 g (177) respectively. The mean (SD) bias was -0.11 mm Hg (3.17), but the 95% limits of agreement (LOA) varied between -6.3 and +6.1 mm Hg. Inotrope usage was significantly higher for BP measurements that fell in the 5% outliers when compared with those that fell within the 95% LOA (62.7 vs. 44.6%, p  = 0.006)., Conclusion: Clinicians showed no systematic bias to over- or underrecord BP, but some of the greatest differences were found in infants receiving inotropes., Key Points: · BP is a commonly recorded cardiovascular parameter in the neonatal intensive care unit.. · Invasively measured BP remains the gold standard.. · Clinician-recorded BP showed no systematic bias in over-or underrecording invasive BP.., Competing Interests: None declared., (Thieme. All rights reserved.)

Despite the promising potential of direct central nervous system (CNS) antibody administration to enhance brain exposure, there remains a significant gap in understanding the disposition of antibodies following different intra-CNS injection routes. To bridge this knowledge gap, this study quantitatively investigated the brain pharmacokinetics (PK) of antibodies following intra-CNS administration. The microdialysis samples from the striatum (ST), cerebrospinal fluid (CSF) samples through cisterna magna (CM) puncture, plasma, and brain homogenate samples were collected to characterize the pharmacokinetics (PK) profiles of a non-targeting antibody, trastuzumab, following intracerebroventricular (ICV), intracisternal (ICM), and intrastriatal (IST) administration. For a comprehensive analysis, these intra-CNS injection datasets were juxtaposed against our previously acquired intravenous (IV) injection data obtained under analogous experimental conditions. Our findings highlighted that direct CSF injections, either through ICV or ICM, resulted in ~ 5-6-fold higher interstitial fluid (ISF) drug exposure than IV administration. Additionally, the low bioavailability observed following IST administration indicates the existence of a local degradation process for antibody elimination in the brain ISF along with the ISF bulk flow. The study further refined a physiologically based pharmacokinetic (PBPK) model based on new observations by adding the perivascular compartments, oscillated CSF flow, and the nonspecific uptake and degradation of antibodies by brain parenchymal cells. The updated model can well characterize the antibody PK following systemic and intra-CNS administration. Thus, our research offers quantitative insight into antibody brain disposition pathways and paves the way for determining optimal dosing and administration strategies for antibodies targeting CNS disorders., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: Despite extensive research on neonatal hypoxic-ischaemic encephalopathy, detailed information about electrographic seizures during active cooling and rewarming of therapeutic hypothermia is sparse. We aimed to describe temporal evolution of seizures and determine whether there is a correlation of seizure evolution with 2-year outcome., Methods: This secondary analysis included newborn infants recruited from eight European tertiary neonatal intensive care units for two multicentre studies (a randomised controlled trial [NCT02431780] and an observational study [NCT02160171]). Infants were born at 36 +0 weeks of gestation with moderate or severe hypoxic-ischaemic encephalopathy and underwent therapeutic hypothermia with prolonged conventional video-electroencephalography (EEG) monitoring for 10 h or longer from the start of rewarming. Seizure burden characteristics were calculated based on electrographic seizures annotations: hourly seizure burden (minutes of seizures within an hour) and total seizure burden (minutes of seizures within the entire recording). We categorised infants into those with electrographic seizures during active cooling only, those with electrographic seizures during cooling and rewarming, and those without seizures. Neurodevelopmental outcomes were determined using the Bayley's Scales of Infant and Toddler Development, Third Edition (BSID-III), the Griffiths Mental Development Scales (GMDS), or neurological assessment. An abnormal outcome was defined as death