Genetic risk converges on regulatory networks mediating early type 2 diabetes.

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet ß cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and ß cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3-5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by ß cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the ß cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by ß cells. RFX6 perturbation in primary human islet cells alters ß cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

The impact of different strategies for modeling associations between medications at low doses and health outcomes: a simulation study and practical application to postpartum opioid use.

Pharmacoepidemiological studies commonly examine the association between drug dose and adverse health outcomes. In situations where no safe dose exists, the choice of modeling strategy can lead to identification of an apparent safe low dose range in the presence of a non-linear relationship or due to the modeling strategy forcing a linear relationship through a dose of 0. We conducted a simulation study to assess the performance of several regression approaches to model the drug dose-response curve at low doses in a setting where no safe range exists, including the use of a (1) linear dose term, (2) categorical dose term, and (3) natural cubic spline terms. Additionally, we introduce and apply an expansion of prior work related to modeling dose-response curves at low and infrequently used doses in the setting of no safe dose ("spike-at-zero" and "slab-and-spline"). Furthermore, we demonstrate and empirically assess the use of these regression strategies in a practical scenario examining the association between the dose of the initial postpartum opioid prescribed after vaginal delivery and the subsequent total dose of opioids prescribed in the entire postpartum period among a cohort of opioid-naïve women with a vaginal delivery enrolled in a State Medicaid program (2007-2014).

Determining the Association Between Insurance Type and Myofascial Release in Large Ventral Hernias.

INTRODUCTION: Abdominal wall reconstruction (AWR) utilizes advanced myofascial releases to perform complex ventral hernia repair (VHR). The relationship between the performance of AWR and disparities in insurance type is unknown. METHODS: The Abdominal Core Health Quality Collaborative was queried for adults who had undergone an elective VHR between 2013 and 2020 with a hernia size ≥10 cm. Patients with missing insurance data were excluded. Comparison groups were divided by insurance type: favorable (private, Medicare, Veteran's Administration, Tricare) or unfavorable (Medicaid and self-pay). Propensity score matching compared the cumulative incidence of AWR between the favorable and unfavorable insurance comparison groups. RESULTS: In total, 26,447 subjects met inclusion criteria. The majority (89%, n = 23,617) had favorable insurance, while (11%, n = 2830) had unfavorable insurance. After propensity score matching, 2821 patients with unfavorable insurance were matched to 7875 patients with favorable insurance. The rate of AWR with external oblique release or transversus abdominis release was significantly higher (23%, n = 655) among the unfavorable insurance group compared to those with favorable insurance (21%, n = 1651; P = 0.013). CONCLUSIONS: This study provides evidence that patients with unfavorable insurance may undergo AWR with external oblique or transversus abdominis release at a greater rate than similar patients with favorable insurance. Understanding the mechanisms contributing to this difference and evaluating the financial implications of these trends represent important directions for future research in elective VHR.

Association of changes in HerQLes scores with objective hernia outcomes: an analysis of the ACHQC database.

BACKGROUND: There are both objective and subjective measures of success following ventral hernia repair (VHR). Using the Abdominal Core Health Quality Collaborative (ACHQC) database, we sought to determine if there is an association between 30-day wound events (objective) and changes in the hernia-related quality-of-life (HerQLes) scores, (subjective). We hypothesized that patients who do not experience a 30-day wound event have a greater improvement in their HerQLes score over the short-term. METHODS: All adult patients who underwent VHR with 30-day follow-up data available between 2013 and 2022 were identified within the ACHQC database. The 30-day wound events included surgical site infection (SSI), surgical site occurrence (SSO), and SSO requiring procedural intervention (SSOPI). The association between 30-day wound events and changes in HerQLes scores was measured using propensity matched score analysis. Further, regression analysis was used to determine if an improvement in HerQLes score at 30-days postoperatively was associated with the likelihood of experiencing a 30-day wound event. RESULTS: Following a 3:1 matched analysis, 17,796 patients were available for analysis; 4449 (25%) patients experienced a 30-day wound event. The most common SSI was a superficial SSI and the most common SSO was a seroma. A 10-point improvement in the HerQLes score was statistically associated with a 3% decrease in SSI and a 4% decrease in the odds of experiencing an SSO. While not statistically significant, a 10-point improvement in the HerQLes score was associated with a 2.4% decrease in the odds of experiencing an SSOPI. CONCLUSIONS: Subjective and objective measures of success following VHR seem to be correlated with one another over the short-term. Additional studies are needed to determine if this correlation exists with other subjective and objective measures of success and to determine if these correlations persist over the long-term. If present, these associations may help to guide patient counseling as experiencing a postoperative wound event following ventral hernia repair may not be detrimental to their quality-of-life over the long-term.

