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.

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 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.

Reducing the incidence of surgical site infection after ventral hernia repair: Outcomes from the RINSE randomized control trial.

BACKGROUND: The clinical and financial impact of surgical site infection after ventral hernia repair is significant. Here we investigate the impact of dual antibiotic irrigation on SSI after VHR. METHODS: This was a multicenter, prospective randomized control trial of open retromuscular VHR with mesh. Patients were randomized to gentamicin â€‹+ â€‹clindamycin (G â€‹+ â€‹C) (n â€‹= â€‹125) vs saline (n â€‹= â€‹125) irrigation at time of mesh placement. Primary outcome was 30-day SSI. RESULTS: No significant difference was seen in SSI between control and antibiotic irrigation (9.91 vs 9.09 â€‹%; p â€‹= â€‹0.836). No differences were seen in secondary outcomes: SSO (11.71 vs 13.64 â€‹%; p â€‹= â€‹0.667); 90-day SSO (11.1 vs 13.9 â€‹%; p â€‹= â€‹0.603); 90-day SSI (6.9 vs 3.8 â€‹%; p â€‹= â€‹0.389); SSIPI (7.21 vs 7.27 â€‹%, p â€‹= â€‹0.985); SSOPI (3.6 vs 3.64 â€‹%; p â€‹= â€‹0.990); 30-day readmission (9.91 vs 6.36 â€‹%; p â€‹= â€‹0.335); reoperation (5.41 vs 0.91 â€‹%; p â€‹= â€‹0.056). CONCLUSION: Dual antibiotic irrigation with G â€‹+ â€‹C did not reduce the risk of surgical site infection during open retromuscular ventral hernia repair.

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.

Does a "hernia center" label provide better 30-day outcomes following elective ventral hernia repair?: An analysis of the ACHQC database.

INTRODUCTION: Currently, there is no agreed upon definition of a designated hernia center (DHC) and no study has investigated the association of hernia center designation with ventral hernia repair (VHR) outcomes. We sought to investigate the current utilization of DHC and the association of hernia center designation with VHR outcomes. METHODS: All patients who underwent elective, ventral hernia repair with mesh with 30-day follow-up from 2013 through 2020 were in the Americas Hernia Society Quality Collaborative (ACHQC) database. Patients were divided into two groups: those that underwent VHR at a DHC and those that underwent VHR at a non-designated hernia center site (NDHC). Using a 1:1 matched analysis, differences in the incidence of 30-day wound events, the total number of 30-day complications, one-year ventral hernia recurrence rates, and 30-day and one-year patient reported outcomes were compared between DHC and NDHC. RESULTS: A total of 261 sites were included in our analysis; 78 (30%) were identified as DHC. After matching, there were 14,186 VHRs available for analysis. There was no significant difference in 30-day wound morbidity events. Patients who underwent VHR at NDHC were less likely to experience any 30-day complication or 1-year hernia recurrence while patients who underwent VHR at DHC had a statistically significant greater improvement in their HerQLes scores at one-year postoperatively. CONCLUSIONS: There is currently no clear superiority to VHR at a DHC. The ACHQC may self-select for surgeons invested in hernia repair outcomes regardless of hernia center designation. More standardized criteria for a hernia center are required in order to positively influence the value of hernia care delivered in the United States.

Revisiting femoral hernia diagnosis rates by patient sex in inguinal hernia repairs.

INTRODUCTION: Guidelines recommend MIS repairs for females with inguinal hernias, despite limited evidence. We investigated rates of femoral hernias intraoperatively noted during MIS and Lichtenstein repairs in females. METHODS: ACHQC was queried for adult females undergoing inguinal hernia repair between January 2014-November 2022. Outcomes included identified femoral hernia and size, hernia recurrence, quality of life, and sex-based recurrence. RESULTS: 1357 and 316 females underwent MIS and Lichtenstein inguinal repair respectively. Femoral hernias were identified more frequently in MIS than open repairs (27%vs12%; (p â€‹< â€‹0.001). Most femoral hernias in MIS (61%) and Lichtenstein repairs (62%) were <1.5 â€‹cm(p â€‹< â€‹0.001). Identification rates of femoral hernias >3 â€‹cm were 1% overall(p â€‹= â€‹0.09). Surgeon and patient-reported recurrences were similar between approaches at 1-5-years for females(p â€‹> â€‹0.05 for all) and similar between sexes(p â€‹> â€‹0.05). CONCLUSION: Most incidental femoral hernias are small and both repair approaches demonstrated similar outcomes. The recommendation for MIS inguinal hernia repairs in females is potentially overstated.