or neurodisability at 2 years. Neurodisability was defined as a composite score of 85 or less on any subscales for BSID-III, a total score of 87 or less for GMDS, or a diagnosis of cerebral palsy (dyskinetic cerebral palsy, spastic quadriplegia, or mixed motor impairment) or epilepsy., Findings: Of 263 infants recruited between Jan 1, 2011, and Feb 7, 2017, we included 129 infants: 65 had electrographic seizures (43 during active cooling only and 22 during and after active cooling) and 64 had no seizures. Compared with infants with seizures during active cooling only, those with seizures during and after active cooling had a longer seizure period (median 12 h [IQR 3-28] vs 68 h [35-86], p<0·0001), more seizures (median 12 [IQR 5-36] vs 94 [24-134], p<0·0001), and higher total seizure burden (median 69 min [IQR 22-104] vs 167 min [54-275], p=0·0033). Hourly seizure burden peaked at about 20-24 h in both groups, and infants with seizures during and after active cooling had a secondary peak at 85 h of age. When combined, worse EEG background (major abnormalities and inactive background) at 12 h and 24 h were associated with the seizure group: compared with infants with a better EEG background (normal, mild, or moderate abnormalities), infants with a worse EEG background were more likely to have seizures after cooling at 12 h (13 [54%] of 24 vs four [14%] of 28; odds ratio 7·09 [95% CI 1·88-26·77], p=0·0039) and 24 h (14 [56%] of 25 vs seven [18%] of 38; 5·64 [1·81-17·60], p=0·0029). There was a significant relationship between EEG grade at 12 h (four categories) and seizure group (p=0·020). High total seizure burden was associated with increased odds of an abnormal outcome at 2 years of age (odds ratio 1·007 [95% CI 1·000-1·014], p=0·046), with a medium negative correlation between total seizure burden and BSID-III cognitive score (r S =-0·477, p=0·014, n=26)., Interpretation: Overall, half of infants with hypoxic-ischaemic encephalopathy had electrographic seizures and a third of those infants had seizures beyond active cooling, with worse outcomes. These results raise the importance of prolonged EEG monitoring of newborn infants with hypoxic-ischaemic encephalopathy not only during active cooling but throughout the rewarming phase and even longer when seizures are detected., Funding: Wellcome Trust, Science Foundation Ireland, and the Irish Health Research Board., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Study Objective: The standard of care for detecting acute kidney injury (AKI) is change in serum creatinine (SCr) and urine output, which are limited. This study aimed to compare urinary biomarkers neutrophil gelatinase-associated lipocalin (uNGAL) with kidney injury molecule-1 (uKIM-1) in critically ill children exposed to vancomycin who did and did not develop AKI as defined by changes in SCr., Design: Single-center, prospective, clinical, observational cohort study., Setting: Tertiary care children's hospital in an urban setting., Patients: Children aged 0 (corrected gestational age 42 weeks) to 18 years admitted to the intensive care unit who received vancomycin were included., Intervention: None., Measurements: The primary outcome was mean change in uNGAL and uKIM-1 between AKI and no-AKI groups. AKI was defined as a minimum 50% increase in SCr from baseline over a 48 h period, within 7 days of first vancomycin exposure. Three urine samples were collected: baseline (between 0 and 6 h of first vancomycin dose), second (18-24 h after the "baseline"), and third (18-24 h after the second sample). Concentrations of uKIM-1 and uNGAL were measured in each sample., Main Results: Forty-eight children (52% male; median age 6 years) were included. Eight (16.7%) children developed AKI. Mean changes in uNGAL (713.196 ± 1,216,474 vs. 16.101 ± 37.812 pg/mL; p = 0.0004) and uKIM-1 (6060 ± 11.165 vs. 340 ± 542 pg/mL; p = 0.0015) were greater in children with AKI versus no-AKI, respectively., Conclusions: uNGAL and uKIM-1 concentrations increased significantly more in critically ill children with AKI compared with those with no-AKI during the first 48-72 h of vancomycin exposure and may be useful as prospective biomarkers of AKI., (© 2023 Pharmacotherapy Publications, Inc.)