Evaluation of 30-day outcomes for open ventral hernia repair using self-gripping versus nonself-gripping mesh.

BACKGROUND: The use of mesh is standard of care for large ventral hernias repaired on an elective basis. The most used type of mesh includes synthetic polypropylene mesh; however, there has been an increase in the usage of a new polyester self-gripping mesh, and there are limited data regarding its efficacy for ventral hernia. The purpose of the study is to determine whether there is a difference in surgical site occurrence (SSO), surgical site infection (SSI), surgical site occurrence requiring procedural intervention (SSOPI), and recurrence at 30 days after ventral hernia repair (VHR) using self-gripping (SGM) versus non-self-gripping mesh (NSGM). METHODS: We performed a retrospective study from January 2014 to April 2022 using the Abdominal Core Health Quality Collaborative (ACHQC). We collected data on patients over 18 years of age who underwent elective open VHR using SGM or NSGM and whom had 30-day follow-up. Propensity matching was utilized to control for variables including hernia width, body mass index, age, ASA, and mesh location. Data were analyzed to identify differences in SSO, SSI, SSOPI, and recurrence at 30 days. RESULTS: 9038 patients were identified. After propensity matching, 1766 patients were included in the study population. Patients with SGM had similar demographic and clinical characteristics compared to NSGM. The mean hernia width to mesh width ratio was 8 cm:18 cm with NSGM and 7 cm:15 cm with SGM (p = 0.63). There was no difference in 30-day rates of recurrence, SSI or SSO. The rate of SSOPI was also found to be 5.4% in the nonself-gripping group compared to 3.1% in the self-gripping mesh group (p < .005). There was no difference in patient-reported outcomes at 30 days. CONCLUSIONS: In patients undergoing ventral hernia repair with mesh, self-gripping mesh is a safe type of mesh to use. Use of self-gripping mesh may be associated with lower rates of SSOPI when compared to nonself-gripping mesh.

The current role of barbed sutures in fascial closure of ventral hernia repair: a multicenter study using the abdominal core health quality collaborative database.

BACKGROUND: Barbed sutures (BS) have been increasingly used in the last two decades across surgical disciplines but little is known about how widespread their adoption has been in ventral hernia repair (VHR). The aim of this study was to document the use of barbed sutures in VHR in a multicenter database with associated clinical and patient-reported outcomes. METHOD: Prospectively collected data from the Abdominal Core Health Quality Collaborative database was retrospectively reviewed, including all adult patients who underwent VHR with fascial closure from 2020 to 2022. A univariate analysis compared patients with BS against non-barbed sutures (NBS) across the preoperative, intraoperative, and postoperative timeframes including patient-reported outcomes concerning quality of life and pain scores. RESULTS: A total of 4054 patients that underwent ventral hernia repair with BS were compared with 6473 patients with non-barbed sutures (NBS). Overall, BS were used in 86.2% of minimally invasive ventral hernia repairs and about 92.2% of robotic surgery compared to only 9.6% of open procedures. Notable differences existed in patient selection, including a higher BMI (32 vs 30.5; p < 0.001), more incisional hernias (63.3% vs 51.1%; p < 0.001), wider hernias (4 cm vs 3 cm; p < 0.001), and higher ASA score (p < 0.001) in patients with BS. Outcomes in patients with BS included a shorter length of stay (mean days; 1.4 vs 2.4; p < 0.001), less SSI (1.5% vs 3.6%; p < 0.001), while having similar SSO (7.6% vs 7.3%; p = 0.657), readmission (3.0 vs 3.2; p = 0.691), and reoperation (1.5% vs 1.45%; p = 0.855), at a longer operative time (p < 0.001). Hernia-specific questionnaires for quality of life (HerQLes) and pain in patients with BS had a worse preoperative score that was later matched and favorable compared to NBS (p = 0.048). PRO concerning hernia recurrence suggest around 10% at two years of follow-up (p = 0.532). CONCLUSION: Use of barbed sutures in VHR is widespread and highly related to MIS. Outcomes from this multicenter database cannot be reported as superior but suggest that barbed sutures do not have a negative impact on outcomes.