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.

Applying the Theoretical Domains Framework to Develop an Intervention to 'Re-implement' Parent-Child Interaction Therapy (PCIT).

Parent-Child Interaction Therapy (PCIT) is an empirically supported treatment for childhood conduct problems, with increasing numbers of clinicians being trained in Aotearoa/New Zealand. However, ensuring sustained delivery of effective treatments by trained clinicians in routine care environments is notoriously challenging. The aims of this qualitative study were to (1) systematically examine and prioritise PCIT implementation barriers and facilitators, and (2) develop a well specified and theory-driven 're-implementation' intervention to support already-trained clinicians to resume or increase their implementation of PCIT. To triangulate and refine existing understanding of PCIT implementation determinants from an earlier cross-sectional survey, we integrated previously unanalysed qualitative survey data (54 respondents; response rate 60%) with qualitative data from six new focus groups with 15 PCIT-trained clinicians and managers in Aotearoa/New Zealand. We deductively coded data, using a directed content analysis process and the Theoretical Domains Framework, resulting in the identification of salient theoretical domains and belief statements within these. We then used the Theory and Techniques Tool to identify behaviour change techniques, possible intervention components, and their hypothesised mechanisms of action. Eight of the 14 theoretical domains were identified as influential on PCIT-trained clinician implementation behaviour (Knowledge; Social/Professional Role and Identity; Beliefs about Capabilities; Beliefs about Consequences; Memory, Attention and Decision Processes; Environmental Context and Resources; Social Influences; Emotion). Two of these appeared to be particularly salient: (1) 'Environmental Context and Resources', specifically lacking suitable PCIT equipment, with (lack of) access to a well-equipped clinic room appearing to influence implementation behaviour in several ways. (2) 'Social/Professional Role and Identity', with beliefs relating to a perception that colleagues view time-out as harmful to children, concerns that internationally-developed PCIT is not suitable for non-Maori clinicians to deliver to Indigenous Maori families, and clinicians feeling obligated yet isolated in their advocacy for PCIT delivery. In conclusion, where initial implementation has stalled or languished, re-implementation may be possible, and makes good sense, both fiscally and practically. This study suggests that re-implementation of PCIT in Aotearoa/New Zealand may be facilitated by intervention components such as ensuring access to a colleague or co-worker who is supportive of PCIT delivery, access to suitable equipment (particularly a time-out room), and targeted additional training for clinicians relating to the safety of time-out for children. The feasibility and acceptability of these intervention components will be tested in a future clinical trial.

Robotic Enhanced-View Totally Extraperitoneal vs Intraperitoneal Onlay Mesh Evaluation: 1-Year Exploratory Outcomes of the REVEAL Randomized Clinical Trial.

BACKGROUND: Patients with small- to medium-sized ventral hernias randomized to robotic enhanced-view totally extraperitoneal (eTEP) or robotic intraperitoneal onlay mesh (rIPOM) previously demonstrated comparable 30-day patient-reported outcomes. Here we report 1-year exploratory outcomes for this multi-center, patient-blinded randomized clinical trial. STUDY DESIGN: Patients with midline ventral hernias 7 cm wide or less undergoing mesh repair were randomized to robotic eTEP or rIPOM. Planned exploratory outcomes at 1 year include pain intensity (using the Patient-Reported Outcomes Measurement Information System [PROMIS 3a]), Hernia-Related Quality of Life Survey (HerQLes) scores, pragmatic hernia recurrence, and reoperation. RESULTS: One hundred randomized patients (51 eTEP, 49 rIPOM) reached a median 12-month follow-up (interquartile range 11 to 13) with 7% lost. After regression analysis adjusting for baseline scores, there was no difference in postoperative pain intensity at 1-year for eTEP compared with rIPOM (odds ratio [OR] 2.1 [95% CI 0.85 to 5.1]; p = 0.11). HerQLes scores were 15 points lower on average (ie less improved) at 1 year after eTEP repairs compared with rIPOM, a difference maintained after regression analysis (OR 0.31 [95% CI 0.15 to 0.67]; p = 0.003). Pragmatic hernia recurrence was 12.2% (6 of 49) for eTEP and 15.9% (7 of 44) for rIPOM (p = 0.834). In the first year, 2 eTEP and 1 rIPOM patients required reoperations related to their index repair (p = 0.82). CONCLUSIONS: Exploratory analyses showed similar outcomes at 1 year in regard to pain, hernia recurrence, and reoperation. Abdominal wall quality of life at 1 year appears to favor rIPOM, and the possibility that an eTEP dissection is less advantageous in that regard should be the subject of future investigation.