Introduction: Recombinant adeno-associated viruses(rAAVs) are an attractive tool to ensure long-term expression monoclonal antibody(mAb) in the central nervous system(CNS). It is still unclear whether systemic injection or local CNS administration of AAV9 is more beneficial for the exposure of the expressed mAb in the brain. Hence, we compared the biodistribution and transgene expression following AAV9-Trastuzumab administration through different routes., Methods and Result: In-house generated AAV9-Trastuzumab vectors were administered at 5E+11 Vgs/rat through intravenous(IV), intracerebroventricular(ICV), intra-cisterna magna(ICM) and intrastriatal(IST) routes. Vector and trastuzumab blood/plasma concentrations were assessed at different time points up to the terminal time point of 21 days. Different brain regions in addition to the spinal cord, cerebrospinal fluid(CSF) and interstitial fluid(ISF), were also analyzed at the terminal time point. Our results show that vector biodistribution and Trastuzumab expression in the brain could the ranked as follows: IST>ICM>ICV>IV. Rapid clearance of vector was observed after administration via the ICM and ICV routes. The ICV route produced similar expression levels across different brain regions, while the ICM route had better expression in the hindbrain and spinal cord region. The IST route had higher expression in the forebrain region compared to the hindbrain region. A sharp decline in trastuzumab plasma concentration was observed across all routes of administration due to anti-trastuzumab antibody response., Conclusion: In this study we have characterized vector biodistribution and transgene mAb expression after AAV9 vector administration through different routes in rats. IST and ICM represent the best administration routes to deliver antibody genes to the brain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice. After 2E11 Vg/mouse dose of AAV8 and AAV9 encoding a monoclonal antibody (mAb) gene, whole-body disposition of both the vector and the transgene mAb was evaluated over 3 weeks. At steady-state, the following tissue-to-blood (T/B) concentration ratios were found for AAV8/9: ∼50 for liver; ∼10 for heart and muscle; ∼2 for brain, lung, kidney, adipose, and spleen; ≤1 for bone, skin, and pancreas. T/B values for mAb were compared with the antibody biodistribution coefficients, and five different clusters of organs were identified based on their transgene expression profile. All the biodistribution data were used to develop a novel AAV PBPK model that incorporates: (i) whole-body distribution of the vector; (ii) binding, internalization, and intracellular processing of the vector; (iii) transgene expression and secretion; and (iv) whole-body disposition of the secreted transgene product. The model was able to capture systemic and tissue PK of the vector and the transgene-produced mAb reasonably well. Pathway analysis of the PBPK model suggested that liver, muscle, and heart are the main contributors for the secreted transgene mAb. Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies. The PBPK model can also serve as a quantitative tool for preclinical study design and preclinical-to-clinical translation of AAV-based gene therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The outcomes in advanced NSCLC have improved owing to the availability of more effective systemic and improved supportive care. This has increased the number of patients who seek treatment in the third line and beyond setting. We conducted this study to compare the quality of life (QoL), toxicity, and outcomes in patients receiving chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) in this setting., Methods: In this phase 3, randomized, open-label study, patients with stage III or IV NSCLC with disease progression on at least two prior lines of chemotherapy, with a life expectancy of at least 3 months, without prior EGFR TKI exposure, and stable brain metastases (if any) were included. Patients were randomized to receive chemotherapy (gemcitabine or docetaxel or paclitaxel or vinorelbine) or an EGFR TKI (erlotinib or gefitinib). The primary end point was the change in QoL at 8 to 10 weeks; the secondary outcomes were safety and overall survival (OS). Patients underwent clinical evaluation at every visit, and toxicity was assessed as per Common Terminology Criteria for Adverse Events version 4.03. A radiological tumor response assessment was done every 8 to 12 weeks from the start of therapy. The QoL was assessed using the EORTC QLQ C30 and LC13 questionnaires. The change in QoL scores was calculated as the difference between scores at baseline and scores at 8 to 10 weeks (Δ) for each QoL domain. The Mann-Whitney U test was used to compare the mean difference (Δ) for each domain. OS and progression-free survival (PFS) were determined using the Kaplan-Meier method and Cox proportional regression analysis., Results: A total of 246 patients were enrolled in the study, with 123 in each arm. There was a male predominance with 69.1% male patients in the chemotherapy arm and 70.7% in the EGFR TKI arm. The median age of