A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53-binding sites could influence cancer. Here, we identify a polymorphic p53 responsive element and demonstrate its influence on cancer risk using genome-wide data sets of cancer susceptibility loci, genetic variation, p53 occupancy, and p53-binding sites. We uncover a single-nucleotide polymorphism (SNP) in a functional p53-binding site and establish its influence on the ability of p53 to bind to and regulate transcription of the KITLG gene. The SNP resides in KITLG and associates with one of the largest risks identified among cancer genome-wide association studies. We establish that the SNP has undergone positive selection throughout evolution, signifying a selective benefit, but go on to show that similar SNPs are rare in the genome due to negative selection, indicating that polymorphisms in p53-binding sites are primarily detrimental to humans.

Remote-Use Applications of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised Clinical Outcome Assessment Tool: A Scoping Review.

OBJECTIVES: In 2021, the US Congress passed the Accelerating Access to Critical Therapies for Amyotrophic Lateral Sclerosis Act. The law encourages development of "tools, methods, and processes" to improve clinical trial efficiency for neurodegenerative diseases. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is an outcome measure administered during in-person clinic visits and used to support investigational studies for persons living with amyotrophic lateral sclerosis. Availability of a standardized, remote-use version of the ALSFRS-R may promote more inclusive, decentralized clinical trials. A scoping literature review was conducted to identify existing remote-use ALSFRS-R tools, synthesize feasibility and comparability of administration modes, and summarize barriers and facilitators to inform development of a standardized remote-use ALSFRS-R tool. METHODS: Included studies reported comparisons between remote and in-person, clinician-reported, ALSFRS-R administration and were published in English (2002-2022). References were identified by searching peer-reviewed and gray literature. Twelve studies met the inclusion criteria and were analyzed to compare findings within and across modes of administration. RESULTS: Remote modes of ALSFRS-R administration were categorized into 4 nonmutually exclusive categories: telephone (n = 6), videoconferencing (n = 3), computer or online platforms (n = 3), mobile applications and wearables (n = 2), and 1 unspecified telemedicine modality (n = 1). Studies comparing in-person to telephone or videoconferencing administration reported high ALSFRS-R rating correlations and nonsignificant between-mode differences. CONCLUSIONS: There is insufficient information in the ALSFRS-R literature to support remote clinician administration for collecting high quality data. Future research should engage persons living with amyotrophic lateral sclerosis, care partners, and providers to develop a standardized remote-use ALSFRS-R version.

A System for In Vitro Generation of Mature Murine Plasma Cells Uncovers Differential Blimp-1/Prdm1 Promoter Usage.

Upon encounter with Ag, B cells undergo a sequential process of differentiation to become Ab-secreting plasma cells. Although the key drivers of differentiation have been identified, research has been limited by the lack of in vitro models recapitulating the full process for murine B cells. In this study, we describe methodology using BCR or TLR ligation to obtain plasma cells that are phenotypically mature, have exited cell cycle and express a gene signature concordant with long-lived plasma cells. Dependent on the initial stimuli, the transcriptomes also show variation including the enhanced expression of matrisome components after BCR stimulation, suggestive of unique functional properties for the resultant plasma cells. Moreover, using the new culture conditions we demonstrate that alternative promoter choice regulating the expression of the master transcription factor Blimp-1/Prdm1 can be observed; when the canonical B cell promoter for Prdm1 is deleted, differentiating B cells exhibit flexibility in the choice of promoter, dictated by the initiating stimulus, with preferential maintenance of expression following exposure to TLR ligation. Thus our system provides a readily tractable model for furthering our understanding of plasma cell biology.

An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model.

A nonsynonymous single-nucleotide polymorphism at codon 47 in TP53 exists in African-descent populations (P47S, rs1800371; referred to here as S47). Here we report that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53 but exhibits a significant defect in cell death induced by cisplatin. We show that, compared with wild-type p53, S47 has nearly indistinguishable transcriptional function but shows impaired ability to transactivate a subset of p53 target genes, including two involved in metabolism:Gls2(glutaminase 2) and Sco2 We also show that human and mouse cells expressing the S47 variant are markedly resistant to cell death by agents that induce ferroptosis (iron-mediated nonapoptotic cell death). We show that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Our data suggest that the S47 variant may contribute to increased cancer risk in individuals of African descent, and our findings highlight the need to assess the contribution of this variant to cancer risk in these populations. These data also confirm the potential relevance of metabolism and ferroptosis to tumor suppression by p53.

