Effects of diet and antibiotics on anastomotic healing: A mouse model study with varied dietary fiber and fat, and pre-operative antibiotics.

INTRODUCTION: This study investigated the separate impacts of diet and pre-operative antibiotics on gut microbiome and colonic anastomotic healing using a mouse model. METHODS: Male C57BL/6J mice were fed either low-fat-high-fibre (SD) or high-fat-low-fiber (WD) groups for 6 weeks, then further received either pre-operative antibiotics or a control sham before a colonic anastomotic procedure was performed. After 7 days, the anastomosis was assessed and microbiota composition and biodiversity were analyzed in anastomotic tissue and stool. RESULTS: WD-fed mice had shorter survival (5.2 â€‹± â€‹2.3 vs. 6.9 â€‹± â€‹2.3 days, p â€‹= â€‹0.022), increased weight loss (5.55 â€‹± â€‹3.80g vs. 2.65 â€‹± â€‹2.36g, p â€‹= â€‹0.03), and reduced biodiversity compared to SD-fed mice. Pre-operative antibiotics improved anastomotic healing scores (1.33 â€‹± â€‹0.65 vs. 2.08 â€‹± â€‹0.79, p â€‹= â€‹0.02) and reduced Enterococcus faecalis growth in tissue and stool (p â€‹= â€‹0.02, p â€‹= â€‹0.02). Improved anastomotic healing correlated with lower Enterococcus abundance (p â€‹= â€‹0.04) and higher collagen III and IV levels (p â€‹= â€‹0.01, 0.04) in anastomotic tissue. CONCLUSION: SD promotes enhanced post-operative recovery and increased microbiome biodiversity, while pre-operative antibiotics enhance anastomotic healing by suppressing Enterococcus faecalis growth, mitigating collagen III/IV degradation.

Screening for asymptomatic nephrolithiasis in primary hyperparathyroidism patients is warranted.

BACKGROUND: We aimed to investigate the prevalence, characteristics, and management of nephrolithiasis in primary hyperparathyroidism (PHPT) patients. METHODS: Medical records of patients who underwent parathyroidectomy at a tertiary care hospital in British Columbia from January 2016 to April 2023 were retrospectively reviewed. Demographic data, laboratory results, imaging reports, and urologic consultations were examined. Descriptive statistics and relevant statistical tests, including logistic regressions, were utilized for data analysis. RESULT: Of the 413 PHPT patients included in the study population, 41.9% harbored renal stones, and nearly half (48.6%) required urological interventions. Male sex, elevated preoperative serum ionized calcium (iCa) and 24-h urinary calcium (24 â€‹h urine Ca) levels were independent risk factors for stone formation. Additionally, male sex, younger age, and lower preoperative serum 25-hydroxyvitamin D (25(OH)D) level were associated with higher odds of requiring urological intervention for stones. CONCLUSIONS: This study identified significant prevalence of asymptomatic renal calcifications in PHPT patients, with a substantial proportion necessitating urological intervention. These findings emphasize the importance of incorporating screening and treatment of renal stones into the management of PHPT patients.

Disparities in Genetic Testing for Neurologic Disorders.

BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.

An examination of rectal prolapse surgery patients' quality of life and symptoms using patient-reported outcome instruments: A prospective cohort study.

BACKGROUND: We measured changes in self-reported health and symptoms attributable to rectal prolapse surgery using patient-reported outcome (PRO) measures. METHODS: A prospectively recruited cohort of patients scheduled for rectal prolapse repair in Vancouver, Canada between 2013 and 2021 were surveyed before and 6-months after surgery using seven PROs: the EuroQol Five-Dimension Instrument (EQ-5D-5L), Generalized Anxiety Disorder Scale (GAD-7), Pain Intensity, Interference with Enjoyment of Life and General Activity (PEG), Patient Health Questionnaire (PHQ-9), Fecal Incontinence Severity Index (FISI), Gastrointestinal Quality of Life Index (GIQLI), and the Fecal Incontinence Quality of Life Scale (FIQL). RESULTS: We included 46 participants who reported improvements in health status (EQ-5D-5L; p â€‹< â€‹0.01), pain interference (PEG; p â€‹< â€‹0.01), depressive symptoms (PHQ-9; p â€‹= â€‹0.01), fecal incontinence severity (FISI; p â€‹< â€‹0.01), gastrointestinal quality of life (GIQLI; p â€‹< â€‹0.01), and fecal incontinence quality of life (FIQL) related to lifestyle (p â€‹= â€‹0.02), coping and behaviour (p â€‹= â€‹0.02) and depression and self-perception (p â€‹= â€‹0.01). CONCLUSION: Surgical repair of rectal prolapse improved patients' quality of life with meaningful improvements in fecal incontinence severity and pain, and symptom interference with daily activities.

The Importance of Offering Exome or Genome Sequencing in Adult Neuromuscular Clinics.

Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.

A Case of Long-Tract Ileocolic Intussusception Secondary to Well-Differentiated Cecal Adenocarcinoma.

Intussusception denotes the intricate phenomenon wherein one segment of the bowel undergoes invagination or telescoping into its contiguous distal segment. The ensuing invaginated segment may be propelled forward through peristaltic movements, potentially precipitating bowel obstruction or ischemia, culminating in necrosis of the affected bowel segment. Although the precise etiology of intussusception remains elusive, particularly in cases devoid of an identifiable lead point, dysrhythmic contractions and lymphoid hyperplasia have been implicated in the pathophysiology of this condition. We present the case of an 86-year-old African American female with a past medical history of hypertension and asthma who presented to our emergency room with a seven-day history of worsening abdominal. The pain was described as sharp and intermittent, and it would worsen with every meal or drink. A physical exam demonstrated the right lower quadrant with vague abdominal tenderness, especially below the umbilical region. Computed tomography of the abdomen and pelvis revealed a long segment of ileocolic obstructing intussusception in the ascending colon, with a 2.6 cm solid mass serving as a lead point. Swift intervention ensued with an urgent exploratory laparotomy, culminating in a right hemicolectomy to excise the intussuscepted segment of the bowel. The pathological examination identified a well-differentiated adenocarcinoma of the cecum, categorized as T1N0M0, with all 20 resected lymph nodes yielding negative results. This illustrative case presents a unique insight into a patient with ileocolic obstructing intussusception, caused by a well-differentiated adenocarcinoma acting as the lead point, a relatively uncommon occurrence in adults. Diagnosing intussusception in adults is challenging due to its nonspecific symptoms, which are similar to those of various other gastrointestinal disorders. Therefore, it is crucial for medical providers to be acutely aware of the possibility that adenocarcinoma can trigger obstructing intussusception in various parts of the bowel.

Inferring compound heterozygosity from large-scale exome sequencing data.

Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

Genetic testing in adults with neurologic disorders: indications, approach, and clinical impacts.

The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.

Polygenic burden of short tandem repeat expansions promote risk for Alzheimer's disease.

Studies of the genetics of Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most of the disease heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms of genetic variation. There are over one million short tandem repeats (STRs) in the genome, and their link to AD risk has not been assessed. As pathogenic expansions of STR cause over 30 neurologic diseases, it is important to ascertain whether STRs may also be implicated in AD risk. Here, we genotyped 321,742 polymorphic STR tracts genome-wide using PCR-free whole genome sequencing data from 2,981 individuals (1,489 AD case and 1,492 control individuals). We implemented an approach to identify STR expansions as STRs with tract lengths that are outliers from the population. We then tested for differences in aggregate burden of expansions in case versus control individuals. AD patients had a 1.19-fold increase of STR expansions compared to healthy elderly controls (p=8.27×10-3, two-sided Mann Whitney test). Individuals carrying > 30 STR expansions had 3.62-fold higher odds of having AD and had more severe AD neuropathology. AD STR expansions were highly enriched within active promoters in post-mortem hippocampal brain tissues and particularly within SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate that expanded STRs within active promoter regions of the genome promote risk of AD.

Factors Influencing Recurrence in Medial Breast Cancer Tumors After Skin Sparing Mastectomy and Immediate Breast Reconstruction.

BACKGROUND: Skin sparing mastectomy (SSM) with immediate breast reconstruction (IBR) has been established as a safe option for curative-intent surgical resection. Prior studies have shown that medial location of the primary tumor is associated with increased risk of local recurrence. The purpose of this study is to determine the factors associated with recurrence and survival in individuals with breast cancers located in the inner quadrants (medial) who underwent SSM with IBR. METHODS: A retrospective chart review was done on individuals with medial breast cancer who received SSM with IBR in British Columbia between 1980 and 2012. RESULTS: Of 136 individuals with medial breast cancer undergoing SSM with IBR, 27.9% experienced local recurrence and 42.6% overall recurrence. Factors associated with recurrence were T-stage (44.8 vs. 22.4% with T2 disease, P = .02), transverse rectus abdominis muscle (TRAM) flap reconstruction (48.3 vs. 29.5%, P = .00395), prior breast surgery (87.9 vs. 63%, P = .002), and prior radiation therapy (74.1 vs. 38.5%, P < .0001). LR was associated with higher mortality (OR 2.78, 95% CI: 1.26-6.09). CONCLUSION: For patients with medial tumors undergoing SSM with IBR, potential risk factors for recurrence are T-stage, TRAM flap reconstruction, prior breast surgery, and prior radiation therapy. Local recurrence is associated with poor survival.

OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity.

Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1-/- embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

Inferring compound heterozygosity from large-scale exome sequencing data.