patients in the chemotherapy arm was 54 years and 55 years in the chemotherapy and EGFR TKI arms, respectively. There was no significant difference in the change in QoL at baseline and the second visit (Δ) in both arms in all domains of EORTC QLQ C30 except cognitive function ( p  = 0.0045) and LC13 except alopecia (0.01249). The mean Δ Global Health Status was -28 in the chemotherapy arm and -26.8 in the EGFR TKI arm; this was not statistically significant ( p  = 0.973). The median follow-up was 88.1 months (95% confidence interval [CI]: 39.04-137.15). On the intention-to-treat analysis, the median PFS was 3.13 months (95% CI: 2.15-4.11) in the chemotherapy arm and 2.26 months (95% CI: 2.1-2.43) in the EGFR TKI arm, with hazard ratio at 1.074 (95% CI: 0.83-1.38) ( p  = 0.58). There were 120 deaths in each arm. The median OS was 7.63 months (95% CI: 5.96-9.30) in the chemotherapy arm and 7.5 months in the EGFR TKI arm (95% CI: 5.85-9.14); hazard ratio at 1.033 (95% CI: 0.80-1.33) ( p  = 0.805). The toxicity profile was similar in both arms except for a significantly higher incidence of fatigue ( p  = 0.043), peripheral neuropathy (0.000), alopecia, hypokalemia (0.037), and pedal edema (0.007) in the chemotherapy arm and dry skin ( p  = 0.000) and skin rash ( p  = 0.019) in the EGFR TKI arm., Conclusions: There was no significant difference in most QoL scales (except cognitive function and alopecia), OS, and PFS of patients with advanced NSCLC receiving an EGFR TKI as compared with chemotherapy TKI in the third-line setting. The toxicity profile is consistent with the known toxicities of the agents., (© 2024 The Authors.)

Monoclonal antibodies (mAbs) are becoming an important therapeutic option in veterinary medicine, and understanding the pharmacokinetic (PK) of mAbs in higher-order animal species is also important for human drug development. To better understand the PK of mAbs in these animals, here we have expanded a platform physiological-based pharmacokinetic (PBPK) model to characterize the disposition of mAbs in three different preclinical species: cats, sheep, and dogs. We obtained PK data for mAbs and physiological parameters for the three different species from the literature. We were able to describe the PK of mAbs following intravenous (IV) or subcutaneous administration in cats, IV administration in sheep, and IV administration dogs reasonably well by fixing the physiological parameters and just estimating the parameters related to the binding of mAbs to the neonatal Fc receptor. The platform PBPK model presented here provides a quantitative tool to predict the plasma PK of mAbs in dogs, cats, and sheep. The model can also predict mAb PK in different tissues where the site of action might be located. As such, the mAb PBPK model presented here can facilitate the discovery, development, and preclinical-to-clinical translation of mAbs for veterinary and human medicine. The model can also be modified in the future to account for more detailed compartments for certain organs, different pathophysiology in the animals, and target-mediated drug disposition., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The main objective of this manuscript was to validate the ability of the monoclonal antibody physiologically-based pharmacokinetic (PBPK) model to predict tissue concentrations of antibodies in the human. To accomplish this goal, preclinical and clinical tissue distribution and positron emission tomography imaging data generated using zirconium-89 ( 89 Zr) labeled antibodies were obtained from the literature. First, our previously published translational PBPK model for antibodies was expanded to describe the whole-body biodistribution of 89 Zr labeled antibody and the free 89 Zr, as well as residualization of free 89 Zr. Subsequently, the model was optimized using mouse biodistribution data, where it was observed that free 89 Zr mainly residualizes in the bone and the extent of antibody distribution in certain tissues (e.g., liver and spleen) may be altered by labeling with 89 Zr. The mouse PBPK model was scaled to rat, monkey, and human by simply changing the physiological parameters, and a priori simulations performed by the model were compared with the observed PK data. It was found that model predicted antibody PK in majority of the tissues in all the species superimposed over the observed data, and the model was also able to predict the PK of antibody in human tissues reasonably well. As such, the work presented here provides unprecedented evaluation of the antibody PPBK model for its ability to predict tissue PK of antibodies in the clinic. This model can be used for preclinical-to-clinical translation of antibodies and for prediction of antibody concentrations at the site-of-action in the clinic., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ventral hernias with large defects (≥ 2 cm) are managed with tension free mesh repair. The growing consensus that sublay (retrorectus) mesh repair is superior to onlay mesh repair due to fewer complications is based on literature dominated by retrospective studies from high and upper-middle