The association of permanent versus absorbable fixation on developing chronic post-herniorrhaphy groin pain in patients undergoing laparoscopic inguinal hernia repair.

INTRODUCTION: Fixation of mesh during minimally invasive inguinal hernia repair is thought to contribute to chronic post-herniorrhaphy groin pain (CGP). In contrast to permanent tacks, absorbable tacks are hypothesized to minimize the likelihood of CGP. This study aimed to compare the rates of CGP after laparoscopic inguinal hernia repair between absorbable versus permanent fixation at maximum follow-up. METHODS: This is a post hoc analysis of a randomized controlled trial in patients undergoing laparoscopic inguinal hernia repair (NCT03835351). All patients were contacted at maximum follow-up after surgery to administer EuraHS quality of life (QoL) surveys. The pain and restriction of activity subdomains of the survey were utilized. The primary outcome was rate of CGP, as defined by a EuraHS QoL pain domain score ≥ 4 measured at ≥ 1 year postoperatively. The secondary outcomes were pain and restriction of activity domain scores and hernia recurrence at maximum follow-up. RESULTS: A total of 338 patients were contacted at a mean follow-up of 28 ± 11 months. 181 patients received permanent tacks and 157 patients received absorbable tacks during their repair. At maximum follow-up, the rates of CGP (27 [15%] vs 28 [18%], P = 0.47), average pain scores (1.78 ± 4.38 vs 2.32 ± 5.40, P = 0.22), restriction of activity scores (1.39 ± 4.32 vs 2.48 ± 7.45, P = 0.18), and the number of patients who reported an inguinal bulge (18 [9.9%] vs 15 [9.5%], P = 0.9) were similar between patients with permanent versus absorbable tacks. On multivariable analysis, there was no significant difference in the odds of CGP between the two groups (OR 1.23, 95% CI [0.60, 2.50]). CONCLUSION: Mesh fixation with permanent tacks does not appear to increase the risk of CGP after laparoscopic inguinal hernia repair when compared to fixation with absorbable tacks. Prospective trials are needed to further evaluate this relationship.

The Efficacy of Parent-Child Interaction Therapy (PCIT) for Youth with Attention-Deficit/Hyperactivity Disorder (ADHD): A Meta-Analysis.

Attention-deficit/hyperactivity disorder (ADHD) is highly prevalent in early childhood and has long-term negative effects when left untreated. Parent-Child Interaction Therapy (PCIT) is an early intervention for children aged 2- to-7-years that has extensive evidence for treating child externalizing problems by teaching parents effective strategies to manage child behavior. However, the effect of PCIT for families with children diagnosed with ADHD is not completely understood. This meta-analysis aims to synthesize research on the use of PCIT for children with ADHD. Nine out of 711 identified studies were analyzed. Summary effect sizes were calculated using the standardized mean gain for child ADHD symptoms, child behaviors, parent stress, and parenting behaviors, and the Fail-Safe N was calculated to determine the robustness of the results. Overall, PCIT had a significant beneficial effect on child ADHD symptoms (g = 0.90), child behavior (g = 0.44), parent stress (g = 0.82), and parenting behaviors (g = 2.15). Results of this meta-analysis suggest that PCIT is an effective treatment for reducing core symptoms of ADHD.

Human pancreatic capillaries and nerve fibers persist in type 1 diabetes despite beta cell loss.