Distressed community index as a predictor of presentation and postoperative outcomes in ventral hernia repair.

BACKGROUND: We evaluated the impact of socioeconomic status on presentation, management, and outcomes of ventral hernias. METHODS: The Abdominal Core Health Quality Collaborative was queried for adult patients undergoing ventral hernia repair. Socioeconomic quintiles were assigned using the Distressed Community Index (DCI): prosperous (0-20), comfortable (21-40), mid-tier (41-60), at-risk (61-80), and distressed (81-100). Outcomes included presenting symptoms, urgency, operative details, 30-day outcomes, and one-year hernia recurrence rates. Multivariable regression evaluated 30-day wound complications. RESULTS: 39,494 subjects were identified; 32,471 had zip codes (82.2%).Urgent presentation (3.6% vs. 2.3%) and contaminated cases (0.83% vs. 2.06%) were more common in the distressed group compared to the prosperous group (p < 0.001). Higher DCI correlated with readmission (distressed: 4.7% vs prosperous: 2.9%,p < 0.001) and reoperation (distressed 1.8% vs prosperous: 0.92%,p < 0.001). Wound complications were independently associated with increasing DCI (p < 0.05). Clinical recurrence rates were similar at one-year (distressed: 10.4% vs prosperous: 8.6%, p = 0.54). CONCLUSIONS: Inequity exists in presentation and perioperative outcomes for ventral hernia repair and efforts should be focused on increasing access to elective surgery and improving postoperative wound care.

Maternal Opioid Use Disorder and the Risk of Postneonatal Infant Mortality.

Importance: The risk of serious long-term outcomes for infants born to individuals with opioid use disorder (OUD) is not fully characterized, nor is it well understood whether risks are modified by infant diagnosis of neonatal opioid withdrawal syndrome (NOWS). Objective: To characterize the risk of postneonatal infant mortality among infants with a NOWS diagnosis or born to individuals with OUD. Design, Setting, and Participants: The study team conducted a retrospective cohort study of 390 075 infants born from 2007 through 2018 to mothers who were enrolled in Tennessee Medicaid from 183 days prior to delivery through 28 days post partum (baseline). Maternal and infant baseline characteristics were measured using administrative claims and birth certificates, and infants were followed up from day 29 post partum through day 365 or death. Deaths were identified using linked death certificates through 2019. These data were analyzed from February 10, 2022, through March 3, 2023. Exposure: Infant exposures included birth to an individual with OUD or postnatal diagnosis of NOWS. The study team defined a pregnant individual's OUD status (maternal OUD) as having OUD diagnosis or a maintenance medication prescription fill during baseline; this study defined NOWS as having NOWS diagnosis up to day 28. Groups were categorized by exposures as maternal OUD with NOWS (OUD positive/NOWS positive), maternal OUD without NOWS (OUD positive/NOWS negative), no documented maternal OUD with NOWS (OUD negative/NOWS positive), and no documented maternal OUD or NOWS (OUD negative/NOWS negative, unexposed). Main Outcome and Measures: The outcome was postneonatal infant death, confirmed by death certificates. Cox proportional hazards models were used, adjusting for baseline maternal and infant characteristics, to estimate adjusted hazard ratios (aHRs) and 95% CIs for the association between maternal OUD or NOWS diagnosis with postneonatal death. Results: Pregnant individuals in the cohort had a mean (SD) age of 24.5 (5.2) years; 51% of infants were male. The study team observed 1317 postneonatal infant deaths and incidence rates of 3.47 (OUD negative/NOWS negative, 375 718), 8.41 (OUD positive/NOWS positive, 4922); 8.95 (OUD positive/NOWS negative, 7196), and 9.25 (OUD negative/NOWS positive, 2239) per 1000 person-years. After adjustment, the risk of postneonatal death was elevated for all groups, relative to the unexposed: OUD positive/NOWS positive (aHR, 1.54; 95% CI, 1.07-2.21), OUD positive/NOWS negative (aHR, 1.62; 95% CI, 1.21-2.17), and OUD negative/NOWS positive (aHR, 1.64; 95% CI, 1.02-2.65). Conclusions and Relevance: Infants born to individuals with OUD or with a NOWS diagnosis had an increased risk of postneonatal infant mortality. Future work is necessary to create and evaluate supportive interventions for individuals with OUD during and after pregnancy to reduce adverse outcomes.