income countries. There is thus a need of more prospective studies from various countries to resolve the controversy. The objective of this study was to compare the outcomes of onlay versus sublay mesh repair in the management of ventral hernias. Our single centre, prospective comparative study set in a low-middle income country comprised of 60 patients with a ventral hernia undergoing open surgical repair using either onlay technique (n = 30) or sublay technique (n = 30). Surgical site infections, seroma formation, recurrence were found in 3.33%, 6.67%, 0% patients in sublay repair group and in 16.67%, 20%, 6.67% patients in onlay repair group respectively. Mean duration of surgery, mean Visual Analogue Scale (VAS) score for chronic pain, mean duration of hospital stay were 46 min, 4.5, 8 days in onlay repair group and 61 min, 4.2, 6 days in sublay repair group respectively. Onlay repair group was associated with shorter duration of surgery. However, sublay repair was associated with lesser rates of surgical site infections, chronic pain and recurrence than onlay repair. Sublay mesh repair had better outcomes than onlay mesh repair for the management of ventral hernias, however superiority of any one technique could not be established., (© 2023. Italian Society of Surgery (SIC).)

Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality globally. Although mild therapeutic hypothermia (TH) may improve outcomes in selected babies, the mechanism of action is not fully understood. A proteomics discovery study was carried out to analyse proteins in the plasma of newborns with HIE. Proteomic analysis of plasma from 22 newborns with moderate-severe HIE that had initially undergone TH, and relative controls including 10 newborns with mild HIE who did not warrant TH and also cord blood from 10 normal births (non-HIE) were carried out using the isobaric Tandem Mass Tag (TMT ® ) 10plex TM labelling with tandem mass spectrometry. A total of 7818 unique peptides were identified in all TMT10plex TM samples, translating to 3457 peptides representing 405 proteins, after applying stringent filter criteria. Apart from the unique protein signature from normal cord blood, unsupervised analysis revealed several significantly regulated proteins in the TH-treated moderate-severe HIE group. GO annotation and functional clustering revealed various proteins associated with glucose metabolism: the enzymes fructose-bisphosphate aldolase A, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate mutase 1, phosphoglycerate kinase 1, and pyruvate kinase PKM were upregulated in newborns with favourable (sHIE+) outcomes compared to newborns with unfavourable (sHIE-) outcomes. Those with favourable outcomes had normal MR imaging or mild abnormalities not predictive of adverse outcomes. However, in comparison to mild HIE and the sHIE- groups, the sHIE+ group had the additional glucose metabolism-related enzymes upregulated, including triosephosphate isomerase, α-enolase, 6-phosphogluconate dehydrogenase, transaldolase, and mitochondrial glutathione reductase. In conclusion, our plasma proteomic study demonstrates that TH-treated newborns with favourable outcomes have an upregulation in glucose metabolism. These findings may open new avenues for more effective neuroprotective therapy.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Although therapeutic hypothermia is an effective treatment, substantial chronic neurological impairment often persists. The long-chain omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, offer therapeutic potential in the post-acute phase. To understand how PUFAs are affected by HIE and therapeutic hypothermia we quantified for the first time the effects of HIE and therapeutic hypothermia on blood PUFA levels and lipid peroxidation. In a cross-sectional approach, blood samples from newborns with moderate to severe HIE, who underwent therapeutic hypothermia (sHIE group) were compared to samples from newborns with mild HIE, who did not receive therapeutic hypothermia, and controls. The sHIE group was stratified into cerebral MRI predictive of good ( n  = 10), or poor outcomes ( n  = 10; nine developed cerebral palsy). Cell pellets were analyzed for fatty acid content, and plasma for lipid peroxidation products, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal. Omega-3 Index (% DHA + EPA) was similar between control and HIE groups; however, with therapeutic hypothermia there were significantly lower levels in poor vs. good prognosis sHIE groups. Estimated Δ-6 desaturase activity was significantly lower in sHIE compared to mild HIE and control groups, and linoleic acid significantly increased in the sHIE group with good prognosis. Reduced long-chain omega-3 PUFAs was associated with poor outcome after HIE and therapeutic hypothermia, potentially due to decreased biosynthesis and tissue incorporation. We speculate a potential role for long-chain omega-3 PUFA interventions in addition to existing treatments to improve neurologic outcomes in sHIE., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dyall, Nessel, Sharpe, Yip, Michael-Titus and Shah.)

