Opportunities and challenges for the use of common controls in sequencing studies.

Genome-wide association studies using large-scale genome and exome sequencing data have become increasingly valuable in identifying associations between genetic variants and disease, transforming basic research and translational medicine. However, this progress has not been equally shared across all people and conditions, in part due to limited resources. Leveraging publicly available sequencing data as external common controls, rather than sequencing new controls for every study, can better allocate resources by augmenting control sample sizes or providing controls where none existed. However, common control studies must be carefully planned and executed as even small differences in sample ascertainment and processing can result in substantial bias. Here, we discuss challenges and opportunities for the robust use of common controls in high-throughput sequencing studies, including study design, quality control and statistical approaches. Thoughtful generation and use of large and valuable genetic sequencing data sets will enable investigation of a broader and more representative set of conditions, environments and genetic ancestries than otherwise possible.

Urodynamic insights: exploring the relationship between detrusor overactivity and pelvic organ prolapse in women with urge incontinence.

PURPOSE: Pelvic organ prolapse (POP) and overactive bladder (OAB) commonly affect the aging female population. We aimed to investigate the possible relationship between the two, as reflected by urodynamic studies. METHODS: A retrospective analysis was conducted on women who underwent urodynamic studies at a university-affiliated tertiary medical center from January 2018 to January 2021. Women presenting with urge incontinence and diagnosed with detrusor overactivity (DO) were included in the study. Based on the presence or absence of a modified POP-Q ≥ grade 2, these women were categorized into two groups. Data on general demographics, clinical symptoms, and urodynamic findings were extracted and compared using SPSS. RESULTS: During the study period, 949 urodynamic evaluations were performed. Of these, 303 (31.92%) reported urge incontinence. Out of this subset, 151 (49.83%) were diagnosed with DO. Within this group, 18 (11.9%) had POP, while 134 (88.1%) did not. The POP group had a notably higher incidence of prior vaginal hysterectomy and anterior colporrhaphy (p = 0.02 and p = 0.01, respectively). While most urodynamic parameters were similar between groups, there was a significant increase in hesitancy in the POP group (13 s vs 8 s, p = 0.03). There was a trend indicating a reduced median Q max (12 ml/s vs. 18 ml/s, p = 0.06) and an increased flow time (55 s vs 40 s, p = 0.08) in the POP group. CONCLUSION: The urodynamic profile of the POP group suggests an obstructive voiding pattern. Further longitudinal research is essential to fully understand the relationship between POP and OAB.

Enteral nutrition optimization program for children undergoing blood & marrow transplantation: A quality improvement project.

BACKGROUND: Malnutrition in children and young adults undergoing blood and marrow transplantation (BMT) increases morbidity and mortality. Addressing this via optimization of enteral nutrition can potentially improve outcomes. METHODS: This Quality Improvement project utilized pre-post-intervention design and post-intervention survey to evaluate a novel program optimizing enteral nutrition support in children undergoing BMT. All patients aged 0-18 who were admitted during the 16-week implementation period followed the Enteral Nutrition Optimization Program from pre-BMT through discharge. Data on biometric indicators, complications, and post-transplant milestone time markers were evaluated via Mann-Whitney U, Fisher's exact, and Chi-square tests as indicated using SPSS™ Version 27. A separate sample of clinical providers completed a post-intervention survey to evaluate the feasibility and acceptance of the intervention. FINDINGS: Six patients received the intervention, with 12 patients evaluated. There were no statistical differences between groups on measured evaluations of weight loss (0.15 kg vs +0.4 kg, p = 0.39), malnutrition (2 vs 3, p = 0.545), graft-versus-host-disease (2 vs 2, p = 1), time to engraftment (platelets day 22 vs 20.5, p = 0.589), infections (p = 0.368), and length of stay (32.5 days vs 31 days, p = 1). The provider sample of 45 participants showed overall feasibility and acceptance of the intervention (88.9% agreed or strongly agreed). DISCUSSION: Feasibility and acceptance were high, resulting in increased use of nasogastric and gastrostomy tubes. Though no clinical significance, interpretation is limited due to the small sample size. PRACTICE IMPLICATIONS: Implementing a novel nutritional support program resulted in a culture shift towards enteral nutrition optimization. Further studies are needed to determine clinical impacts.

Implementation, Reach, and Effectiveness of the Direct Observation of Residents in Clinic Program.