Recommendations on the Selection, Development, and Modification of Performance Outcome Assessments: A Good Practices Report of an ISPOR Task Force.

In evaluating the clinical benefit of new therapeutic interventions, it is critical that the treatment outcomes assessed reflect aspects of health that are clinically important and meaningful to patients. Performance outcome (PerfO) assessments are measurements based on standardized tasks actively undertaken by a patient that reflect physical, cognitive, sensory, and other functional skills that bring meaning to people's lives. PerfO assessments can have substantial value as drug development tools when the concepts of interest being measured best suit task performance and in cases where patients may be limited in their capacity for self-report. In their development, selection, and modification, including the evaluation and documentation of validity, reliability, usability, and interpretability, the good practice recommendations established for other clinical outcome assessment types should continue to be followed, with concept elicitation as a critical foundation. In addition, the importance of standardization, and the need to ensure feasibility and safety, as well as their utility in patient groups, such as pediatric populations, or those with cognitive and psychiatric challenges, may enhance the need for structured pilot evaluations, additional cognitive interviewing, and evaluation of quantitative data, such as that which would support concept confirmation or provide ecological evidence and other forms of construct evidence within a unitary approach to validity. The opportunity for PerfO assessments to inform key areas of clinical benefit is substantial and establishing good practices in their selection or development, validation, and implementation, as well as how they reflect meaningful aspects of health is critical to ensuring high standards and in furthering patient-focused drug development.

Esophagogastric junction compliance on impedance planimetry (EndoFLIP™) following peroral endoscopic myotomy (POEM) predicts improvement in postoperative eckardt score.

BACKGROUND: Peroral endoscopic myotomy (POEM) is a mainstay of treatment for achalasia. Tailored myotomy based on compliance, as measured with impedance planimetry (FLIP), has yet to be described. In this study we describe the associations between Eckardt score, postoperative GERD, and compliance. METHODS: A retrospective review of a prospectively maintained database was performed, evaluating patients who underwent POEM and intraoperative FLIP between January 2019 and November 2021. Group comparisons were made using two-tailed Wilcoxon rank-sum and Fisher's exact tests. Spearman's correlation coefficients (r) were used to assess the relationship between compliance and outcomes, all with two-tailed statistical significance of p < 0.05. RESULTS: Thirty five patients underwent POEM with intraoperative FLIP. At a 30 mL and 40 mL fill, respectively, compliance increased by 80% (180 ± 152%) and 77% (177 ± 131%) from pre to post myotomy. Mean Eckardt score improved from 5.5 ± 2.6 preoperatively to 1.3 ± 1.6 and 1.8 ± 1.9 at first and second follow up, respectively. Median times to first and second follow up were 22 days (IQR 16-23) and 65 days (IQR 58-142). A higher compliance at 40 mL fill was moderately associated with lower Eckardt score at first (r = -0.49, p = 0.012) and second (r = -0.64, p = 0.014) follow up. Post myotomy compliance ≥ 125 mm3/mmHg at 40 mL fill was associated with lower Eckardt scores, < 3, at first (0.4 ± 0.5 vs 1.8 ± 1.3, p = 0.008) and second (0.4 ± 0.5, vs 2.0 ± 1.4, p = 0.027) follow up. Compliance ≥ 125 mm3/mmHg performed better than previously defined ideal ranges of DI and CSA in predicting postoperative Eckardt scores. Compliance was not significantly associated with development of postoperative GERD. CONCLUSIONS: A target post myotomy compliance of ≥ 125 mm3/mmHg at a 40 mL fill is associated with normal Eckardt scores at first and second postoperative visits, and performs better than previously defined ideal ranges of DI and CSA in predicting post-operative Eckardt scores. Compliance is a poor predictor of developing GERD after POEM.