The autonomic nervous system regulates pancreatic function. Islet capillaries are essential for the extension of axonal projections into islets, and both of these structures are important for appropriate islet hormone secretion. Because beta cells provide important paracrine cues for islet glucagon secretion and neurovascular development, we postulated that beta cell loss in type 1 diabetes (T1D) would lead to a decline in intraislet capillaries and reduction of islet innervation, possibly contributing to abnormal glucagon secretion. To define morphological characteristics of capillaries and nerve fibers in islets and acinar tissue compartments, we analyzed neurovascular assembly across the largest cohort of T1D and normal individuals studied thus far. Because innervation has been studied extensively in rodent models of T1D, we also compared the neurovascular architecture between mouse and human pancreas and assembled transcriptomic profiles of molecules guiding islet angiogenesis and neuronal development. We found striking interspecies differences in islet neurovascular assembly but relatively modest differences at transcriptome level, suggesting that posttranscriptional regulation may be involved in this process. To determine whether islet neurovascular arrangement is altered after beta cell loss in T1D, we compared pancreatic tissues from non-diabetic, recent-onset T1D (<10-yr duration), and longstanding T1D (>10-yr duration) donors. Recent-onset T1D showed greater islet and acinar capillary density compared to non-diabetic and longstanding T1D donors. Both recent-onset and longstanding T1D had greater islet nerve fiber density compared to non-diabetic donors. We did not detect changes in sympathetic axons in either T1D cohort. Additionally, nerve fibers overlapped with extracellular matrix (ECM), supporting its role in the formation and function of axonal processes. These results indicate that pancreatic capillaries and nerve fibers persist in T1D despite beta cell loss, suggesting that alpha cell secretory changes may be decoupled from neurovascular components.NEW & NOTEWORTHY Defining the neurovascular architecture in the pancreas of individuals with type 1 diabetes (T1D) is crucial to understanding the mechanisms of dysregulated glucagon secretion. In the largest T1D cohort of biobanked tissues analyzed to date, we found that pancreatic capillaries and nerve fibers persist in human T1D despite beta cell loss, suggesting that alpha cell secretory changes may be decoupled from neurovascular components. Because innervation has been studied extensively in rodent T1D models, our studies also provide the first rigorous direct comparisons of neurovascular assembly in mouse and human, indicating dramatic interspecies differences.

Robotic vs. Open Approach for Older Adults Undergoing Retromuscular Ventral Hernia Repair.

OBJECTIVE: To describe 30-day outcomes including post-operative complications, readmissions, and quality of life score changes for older adults undergoing elective ventral hernia repair with retromuscular mesh placement and to compare rates of these outcomes for individuals undergoing robotic versus open approaches. SUMMARY OF BACKGROUND DATA: Over one third of patients presenting for elective ventral hernia repair are over the age of 65 and many have complex surgical histories that warrant intricate hernia repairs. Robotic ventral hernia repairs have gained increasing popularity in the US and in some studies have demonstrated decreased rates of postoperative complications, and less pain resulting in shorter hospital stays. However, the robotic approach has several downsides including prolonged operative times as well as the use of pneumo-peritoneum which may be risky in older patients. METHODS: We performed a retrospective review of prospectively collected data in a national hernia specific registry (the Abdominal Core Health Quality Collaborative) and identified patients over the age of 65 undergoing either an open or robotic retromuscular ventral hernia repair. After propensity score matching adjusting for demographic, clinical, and hernia related factors, logistic regression was used to compare 30-day complications, readmission, and quality of life (QoL) scores as captured by the HerQLes scale for patients undergoing each approach. RESULTS: Of 2128 patients who met inclusion criteria, 1695 (79.7%) underwent open ventral hernia repair while 433 (20.3%) underwent robotic repair. After propensity score matching, there were 350 robotic cases and 759 open cases for analysis. Patients undergoing robotic repairs demonstrated significantly shorter length of stays (1 vs 4 days, P < 0.01) and had equivalent odds of both 30-day post-operative complications (odds ratio [OR] 1.15 95% confidence interval 0.92-1.44) and readmission (OR 1.09 95% confidence interval 0.74-1.6) compared to the open approach. QoL scores were similar between groups at 30 days but were slightly better for robotic patients at 1 year (92 vs 84 P < 0.01). CONCLUSIONS: Robotic ventral hernia repair is an option for appropriately selected older patients undergoing retromuscular ventral hernia repair, demonstrating shorter hospital stays and equivalent rates of complications and readmissions in the post-operative period. However, more data is needed regarding QoL outcomes and long-term function, especially as it relates to recurrence rates, between the two approaches.