BACKGROUND: Direct observation is important, yet medical residents are rarely observed. We implemented and evaluated a direct observation program in resident clinics to increase the frequency of observation and feedback and improve perceptions about direct observation. METHODS: We assigned faculty as observers in our resident clinics between June 2019 and February 2020. We surveyed residents and faculty before and after the program. Faculty completed a form for each observation performed. We analyzed surveys to examine changes in barriers, frequency and type of observations and feedback, and attitudes toward observation. The analytical sample included 38 and 37 pre- and postresident surveys, respectively, and 20 and 25 pre- and postfaculty surveys, respectively. RESULTS: Resident survey response rates were 32.3% (40/124) pre- and 30.7% (39/127) postintervention. Most residents (76% [pre], 86% [post], P = 0.258) reported being observed in at least one of the four areas: history, examination, counseling, or wrap-up. We received observation tracking forms on 68% of eligible residents. Observed history taking increased from 30% to 79% after the program (P = 0.0010). Survey response rates for faculty were 64.7% (22/34) pre- and 67.5% (25/37) postintervention. Fewer faculty reported time (80% [pre], 52% [post], P = 0.051) and competing demands (65% [pre], 52% [post], P = 0.380) as barriers postintervention. Fewer faculty postintervention viewed observation as a valuable teaching tool (100% [pre], 79% [post], P = 0.0534). All faculty who did not view observation as valuable were the least experienced. DISCUSSION: Assigning faculty as observers can increase observation, especially in history taking, though data suggest an increase in negative perceptions of observation by faculty.

Body-composition phenotypes and their associations with cardiometabolic risks and health behaviours in a representative general US sample.

Body mass index is poor at distinguishing between adiposity and muscle. Based on dual energy X-ray absorptiometry data, a diagnostic framework to analyze body composition by categorizing fat- and muscle-mass body composition into four phenotypes has been proposed. The objective of this study was to assess the association between body-composition phenotypes with adiposity measures, health behaviours and cardiometabolic risks in a representative U.S. adult population. Data were from NHANES (1999-2006: n = 9867; 2011-2018: n = 10,454). Four phenotypes based on being above/below the 50th percentile of age- and sex- adjusted reference curves of fat-mass and muscle-mass were identified. Multiple linear and logistic regressions were used to assess phenotypes (high [H] or low [L] adiposity [A] or muscle mass [M]) against adiposity measures, health behaviours, cardiometabolic risk, and dietary intake. Low-adiposity/high-muscle (LA-HM) was the referent. Analyses incorporated the complex sampling design and survey weights, and were adjusted for age, sex, race, and education. Compared to the LA-HM reference group, the HA-LM phenotype was less physically active, had higher total and lower high-density lipoprotein cholesterol, and had lower intake of all examined nutrients (all p < 0.01). For the HA-HM phenotype, unfavourable values were detected for all adiposity and cardiometabolic measures compared to the LA-HM phenotype (all p < 0.01). The two high adiposity phenotypes were associated with poorer health behaviours and cardiovascular risk factors, regardless of muscle-mass, but associations differed across the phenotypes. Results further underscores the importance of accounting for both adiposity and muscle mass in measurement and analysis. Further longitudinal investigation is needed.

A reliable, reproducible flow cytometry protocol for immune cell quantification in human adipose tissue.

The ability to accurately identify and quantify immune cell populations within adipose tissue is important in understanding the role of immune cells in metabolic disease risk. Flow cytometry is the gold standard method for immune cell quantification. However, quantification of immune cells from adipose tissue presents a number of challenges because of the complexities of working with an oily substance and the rapid deterioration of immune cell viability before analysis can be performed. Here we present a highly reproducible flow cytometry protocol for the quantification of immune cells in human adipose tissue, which overcomes these issues.

Reporting Outcomes and Outcome Measures in Thumb Carpometacarpal Joint Osteoarthritis: A Systematic Review.