Recessive diseases arise when both the maternal and the paternal copies of a gene are impacted by a damaging genetic variant in the affected individual. When a patient carries two different potentially causal variants in a gene for a given disorder, accurate diagnosis requires determining that these two variants occur on different copies of the chromosome (i.e., are in trans) rather than on the same copy (i.e. in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. We developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in exome sequencing data from the Genome Aggregation Database (gnomAD v2, n=125,748). When applied to trio data where phase can be determined by transmission, our approach estimates phase with 95.7% accuracy and remains accurate even for very rare variants (allele frequency < 1×10-4). We also correctly phase 95.9% of variant pairs in a set of 293 patients with Mendelian conditions carrying presumed causal compound heterozygous variants. We provide a public resource of phasing estimates from gnomAD, including phasing estimates for coding variants across the genome and counts per gene of rare variants in trans, that can aid interpretation of rare co-occurring variants in the context of recessive disease.

Long-term effect of childhood pandemic experience on medical major choice: Evidence from the 2003 severe acute respiratory syndrome outbreak in China.

This study examines the long-term effect of a pandemic on a crucial human capital decision, namely college major choice. Using China's 2008-2016 major-level National College Entrance Examination (Gaokao) entry grades, we find that the 2003 severe acute respiratory syndrome (SARS) had a substantial deterrent effect on the choice of majoring in medicine among high school graduates who experienced the pandemic in their childhood. In provinces with larger intensities of SARS impact, medical majors become less popular as the average Gaokao grades of enrolled students decline. Further evidence from a nationally representative survey shows that the intensity of the SARS impact significantly decreases children's aspirations to pursue medical occupations, but does not affect their parents' expectations for their children to enter the medical profession. Our discussion on the effect mechanism suggests that the adverse influence of SARS on the popularity of medical majors likely originates from students' childhood experiences.

Use of dual energy computed tomography versus conventional techniques for preoperative localization in primary hyperparathyroidism: Effect of preoperative calcium and parathyroid hormone levels.

BACKGROUND: We aimed to investigate the association of preoperative calcium and parathyroid hormone (PTH) levels with sensitivity and accuracy of dual energy computed tomography (DECT), single-photon emission CT with 99mTc-sestamibi (CT-MIBI), and ultrasound (US) for pre-operative localization primary hyperparathyroid (PHP) patients. METHODS: Patients undergoing parathyroidectomy for PHP at a tertiary care facility who underwent DECT, CT-MIBI and US between 2012 and 2021 were stratified by preoperative calcium and PTH levels. RESULTS: Of 278 patients, those with high calcium and PTH levels had a higher sensitivity and accuracy with DECT (87.7%, 85.2%) compared to CT-MIBI (82.3%, 79.0%), and US (61.7%, 53.1%). DECT was more sensitive and accurate than other preoperative localization techniques in subgroups with normal PTH (DECT sensitivity 60.9%, accuracy 52.1%) and normal calcium levels (41.7%, 33.3%). CONCLUSION: Preoperative calcium and PTH were associated with sensitivity and accuracy of pre-operative localization in PHP. DECT was sensitive and accurate for preoperative localization compared to other first-line imaging techniques.

Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. RESULTS: We utilize chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We find that CD4 T and B cells are independently enriched for MS genetics and further refine the driver subsets to Th17 and memory B cells, respectively. We replicate our findings in data from untreated and treated MS patients and find that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominate numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. CONCLUSIONS: Overall, our study finds that open chromatin regions in CD4 T cells and B cells independently drive MS genetic signals. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.

Prioritization of autoimmune disease-associated genetic variants that perturb regulatory element activity in T cells.

Genome-wide association studies (GWASs) have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variants within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naive CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness and, upon acute viral infection, displayed greater propensity to become effector T cells. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.

Prioritization and surgical wait lists: A cross-sectional survey of patient's health-related quality of life.

INTRODUCTION: In many countries, there are waits for elective (planned) surgery. In these settings, processes for triaging patients are applied to determine how long patients wait for their surgery. There are very few instances that evaluate the effectiveness of surgical triage processes. METHODS: A sample of patients from four acute care hospitals in Vancouver, Canada, completed a number of patient-reported outcomes shortly after being registered on the surgical wait list. Patients' diagnosis was used to triage and determine their expected wait for surgery. The associations between patient-reported outcomes with surgical triage were measured. RESULTS: The mean wait times for participants were similar across wait times categories. Participants whose expected waits for surgery were the longest reported successively lower levels of self-rated health (p < 0.01) and successively higher levels of pain (p < 0.01.) There was no difference in symptoms of anxiety among participants expected to wait the longest. DISCUSSION: The diagnosis-based system for prioritizing patients found higher levels of pain and lower health status among those expected to wait the longest for their surgery. Screening waiting patients for treatable mental health conditions should be implemented and the process of surgical triage could be redesigned to allow for a broader set of attributes of health to determine how long a patient waits for their elective surgery.