We have previously published a PBPK model comprising the ocular compartment to characterize the disposition of monoclonal antibodies (mAbs) in rabbits. While rabbits are commonly used preclinical species in ocular research, non-human primates (NHPs) have the most phylogenetic resemblance to humans including the presence of macula in the eyes as well as higher sequence homology. However, their use in ocular research is limited due to the strict ethical guidelines. Similarly, in humans the ocular samples cannot be collected except for the tapping of aqueous humor (AH). Therefore, we have translated this rabbit model to monkeys and human species using literature-reported datasets. Parameters describing the tissue volumes, physiological flows, and FcRn-binding were obtained from the literature, or estimated by fitting the model to the data. In the monkey model, the values for the rate of lysosomal degradation for antibodies (K deg ), intraocular reflection coefficients (σ aq , σ ret, σ cho ), bidirectional rate of fluid circulation between the vitreous chamber and the aqueous chamber (Q VA ), and permeability-surface area product of lens (PS lens ) were estimated; and were found to be 31.5 h -1 , 0.7629, 0.6982, 0.9999, 1.64 × 10 -5 L/h, and 4.62 × 10 -7 L/h, respectively. The monkey model could capture the data in plasma, aqueous humor, vitreous humor and retina reasonably well with the predictions being within twofold of the observed values. For the human model, only the value of K deg was estimated to fit the model to the plasma pharmacokinetics (PK) of mAbs and was found to be 24.4 h -1 (4.14%). The human model could also capture the ocular PK data reasonably well with the predictions being within two- to threefold of observed values for the plasma, aqueous and vitreous humor. Thus, the proposed framework can be used to characterize and predict the PK of mAbs in the eye of monkey and human species following systemic and intravitreal administration. The model can also facilitate the development of new antibody-based therapeutics for the treatment of ocular diseases as well as predict ocular toxicities of such molecules following systemic administration., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mice are rarely used in pharmacokinetic (PK) studies of ocular therapeutics due to the small size of their eyes and challenges in drug administration, tissue collection, and analysis of drug concentrations. Therefore, ocular PK of protein therapeutics in mouse eye following intravitreal (IVT) administration is not known. Here, we have presented the first of its kind investigation, to study the PK of 4 different size non-binding protein therapeutics in mouse plasma, cornea/ICB, vitreous humor, retina, and posterior cup (including choroid) following IVT administration. Administered proteins include trastuzumab (150 kDa) and F(ab) 2 (100 kDa), Fab, and scFv (27 kDa) fragments of trastuzumab. An imaging and injection apparatus suitable for performing small (50 nL) IVT injections in mice was developed, and techniques for enucleation of the eye and dissection of ocular tissues were developed. Furthermore, a sensitive enzyme-linked immunosorbent assay (ELISA) for detection of proteins in very small amounts of ocular tissues were developed. It was observed that elimination from the vitreous chamber was the primary driver of PK in the cornea/ICB, retina, posterior cup, and plasma. Trastuzumab displays first-order kinetics in the vitreous humor with a half-life of 18.8 h. F(ab) 2 , Fab, and ScFv show biphasic PK profiles with distribution phases becoming more rapid as molecular weight decreases, and terminal elimination becoming longer as molecular weight decreases, with terminal half-lives of 16.3, 20.6, and 48.9 h, respectively. The mean residence times of trastuzumab, F(ab) 2 , Fab, and scFv in the vitreous humor were 26.0, 12.2, 10.7, and 8.16 h, respectively. It was found that the mean residence time in vitreous humor doubles with an increase in molecular weight of ∼69 kDa. Interestingly, the PK of proteins measured in the un-injected eye suggest the presence of a pathway for drug transfer between the eyes, which needs to be further validated. Overall, the findings presented here pave the way for drug discovery and development studies of protein therapeutics for ophthalmic indications in mice., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