PURPOSE: In the thumb carpometacarpal (CMC) joint osteoarthritis (OA) literature, there is substantial heterogeneity in outcome and outcome measure reporting. This could be rectified by a standardized core outcome set (COS). This study aimed to identify a comprehensive list of outcomes and outcome measures for thumb CMC joint OA, which represents the first step in developing a COS. METHODS: A computerized search of MEDLINE, EMBASE, Cochrane, and CINAHL was performed to identify randomized controlled trials, as well as observational studies involving at least 50 participants aged greater than 18 years undergoing surgery for thumb CMC joint OA. Reported outcomes and outcome measures were extracted from these trials and summarized. RESULTS: This search yielded 3,498 unique articles, 97 of which were used for analysis. A total of 33 unique outcomes and 25 unique outcome measures were identified. The most frequently used outcomes were complications (78), postoperative pain (73), radiologic outcomes (64), and grip strength (63). Within each reported outcome, there was substantial variation in how the outcome was measured. Of the 25 unique outcome measures, 10 were validated. Of the remaining 15, 12 were created ad hoc by the author. The Disabilities of the Arm, Shoulder, and Hand questionnaire was the most commonly reported outcome measure (34%). CONCLUSIONS: There is a lack of consensus on critical outcomes after surgery for thumb CMC joint OA. A standardized COS created by stakeholder consensus would improve the consistency and therefore the quality of future research. CLINICAL RELEVANCE: This systematic review of outcomes represents the first step in developing a core outcome set for thumb CMC joint OA.

Reporting Outcomes and Outcome Measures in Cubital Tunnel Syndrome: A Systematic Review.

PURPOSE: Comparison between studies assessing outcomes after surgical treatment of cubital tunnel syndrome (CuTS) has proven to be difficult owing to variations in outcome reporting. This study aimed to identify outcomes and outcome measures used to evaluate postoperative results for CuTS. METHODS: We performed computerized database searches of MEDLINE and EMBASE. Studies with 20 or more patients aged 18 and older who were undergoing medial epicondylectomy, endoscopic decompression, open simple decompression, or decompression with subcutaneous, submuscular, or intramuscular transposition for ulnar neuropathy at the elbow were included. Outcomes and outcome measures were extracted and tabulated. RESULTS: Of the 101 studies included, 45 unique outcomes and 31 postoperative outcome measures were identified. These included 7 condition-specific, clinician-reported instruments; 4 condition-specific, clinician-reported instruments; 8 patient-reported, generic instruments; 11 clinician-generated instruments; and one utility measure. Outcome measures were divided into 6 unique domains. Overall, 60% of studies used condition-specific outcome measures. The frequency of any condition-specific outcome measure ranged from 1% to 37% of included studies. CONCLUSIONS: There is marked heterogeneity in outcomes and outcome measures used to assess CuTS. A standardized core outcome set is needed to compare results of various techniques of cubital tunnel decompression. CLINICAL RELEVANCE: This study builds on the existing literature to support the notion that there is marked heterogeneity in outcomes and outcome measures used to assess CuTS. The authors believe that a future standardized set of core outcomes is needed to limit heterogeneity among studies assessing postoperative outcomes in CuTS to compare these interventions more easily and pool results in the form of systematic reviews and meta-analyses.

Pregnancy and parental leave among plastic surgery residents in Canada: a nationwide survey of attitudes and experiences.

SUMMARY: Small surgical residency programs like plastic surgery can be challenging environments to accommodate parental leave. This study aimed to report the experiences, attitudes and perceived support of Canadian plastic surgery residents, recent graduates and staff surgeons with respect to pregnancy and parenting during training. Residents and staff surgeons were invited via email to participate in an online survey. The results presented here explore experiences of pregnancy and parental leave of current plastic surgery residents and staff surgeons. Residents' and staff surgeons' perceptions of program director support, policies, negative comments and the impact of parental leave on the workload of others were also explored. Although the findings suggest that there may be improvements in the support of program directors, there continues to be a negative attitude in surgical culture toward pregnancy during residency. The perceived confusion of respondents with respect to programspecific policies emphasizes the need for open conversations and standardization of parental leave.

Outcomes and Outcome Measures in Breast Reduction Mammaplasty: A Systematic Review.

BACKGROUND: Reduction mammaplasty remains critical to the treatment of breast hypertrophy. No technique has been shown to be superior; however, comparison between studies is difficult due to variation in outcome reporting. OBJECTIVES: The authors sought to identify a comprehensive list of outcomes and outcome measures in reduction mammaplasty. METHODS: A comprehensive computerized search was performed. Included studies were randomized or nonrandomized controlled trials involving at least 100 cases of female breast hypertrophy and patients of all ages who underwent 1 or more defined reduction mammaplasty technique. Outcomes and outcome measures were extracted and tabulated. RESULTS: A total 106 articles were eligible for inclusion; 57 unique outcomes and 16 outcome measures were identified. Frequency of patient-reported and author-reported outcomes were 44% and 88%, respectively. Postoperative complications were the most frequently reported outcome (82.2%). Quality-of-life outcomes were accounted for in 37.7% of studies. Outcome measures were either condition-specific or generic; frequencies were as low as 1% and as high as 5.6%. Five scales were formally assessed in the breast reduction populations. Clinical measures were defined in 15.1% of studies. CONCLUSIONS: There is marked heterogeneity in reporting of outcomes and outcome measures in the literature. A standardized outcome set is needed to compare outcomes of various reduction mammaplasty techniques.