"Into the fire" approach to teaching endoscopic foreign body removal using a modular simulation curriculum.

BACKGROUND: As flexible endoscopy becomes an increasingly valuable minimally invasive approach to surgical challenges, an efficient and comprehensive training curriculum is needed to train surgeons in therapeutic endoscopy. We developed a modular curriculum utilizing a simulation-based, "into the fire" approach to endoscopic foreign body removal for practicing physicians with task performance pre- and post-testing. METHODS: From 2020 to 2021, two sessions of our advanced flexible endoscopy course were taught by two expert surgical endoscopists using ex-vivo porcine models. The course focused on safe removal techniques for various foreign bodies as part of an overall endoscopy curriculum that uses hands-on simulation-based pre-testing, didactics, and mentored practice sessions, followed by post-course examination. Pre- and post-course assessments and surveys were used to evaluate knowledge, performance, and confidence of participants, and subsequently analyzed using the Wilcoxon-signed rank test. RESULTS: Of the 16 practicing physicians who participated in the course, 43.8% were certified in Fundamentals of Endoscopic Surgery, and 62.5% had completed > 200 prior upper endoscopies. Upon course completion, scoring on knowledge-based written examinations improved from 3.4 ± 1.9 to 5.8 ± 2.0 (p < 0.001). Technical facility of each participant demonstrated significant overall improvement with post-course score increased from 15.8 ± 2.5 to 23.6 ± 1.6 (p < 0.001), with skill refinement noted in technical subcategories of appropriate instrument use (p < 0.001), foreign body manipulation (p < 0.001), and successful foreign body removal (p < 0.001). Confidence surveys likewise demonstrated significant increase in confidence after completion of the curriculum 11.6 ± 3.4 to 23.0 ± 5.5 (p < 0.001). CONCLUSIONS: The "into the fire" approach to teaching endoscopic foreign body removal utilizing our simulation module provides an effective curriculum to improve knowledge, confidence, and overall technical performance. Our methodology utilizes hands-on, simulation-based pre-testing prior to instruction. This introduces clinical scenarios and technical challenges, while accounting for and tailoring to provider-specific variation in knowledge and experience, facilitating training efficiency.

Identification of 14 novel susceptibility loci for diaphragmatic hernia development and their biological and clinical implications: results from the UK Biobank.

INTRODUCTION: Genetic contributions to hernia development are incompletely understood. This study performed the first comprehensive genome-wide association study (GWAS) for diaphragmatic hernia using a large population-based cohort in the UK Biobank (UKB). METHODS AND PROCEDURES: Two-stage GWAS (discovery and confirmation) was performed for diaphragmatic hernia in the UKB. Briefly, 275,549 and 91,850 subjects were randomly selected for association tests in Stages 1 and 2, respectively. Association tests between 8,568,156 SNPs (genotyped or imputed with MAF > 0.01) in the autosomal genome and diaphragmatic hernia were performed in Stage 1. SNPs with P < 1 × 10-5 were selected for confirmation in Stage 2, and those with P < 0.05 and the same direction of association as Stage 1 were selected for combined association testing; SNPs with combined P < 5 × 10-8 were considered GWAS-significant. LD clumping analysis identified genetically independent chromosomal regions (loci). A genetic risk score (GRS) measured the cumulative risk of independent SNPs in 91,849 additional subjects using odds ratios (ORs) from Stages 1 and 2. RESULTS: 36,351 patients were identified with diaphragmatic hernia (ICD-10 K44). In Stage 1 analysis, 2654 SNPs were associated (P < 1 × 10-5) with diaphragmatic hernia. Stage 2 analysis confirmed 338 SNPs (P < 0.05). In combined analysis, 245 SNPs reached GWAS significance (P < 5 × 10-8). LD clumping analysis revealed 14 independent loci associated with diaphragmatic hernia. Two loci have been previously associated with inguinal hernia at 2p16 (rs181661155) and 11p13 (rs5030123). eQTL analysis suggested genes CRLF1, UBA52, and CALD1 are also significantly associated with these loci. GRS showed significant increase in cases compared to controls (P < 1 × 10-16) and is associated with increased risk of diaphragmatic hernia (P < 1 × 10-7). CONCLUSIONS: We identified 245 SNPs at 14 susceptibility loci associated with diaphragmatic hernia in a large population-based cohort. These results offer insight into pathogenetic mechanisms of diaphragmatic hernia development and may be used in genetic risk scores for pre-operative risk-stratification and clinical prediction models.