The effect of smoking status on inguinal hernia repair outcomes: An ACHQC analysis.

BACKGROUND: Smoking has been shown to negatively affect surgical outcomes, so smoking cessation prior to elective operations is often recommended. However, the effects of smoking status on inguinal hernia repair outcomes have not been extensively studied. Hence, we investigated the association between smoking status and short-term adverse outcomes following inguinal hernia repair. METHODS: Abdominal Core Health Quality Collaborative database was queried for elective, clean inguinal hernia repairs, excluding those with concomitant procedures or where length of stay > 30 days. The resulting cohort was divided into three groups: current smokers, former smokers, and never smokers. Baseline patient, hernia, operative characteristics, and 30-day outcomes were compared. Multivariable logistic regression was used to evaluate the association between smoking status and overall and wound complications. RESULTS: 19,866 inguinal hernia repairs were included (current smokers = 2239, former smokers = 4064 and never smokers = 13,563). Current smokers and former smokers, compared to never smokers, had slightly higher unadjusted rates of overall complication rates (9% and 9% versus 7%, p = 0.003) and surgical site occurrences/infection (6% and 6% versus 4%, p < 0.001). However, on multivariable analysis, compared to current smokers, neither the rates of overall complications nor surgical site occurrences were significantly different in former smokers (OR = 0.93, 95% CI [0.76, 1.13] and OR = 0.92, 95% CI [0.73, 1.17]) and never smokers (OR = 0.99, 95% CI [0.83, 1.18] and OR = 0.86, 95% CI [0.70,1.06]) respectively. CONCLUSIONS: Smoking status is not associated with short-term adverse outcomes following inguinal hernia repair. Mandating smoking cessation does not appear necessary to prevent short-term adverse outcomes.

Mediumweight polypropylene mesh fractures after open retromuscular ventral hernia repair: incidence and associated risk factors.

PURPOSE: Mediumweight (MW) and heavyweight (HW) polypropylene have demonstrated similar clinical and patient-reported outcomes in the setting of open retromuscular ventral hernia repair (VHR). While MW mesh has an anecdotal risk of central mesh fracture, that phenomenon is not well-characterized. We sought to assess the incidence of and risk factors for MW polypropylene mesh fractures after VHR. METHODS: The ACHQC registry was queried for patients with CT-documented hernia recurrence after open retromuscular VHR with MW polypropylene mesh at our institution with 1-year follow-up between January 2014 and April 2022. Images were reviewed by five blinded surgeons at Cleveland Clinic to reach consensus that hernia recurrence mechanism was central mesh fracture. Patients without clinical recurrence or patient-reported bulge were used as a comparator group. RESULTS: Eighty patients were identified with radiographically documented recurrence; 28 had recurrence from mesh fractures and these were compared to 644 patients without recurrence. Incidence of MW fracture was 4.2%. Bridging of anterior fascia was more common in the group with the central mesh fracture (33.3% vs 3.3%, p < 0.001); the incidence of fracture was 30% (9/30) in patients requiring a bridged closure. Mesh fracture was associated with larger hernias (median width: 20 cm [16-26] vs 15 cm [12-18], p < 0.001,), length (25 cm [23-30] vs 23 cm [19-26], p = 0.004). CONCLUSION: MW polypropylene mechanical failures are surprisingly common, particularly in settings of bridged fascial closure and larger hernias. Use of HW polypropylene should be considered in this setting, and industry should be encouraged to create larger pieces of HW polypropylene mesh.

Efficacy and toxicity of anti-vascular endothelial growth receptor tyrosine kinase inhibitors in patients with neuroendocrine tumours - A systematic review and meta-analysis.