Users' guide to the surgical literature: how to assess a qualitative study.

SUMMARY: Qualitative research contributes to the medical literature through the observation, description and interpretation of theories about social interactions and individual experiences as they occur in their natural setting. This type of research has the potential to enhance the understanding of surgeons' and patients' preferences, attitudes and beliefs, as well as assess how these may change with time. To date, there is no widely accepted standard for the methodological assessment of qualitative research. Despite ongoing debate, this article seeks to familiarize surgeons with the basic techniques for the critical appraisal of qualitative studies in the surgical literature.

Dupuytren's contracture and handwork: A case-control study.

OBJECTIVE: The objective of this study was to examine the association between Dupuytren's contracture (DC), repetitive handwork (RHW), heavy handwork (HHW), and/or vibration exposure. METHODS: Frequency and intensity of the three types of handwork were collected and compared between DC patients and controls. Hours of work were weighted by average "frequency," for RHW, and average "intensity," for HHW and use of vibrating tool. Logistic regression was used to evaluate risk of developing DC associated with the above-mentioned factors. RESULTS: Data from 129 cases (74 clinical, 106 controls) was analyzed. Family history, male gender and age (decades) were associated with increased risk of DC. Results indicate that the risk becomes substantial after about 30 years of steady RHW. Independent effects of intensity-weighted HHW and vibrating exposure were not established. CONCLUSIONS: Frequency-weighted RHW increases DC risk. Additionally, a strong association between DC, male gender and heredity was found.

Identification of neutrophil-derived proteases and angiotensin II as biomarkers of cancer cachexia.

BACKGROUND: Cachexia is a metabolic disorder characterised by muscle wasting, diminished response to anti-cancer treatments and poor quality of life. Our objective was to identify blood-based biomarkers of cachexia in advanced cancer patients. Hence, we characterised the plasma cytokine and blood cell mRNA profiles of patients grouped in three cohorts: patients with cachexia, pre-cachexia (no cachexia but high CRP levels: ⩾ 5 mg l⁻¹) and no cachexia (no cachexia and CRP: < 5 mg l⁻¹). METHODS: A total of 122 newly diagnosed cancer patients with seven cancer types were studied prior to their initial therapy. Plasma levels of 22 cytokines were quantified using the bio-plex technology. mRNAs isolated from whole blood and expression profiles were determined by the chip array technology and Ingenuity Pathway Analysis (IPA) software. RESULTS: In comparison with non-cachectic individuals, both pre-cachectic and cachectic patients showed an increase (⩾ 1.5-folds) in mRNA expression of neutrophil-derived proteases (NDPs) and significantly elevated angiotensin II (Ang II) (P = 0.005 and P = 0.02, respectively), TGFß1 (P = 0.042 and P < 0.0001, respectively) and CRP (both P < 0.0001) in the plasma. Moreover, cachectic patients displayed a significant increase in IL-6 (P = 0.005), IL-8 (P = 0.001) and absolute neutrophil counts (P = 0.007). CONCLUSIONS: Ang II, TGFß1, CRP and NDP are blood biomarkers for cancer cachexia. These findings contribute to early diagnosis and prevention of cachexia.

Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines.

The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca(2+) permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca(2+) signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. Activation of ß-adrenergic and D1/D5-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDAR Ca(2+) permeation, synaptic currents, and Ca(2+) rises in dendritic spines. We further show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca(2+) signaling at synapses and regulated by the emotional response to stress.

Revisiting Chronic Pain Patient Profiling: An Acceptance-based Approach in an Online Sample.