Changes in impedance planimetry (EndoFLIP) measurements at follow-up after peroral endoscopic myotomy (POEM).

BACKGROUND: Numerous studies show changes in functional lumen imaging probe (FLIP) measurements after myotomy during peroral endoscopic myotomy (POEM), but few report on FLIP measurements at follow-up esophagogastroduodenoscopy (EGD). The purpose of this study was to compare perioperative FLIP measurements to those at follow-up EGD. METHODS: Patients who underwent POEM with FLIP in the operating room and POEM patients who had EGD with FLIP at follow-up were included. FLIP measurements, including diameter (Dmin), pressure, cross-sectional area (CSA), and distensibility index (DI), were analyzed at a 30-mL balloon fill. Differences between measurements at different timepoints were assessed using a two-tailed Wilcoxon signed-rank test. RESULTS: A total of 97 patients who underwent POEM and 28 who underwent EGD with FLIP were analyzed. The average age was 63 ± 18 years and 46.4% of the patients were male. Mean preoperative Eckardt score was 6.5 ± 4.8, decreasing to 1.6 ± 2.0 at follow-up. EGDs were performed at a median of 15 months after surgery. When compared to mean measurements obtained post-myotomy, at the time of EGD, pressure was found to be significantly lower (p = 0.007) and DI significantly higher (p = 0.045). Of the patients who underwent EGD, 70.8% had an increase in DI, 55.6% had evidence of reflux esophagitis, and 81.0% met diagnostic criteria for reflux on esophageal pH monitoring. However, there was no correlation with the development of esophagitis or reflux and increase or decrease in DI at follow-up. CONCLUSIONS: There are significant changes in FLIP measurements between the time of surgery and at follow-up EGD. These results suggest that esophageal remodeling may cause changes in lower esophageal sphincter geometry after POEM and postoperative FLIP targets immediately post-myotomy may need to be adjusted to account for these changes.

A modular simulation curriculum to teach endoscopic stenting to practicing surgeons: an "Into the fire" approach.

BACKGROUND: Flexible endoscopy is a valuable tool for the gastrointestinal (GI) surgeon, creating a need for effective and efficient training curricula in therapeutic endoscopic techniques for trainees and practicing providers. Here, we present a simulation-based modular curriculum using an "into the fire" approach with hands-on pre- and post-testing to teach endoscopic stenting to practicing surgeons. METHODS: Three advanced flexible endoscopy courses were taught by expert surgical endoscopists from 2018 to 2019. The stenting module involved using self-expandable metal stents to manage simulated esophageal and gastroduodenal strictures on a non-tissue GI model. Based on the educational theories of inquiry-based learning, the simulation curriculum was designed with a series of pre-tests, didactics, mentored hands-on instructions, and post-tests. Assessments included a confidence survey, knowledge-based written test, and evaluation form specific to the hands-on performance of endoscopic stenting. RESULTS: Twenty-eight practicing surgeons with varying endoscopic experiences participated in the course. Most of the participants (67.9%) had completed over 100 upper endoscopic procedures and 57.1% were certified in Fundamentals of Endoscopic Surgery. After completing the modular curriculum, participant confidence survey scores improved from 11.4 ± 4.2 to 20.7 ± 4.0 (p < 0.001). Knowledge-based written test scores also improved from 7.1 ± 1.2 to 8.4 ± 0.9 (p < 0.001). In terms of technical performance, overall hands-on performance scores improved from 21.3 ± 2.7 to 28.9 ± 1.2 (p < 0.001) with significant improvement in each individual component of the assessment (all p values < 0.01) and the greatest improvement seen in equipment handling (88%) and flow of procedure (54%). CONCLUSION: Our modular simulation curriculum using an "into the fire" approach to teach endoscopic stenting is effective in improving learner knowledge, confidence, and hands-on performance of endoscopic stenting. This approach to simulation is effective, efficient, and adaptable to teaching practicing surgeons with varying levels of experience.