In this work, a numerical assessment of the optoelectrical properties of the ZnO-ZnSe-CdSe heterojunction for a thin and cost-effective solar cell was made by using the PC1D simulation software. The photovoltaic (PV) properties have been optimized by varying thicknesses of the absorber layer of the p-CdSe layer, the window layer of n-ZnSe, and the antireflection coating (ARC) layer of ZnO, a transparent conductive oxide with enhanced light trapping, and wide bandgap engineering. There is a positive conduction band offset (CBO) of ΔEc = 0.25 eV and a negative valence band offset (VBO) of ΔEv = 1.2 - 2.16 =  - 0.96 eV. The positive CBO prevents the flow of electrons from the CdSe to the ZnSe layer. Further, the impact of doping concentration on the performance of solar cells has been analyzed. The simulation results reveal the increase in the efficiency of solar cells by adding an ARC. The rapid and sharp increase in the efficiency with the thickness of the window layer beyond 80 nm is interesting, unusual, and unconventional due to the combined effect of morphology and electronics on a macro-to-micro scale. The thin-film solar cell with the structure of ZnO/ZnSe/CdSe exhibited a high efficiency of 11.98% with short-circuit current (I sc ) = 1.72 A, open-circuit voltage (V oc ) = 0.81 V and fill factor (FF) = 90.8% at an optimized thickness of 2 μm absorber layer, 50 nm window layer, and 78 nm ARC layer. The EQE of solar cells has been observed at about 90% at a particular wavelength at 470 nm (visible light range). Around 12% of efficiency from such a thin-layered solar cell is highly applicable., (© 2023. The Author(s).)

Study Objective: To compare postoperative complication rates between same-day discharge patients and patients admitted to hospital after minimally invasive myomectomy, stratified by patient demographics and perioperative variables including myoma burden., Design: Retrospective cohort study. Setting Hospitals participating in the National Surgical Quality Improvement Program database from January 2015 to December 2019., Patients: Female patients aged ≥18 years undergoing minimally invasive myomectomy., Interventions: Patients were categorized into either the same-day discharge or admitted patient cohort. Univariate comparisons of demographics, perioperative variables, and 30-day postoperative complications were performed. Multivariate logistic regression was used to 1) identify demographic and perioperative factors associated with admission, and 2) compare postoperative complication rates of same-day discharge patients with those of admitted patients while adjusting for demographic and perioperative factors., Measurements and Main Results: Eight thousand one hundred patients were recruited during the study period. The overall rate of same-day discharge was 57.2% in 2015 and 65.0% in 2019. The same-day discharge rate was 64.6% for patients with a smaller myoma burden (1-4 fibroids and ≤250 grams, Current Procedural Terminology 58545) and 56.8% for larger myoma burden (≥5 fibroids or >250 grams, Current Procedural Terminology 58546). Age, race, American Society of Anesthesiologists classification III or IV, preoperative hematocrit <36%, hypertension, diabetes, bleeding disorder, and increasing operative time were associated with admission to hospital. After adjusting for these variables, composite postoperative complication rates were similar between admitted patients and patients who were discharged the same day regardless of myoma burden (adjusted OR [aOR], 0.66; 95% confidence interval [CI] 0.18-2.47 for low myoma burden and aOR, 0.91; 95% CI 0.18-4.63 for high myoma burden). Admitted patients with both low (aOR, 9.1; 95% CI 2.27-37.04) and high (aOR, 8.24; 95% CI 1.59-42.49) myoma burdens were significantly more likely to receive a blood transfusion compared to same-day discharge patients., Conclusion: Same-day discharge after minimally invasive myomectomy, regardless of myoma burden, is associated with low complication rates. Our findings may aid in shared decision making on discharge planning., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)