UNLABELLED: Over 116 million Americans experience chronic pain, incurring an annual cost of $635 bn in healthcare and lost work. Acceptance-based therapies have gained increasing recognition for improving functional outcomes. In our online chronic pain sample, we predicted that (1) patients would cluster into low, medium and high groups of chronic pain acceptance and (2) positive affect, negative affect and perceived disability scores would differ overall by cluster, with the most positive outcomes found in the high cluster and the least found in the low cluster. Participants completed the Chronic Pain Acceptance Questionnaire, Positive and Negative Affect Scales and the Pain Disability Index. A k-means cluster analysis was conducted using activity engagement (AE) and pain willingness (PW) totals from the Chronic Pain Acceptance Questionnaire. As predicted, cluster analysis specified three groups: low AE/low PW, high AE/high PW and medium AE/medium PW. Significant multivariate analysis of covariance results were obtained according to Wilks' λ (0.55), F(6,266) = 15.39, p < 0.01, and indicated differences in positive affect, negative affect and perceived disability within each cluster. Follow-up analyses of covariance revealed mean differences in the predicted directions: the high-high group showed the most positive affect and the least negative affect and perceived disability. Conversely, the low-low group displayed the least positive affect (M = 20.28, SD = 7.86), the most negative affect (M = 28.05, SD = 9.33) and perceived disability (M = 49.57, SD = 9.46). The presence of these clusters introduces key questions about the possibility of creating tailored interventions based on cluster profiles. KEY PRACTITIONER MESSAGE: Higher levels of Acceptance are associated with better functional and affective outcomes for chronic pain patients. Lower Acceptance is associated with poorer functional and affective outcomes. Tailoring interventions using Acceptance-based profiling may improve chronic pain therapies.

Unannounced standardized patients: a promising method of assessing patient-centered care in your health care system.

BACKGROUND: While unannounced standardized patients (USPs) have been used to assess physicians' clinical skills in the ambulatory setting, they can also provide valuable information on patients' experience of the health care setting beyond the physician encounter. This paper explores the use of USPs as a methodology for evaluating patient-centered care in the health care system. METHODS: USPs were trained to complete a behaviorally-anchored assessment of core dimensions of patient-centered care delivered within the clinical microsystem, including: 1) Medical assistants' safe practices, quality of care, and responsiveness to patients; 2) ease of clinic navigation; and 3) the patient-centeredness of care provided by the physician. Descriptive data is provided on these three levels of patient-centeredness within the targeted clinical microsystem. Chi-square analyses were used to signal whether variations by teams within the clinical microsystem were likely to be due to chance or might reflect true differences in patient-centeredness of specific teams. RESULTS: Sixty USP visits to 11 Primary Care teams were performed over an eight-month period (mean 5 visits/team; range 2-8). No medical assistants reported detecting an USP during the study period. USPs found the clinic easy to navigate and that teams were functioning well in 60% of visits. In 30% to 47% of visits, the physicians could have been more patient-centered. Medical assistants' patient safety measures were poor: patient identity was confirmed in only 5% of visits and no USPs observed medical assistants wash their hands. Quality of care was relatively high for vital signs (e.g. blood pressure, weight and height), but low for depression screening, occurring in only 15% of visits. In most visits, medical assistants greeted the patient in a timely fashion but took time to fully explain matters in less than half of the visits and rarely introduced themselves. Physicians tried to help patients navigate the system in 62% of visits. CONCLUSIONS: USP assessment captured actionable, critical, behaviorally-specific information on team and system performance in an urban community clinic. This methodology provides unique insight into the patient-centeredness and quality of care in medical settings.

Improvements in cardiorespiratory fitness, muscle strength and body composition to modest weight loss are similar in those with adult- versus childhood-onset obesity.

Adults who have had obesity from childhood are at greater risk of obesity-related comorbidities compared to those who only develop obesity in adulthood. The main way of mitigating these risks in obesity is with weight loss, which has been shown to positively affect the cardiorespiratory fitness (CRF) and body composition of adults. However, it is unclear whether the response of these outcomes to weight loss may be influenced by age of obesity onset. The objective of our study was to investigate how age of obesity onset mitigates the responsiveness of CRF, muscle strength and body composition to modest weight loss. Measurements were conducted at baseline and 12 weeks. In total, 37 participants (childhood-onset = 19, adult-onset = 18) lost 3.7% ± 0.4% through aerobic exercise and diet. The YMCA cycle ergometer test (YMCA) and the 20-m shuttle run test (20MSR) were used to estimate CRF (mL kg-1 min-1 ) and a handgrip dynamometer was used to estimate muscle strength. Total body composition was assessed by dual-energy x-ray absorptiometry (DEXA). Overall, CRF and body composition improved (time effect: p < 0.05) after 12 weeks. There was no group-by-time interaction for YMCA, 20MSR, muscle strength and body composition variables. Therefore, the present study suggests that individuals with childhood-onset obesity and adult-onset obesity can improve their CRF and body composition similarly after mild weight loss.