Impedance planimetry (EndoFLIP™) reveals changes in gastroesophageal junction compliance during fundoplication.

INTRODUCTION: Compliance is the ability of a hollow organ to dilate and increase volume with an increase in pressure, an accurate representation of food bolus transit through the gastroesophageal junction (GEJ). Impedance planimetry system can calculate compliance (change in volume over pressure) and distensibility (cross-sectional area over pressure) of the GEJ. We aim to describe the changes in compliance during anti-reflux surgery and hypothesize that compliance is a better predictor of patient outcomes than distensibility (DI). METHODS AND PROCEDURES: A review of a prospectively maintained quality database was performed. Patients with FLIP measurements during laparoscopic fundoplication between August 2018 and June 2021 were included. GEJ compliance and DI were measured after hernia reduction, cruroplasty, and fundoplication. Patient-reported outcomes were collected through standardized surveys up to 2 years after surgery. A scatter plot was used to identify a correlation between compliance and DI. Comparisons of measurements between time points were made using paired t-tests. Spearman's correlation coefficients (ρ), Wilcoxon rank-sum, and chi-square tests were used to evaluate associations between measurements and outcomes. RESULTS: One hundred and forty-four patients underwent laparoscopic fundoplication. Compliance is strongly associated with DI (r = 0.96), and a comparison of measurements showed similar trends at specific time points during the operation. After hernia reduction, compliance at the GEJ was 168 ± 74 mm3/mmHg, cruroplasty 79 ± 39 mm3/mmHg, and fundoplication 90 ± 33 mm3/mmHg (all comparisons p < 0.05). GEJ compliance of 80-92 mm3/mmHg after fundoplication was associated with the best patient-reported outcome scores. A compliance of ≤ 79 mm3/mmHg had the highest percentage of patients who reported dysphagia. CONCLUSIONS: Compliance and DI are strongly associated displaying the same directional change during anti-reflux surgery. GEJ compliance of 80-92 mm3/mmHg revealed the best patient-reported outcome scores, and avoiding a compliance ≤ 79 mm3/mmHg may prevent postoperative dysphagia. Therefore, GEJ compliance is an underutilized FLIP measurement warranting further investigation.

Impedance planimetry (EndoFLIP™) after magnetic sphincter augmentation (LINX®) compared to fundoplication.

INTRODUCTION: Functional luminal imaging probe (FLIP) use during laparoscopic fundoplication (LF) for gastroesophageal reflux disease is well described. However, there is a lack of data on FLIP measurements during magnetic sphincter augmentation (MSA). This study aims to report our institutional experience in performing FLIP during MSA and to compare these measurements to those obtained during Nissen and Toupet fundoplication. METHODS AND PROCEDURES: A retrospective review of a prospectively maintained quality database was performed. Patients who underwent MSA or LF and had FLIP measurements between April 2018 and June 2021 were included. FLIP measurements at the gastroesophageal junction (GEJ) were recorded without pneumoperitoneum at 40 mL balloon fill after hernia reduction, cruroplasty, and MSA or fundoplication. Reflux symptom index (RSI), GERD-HRQL, and dysphagia score were collected up to 2 years. Group comparisons were made using two-tailed Wilcoxon rank-sum and χ2 tests, with statistical significance of p < 0.05. RESULTS: Twenty-seven patients underwent MSA and 100 patients underwent LF (66% Toupet, 34% Nissen). Type III hiatal hernia was present in 3.7% of MSA patients versus over 50% for fundoplication patients. Minimum diameter, cross-sectional area, and distensibility index (DI) were lower after MSA device placement compared to Nissen or Toupet fundoplication (p < 0.05). Postoperative follow-up showed no differences in RSI, GERD-HRQL, and dysphagia score between MSA and Nissen fundoplication (p > 0.05). CONCLUSION: Intraoperative impedance planimetry provided objective information regarding the geometry of the GEJ during MSA. The ring of magnetic beads restores the anti-reflux barrier and transiently opens with food bolus and belching. The magnetic force of the beads may explain why the DI after MSA is lower yet postoperative quality of life is no different than Nissen fundoplication.

Patient-reported bowel and bladder function is not adversely impacted by bariatric surgery.

INTRODUCTION: This study aims to assess the effect of bariatric surgery on patient-reported outcomes of bowel and bladder function. We hypothesized that bariatric surgery does not worsen bowel and bladder function. METHODS AND PROCEDURES: A retrospective review was conducted of a prospectively maintained surgical quality database. We included patients who underwent primary bariatric surgery at a single institution between 2012 and 2020, excluding revisional procedures. Patient-reported outcomes were assessed using Surgical Outcomes Measurement System (SOMS) bowel and bladder function questionnaires at time of pre-operative consult and routine post-operative follow-up visits through 2 years. Data were analyzed using a statistical mixed effects model. RESULTS: 573 patients (80.6% female) were identified with completed SOMS questionnaire data on bowel and bladder function. Of these, 370 (64.6%) underwent gastric bypass, 190 (33.2%) underwent sleeve gastrectomy, and 13 (2.3%) underwent either gastric banding or duodenal switch. Compared to pre-operative baseline scores, patients reported a transient worsening of bowel function at 2-weeks post-op (p = 0.009). However, by 3-months post-op, bowel function improved and was significantly better than baseline (p = 0.006); this improvement was sustained at every point through 2-year follow-up (p = 0.026). Bladder function scores improved immediately at 2-weeks post-op (p = 0.026) and showed sustained improvement through 1-year follow-up. On subgroup analysis, sleeve patients showed greater improvement in bowel function than bypass patients at 1-year (p = 0.031). Multivariable analysis showed significant improvement in bowel function associated with greater total body weight loss (TBWL) (p = 0.002). CONCLUSIONS: Bariatric surgery does not worsen patient-reported bowel or bladder function. In fact, there is overall improvement from pre-operative scores for both bowel and bladder function by 3-months post-op which is sustained through 2-year and 1-year follow-up, respectively. Most encouragingly, a greater TBWL is significantly associated with improved bowel function after bariatric surgery.

Associations of amyloid and neurodegeneration plasma biomarkers with comorbidities.

INTRODUCTION: Blood-based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect the levels of these markers. METHODS: Plasma markers (Aß42, Aß40, NfL, T-tau, Aß42/40 ratio) were measured on the Quanterix Simoa HD-1 analyzer for 996 Mayo Clinic Study of Aging (MCSA) participants, aged 51 to 95 years. All other data were collected during in-person MCSA visits or abstracted from the medical record. RESULTS: Among cognitively unimpaired (CU) participants, all plasma markers correlated with age. Linear regression models revealed multiple relationships. For example, higher Charlson Comorbidity Index and chronic kidney disease were associated with higher levels of all biomarkers. Some relationships differed between mild cognitive impairment and dementia participants. DISCUSSION: Multiple variables affect plasma biomarkers of amyloid pathology and neurodegeneration among CU in the general population. Incorporating this information is critical for accurate interpretation of the biomarker levels and for the development of reference ranges.

Profile of women with pelvic organ prolapse at the University Hospital of the West Indies risk factors and presentation.

POP affected 40% of participants in the WHI trial. Risk factors include parity, vaginal delivery, large babies, advancing age, obesity, hysterectomy and lifting. Data suggest African-American women have a lower prevalence of symptomatic POP than other racial groups. Literature review did not show a study of risk factors and symptoms in a black population. Cross-sectional study of women with POP attending urogynaecology clinic at the UHWI from May to October 2013, using an interviewer administered questionnaire was performed and analysed using SPSS version 19 program (SPSS Inc., Chicago, IL). One hundred and eight participants were included: 94.7% postmenopausal (mean 65.08 years) and 94.5% parous (mean 4). Risk factors included obesity (mean BMI 28.82 kg/m2), hysterectomy (28.7%), heavy lifting (51.9%) and chronic cough (13.9%). Symptoms included stress incontinence (40.7%), stranguria (16.7%), faecal incontinence (13.9%), constipation (31.5%), coital urinary and faecal incontinence (6.3%, 12.6%). We concluded risk factors for POP in this population correlates with other studies. Stress urinary incontinence and constipation most frequently reported symptoms in this population.Impact StatementWhat is already known on this subject? Pelvic organ prolapse (POP) is a common condition with multifactorial aetiology. As seen in systematic reviews (Vergeldt TFM, Weemhoff M, IntHout J, Kluivers KB. 2015. Risk factors for pelvic organ prolapse and its recurrence: a systematic review. International Urogynecology Journal 26(11):1559-1573). Study shows white women appeared to have more overall symptoms both from prolapse, as well as urinary symptoms, as compared with black women (Ford AT, Eto CU, Smith M, Northington GM. 2019. Racial differences in pelvic organ prolapse symptoms among women undergoing pelvic reconstructive surgery for prolapse. Female Pelvic Medicine & Reconstructive Surgery 25:130-133).What do the results of this study add? The result highlights the fact that Black women are exposed to similar risk factors and have similar symptoms to other racial groups for POP.What are the implications of these findings for clinical practice and/or further research? These findings can be used to educate women with risk factors about the possibility of developing symptomatic POP. Further research is needed to ascertain the prevalence of POP and to assess knowledge and attitude in this population as we hypothesise that there is generalised assumption in that being black is protective from POP.

Public-private partnerships in transplant drug development.

The Transplant Therapeutics Consortium (TTC), a public-private partnership (PPP) led by the Critical Path Institute (C-Path), recently published a whitepaper titled "The Importance of Drug Safety and Tolerability in the Development of New Immunosuppressive Therapy for Transplant Recipients" by Stegall et al in the American Journal of Transplantation. As staff members of the Food and Drug Administration's (FDA), Center for Drug Evaluation and Research (CDER), Office of New Drugs and Office of Translational Science, and the Oncology Center of Excellence, we would like to provide our perspective on the TTCs efforts and the whitepaper.

Informing the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop.

The US Food and Drug Administration and the Critical Path Institute's Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug's overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics.

Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation.

Cellular stresses activate the tumor suppressor p53 protein leading to selective binding to DNA response elements (REs) and gene transactivation from a large pool of potential p53 REs (p53REs). To elucidate how p53RE sequences and local chromatin context interact to affect p53 binding and gene transactivation, we mapped genome-wide binding localizations of p53 and H3K4me3 in untreated and doxorubicin (DXR)-treated human lymphoblastoid cells. We examined the relationships among p53 occupancy, gene expression, H3K4me3, chromatin accessibility (DNase 1 hypersensitivity, DHS), ENCODE chromatin states, p53RE sequence, and evolutionary conservation. We observed that the inducible expression of p53-regulated genes was associated with the steady-state chromatin status of the cell. Most highly inducible p53-regulated genes were suppressed at baseline and marked by repressive histone modifications or displayed CTCF binding. Comparison of p53RE sequences residing in different chromatin contexts demonstrated that weaker p53REs resided in open promoters, while stronger p53REs were located within enhancers and repressed chromatin. p53 occupancy was strongly correlated with similarity of the target DNA sequences to the p53RE consensus, but surprisingly, inversely correlated with pre-existing nucleosome accessibility (DHS) and evolutionary conservation at the p53RE. Occupancy by p53 of REs that overlapped transposable element (TE) repeats was significantly higher (p<10-7) and correlated with stronger p53RE sequences (p<10-110) relative to nonTE-associated p53REs, particularly for MLT1H, LTR10B, and Mer61 TEs. However, binding at these elements was generally not associated with transactivation of adjacent genes. Occupied p53REs located in L2-like TEs were unique in displaying highly negative PhyloP scores (predicted fast-evolving) and being associated with altered H3K4me3 and DHS levels. These results underscore the systematic interaction between chromatin status and p53RE context in the induced transactivation response. This p53 regulated response appears to have been tuned via evolutionary processes that may have led to repression and/or utilization of p53REs originating from primate-specific transposon elements.

RNA-Seq analysis of seasonal and individual variation in blood transcriptomes of healthy managed bottlenose dolphins.

BACKGROUND: The blood transcriptome can reflect both systemic exposures and pathological changes in other organs of the body because immune cells recirculate through the blood, lymphoid tissues, and affected sites. In human and veterinary medicine, blood transcriptome analysis has been used successfully to identify markers of disease or pathological conditions, but can be confounded by large seasonal changes in expression. In comparison, the use of transcriptomic based analyses in wildlife has been limited. Here we report a longitudinal study of four managed bottlenose dolphins located in Waikoloa, Hawaii, serially sampled (approximately monthly) over the course of 1 year to establish baseline information on the content and variation of the dolphin blood transcriptome. RESULTS: Illumina based RNA-seq analyses were carried out using both the Ensembl dolphin genome and a de novo blood transcriptome as guides. Overall, the blood transcriptome encompassed a wide array of cellular functions and processes and was relatively stable within and between animals over the course of 1 year. Principal components analysis revealed moderate clustering by sex associated with the variation among global gene expression profiles (PC1, 22 % of variance). Limited seasonal change was observed, with < 2.5 % of genes differentially expressed between winter and summer months (FDR < 0.05). Among the differentially expressed genes, cosinor analysis identified seasonal rhythmicity for the observed changes in blood gene expression, consistent with studies in humans. While the proportion of seasonally variant genes in these dolphins is much smaller than that reported in humans, the majority of those identified in dolphins were also shown to vary with season in humans. Gene co-expression network analysis identified several gene modules with significant correlation to age, sex, or hematological parameters. CONCLUSIONS: This longitudinal analysis of healthy managed dolphins establishes a preliminary baseline for blood transcriptome analysis in this species. Correlations with hematological parameters, distinct from muted seasonal effects, suggest that the otherwise relatively stable blood transcriptome may be a useful indicator of health and exposure. A robust database of gene expression in free-ranging and managed dolphins across seasons with known adverse health conditions or contaminant exposures will be needed to establish predictive gene expression profiles suitable for biomonitoring.

Ultrasound Assessment of Abdominal Muscle Thickness in Postpartum vs Nulliparous Women.

OBJECTIVE: The purpose of this study was to determine the effect size in measurable change of abdominal musculature morphology using ultrasonography in postpartum women within 1 month of a healthy, vaginal delivery. METHODS: One hundred fifty-six participants were recruited for this study. B-mode ultrasound imaging was used to measure abdominal muscle thickness on 80 nulliparous women and 76 mothers who had delivered within the past 4 weeks. Measures were taken for the upper and lower rectus abdominus, external and internal obliques, and transversus abdominus at rest. RESULTS: Statistically significant differences were found in the thickness of the rectus abdominus muscle at both sites; upper (P < .0001) and lower (P < .0001) as well as the internal oblique (P < .0001). All 3 muscles were thinner in postpartum participants (8.29 ± 1.83 mm, 8.89 ± 2.29 mm, and 7.06 ± 1.82 mm, respectively) within the first month of delivery than in controls (10.82 ± 1.93 mm, 11.13 ± 2.38 mm, and 8.36 ± 1.87 mm, respectively). Large effect sizes were found for the influence of pregnancy on the rectus muscle segments (1.35 for the upper rectus abdominus and 1.00 for the lower rectus abdominus) and a medium effect size for the internal oblique (0.71). No significant differences were observed in the remaining 2 muscles. CONCLUSION: This study showed that there are differences in morphology of the abdominal muscles in pregnant women vs nonpregnant controls. The large effect sizes reported may provide the basis for future studies examining relationships between morphology, functional change, and back pain during pregnancy.