AIM: Although anti-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (RTKIs) have been tested in patients with neuroendocrine tumours (NETs) over the last two decades, no study to date has benchmarked efficacy and toxicity of these drugs in this patient population. METHODS: All phase II and phase III studies of anti-VEGF RTKIs in patients with NETs, published between January 1, 2000 andJuly 31, 2021, across major trial databases, were searched in August 2021 for relevant studies. The primary objectives of the meta-analysis were to compare objective response rate (ORR) and progression-free survival (PFS) between patients with pancreatic NETs (pNETs) and extra-pancreatic NETs (epNETs), and the incidence rate ratio (IRR) of adverse events between patients receiving anti-VEGF RTKIs and control. RESULTS: 1611 patients were available for the meta-analysis; 1194 received anti-VEGF RTKIs. ORR in pNETs was 18% (95% confidence interval (CI) 13-25%), while ORR in epNETs was 8% (95% CI 5-12%); test for differences between pNETs and epNETs (x12 = 8.38, p < .01). Median PFS in pNETs was 13.9 months (95% CI 11.43-16.38 months), while median PFS in epNETs was 12.71 months (95% CI 9.37-16.05 months); test for differences between pNETs and epNETs (x12 = .35, p = .55). With regards to common grade 3/4 adverse events , patients who received anti-VEGF RTKIs were more likely to experience hypertension (IRR 3.04, 95% CI 1.63-5.65) and proteinuria (IRR 5.79, 95% CI 1.09-30.74) in comparison to those who received control. CONCLUSIONS: Anti-VEGF RTKIs demonstrate anti-tumour effect in both pNETs and epNETs, supporting their development in both populations. These agents also appear to be safe in patients with NETs.

A Multicenter Retrospective Chart Review of Clinical Outcomes Among Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer.

BACKGROUND: On May 28, 2021, the United States Food and Drug Administration (FDA) granted accelerated approval to sotorasib for second-line or later treatment of patients with locally advanced or metastatic KRAS G12C mutant non-small cell lung cancer (NSCLC). This was the first FDA-approved targeted therapy for this patient population. Due to a paucity of real world data describing clinical outcomes in patients with locally advanced or metastatic KRAS G12C mutated NSCLC in the second-line or later, we sought to compile a large, academic medical center-based historical dataset to clarify clinical outcomes in this patient population. MATERIALS AND METHODS: The clinical outcomes of 396 patients with stage IV (n = 268, 68%) or recurrent, metastatic (n = 128, 32%) KRAS G12C mutant NSCLC were evaluated in this multicenter retrospective chart review conducted through the Academic Thoracic Oncology Medical Investigator's Consortium (ATOMIC). Patients treated at 13 sites in the United States and Canada and diagnosed between 2006 and 2020 (30% 2006-2015, 70% 2016-2020) were included. Primary outcomes included real-world PFS (rwPFS) and overall survival (OS) from time of stage IV or metastatic diagnosis, with particular interest in patients treated with second-line docetaxel-containing regimens, as well as clinical outcomes in the known presence or absence of STK11 or KEAP1 comutations. RESULTS: Among all patients with stage IV or recurrent, metastatic KRAS G12C mutant NSCLC (n = 201 with KRAS G12C confirmed prior to first line systemic therapy), the median first-line rwPFS was 9.3 months (95% CI, 7.3-11.8 months) and median OS was 16.8 months (95% CI, 12.7-22.3 months). In this historical dataset, first line systemic therapy among these 201 patients included platinum doublet alone (44%), PD-(L)1 inhibitor monotherapy (30%), platinum doublet chemotherapy plus PD-(L)1 inhibitor (18%), and other regimens (8%). Among patients with documented second-line systemic therapy (n = 123), the second-line median rwPFS was 8.3 months (95% CI, 6.1-11.9 months), with median rwPFS 4.6 months (95% CI, 1.4-NA) among 10 docetaxel-treated patients (9 received docetaxel and 1 received docetaxel plus ramucirumab). Within the total study population, 49 patients (12%) had a co-occurring STK11 mutation and 3 (1%) had a co-occurring KEAP1 mutation. Among the 49 patients with a co-occurring KRAS G12C and STK11 mutation, median rwPFS on first-line systemic therapy (n = 23) was 6.0 months (95% CI, 4.7-NA), and median OS was 14.0 months (95% CI, 10.8-35.3 months). CONCLUSION: In this large, multicenter retrospective chart review of patients with KRAS G12C mutant NSCLC we observed a relatively short median rwPFS of 4.6 months among 10 patients with KRAS G12C mutant NSCLC treated with docetaxel with or without ramucirumab in the second-line setting, which aligns with the recently reported CodeBreak 200 dataset.

Walk before you run: Feasibility challenges and lessons learned from the PROCLAIM study, a multicenter randomized controlled trial of misoprostol for prevention of recurrent Clostridioides difficile during COVID-19.

We analyzed our challenging experience with a randomized controlled trial of misoprostol for prevention of recurrent C. difficile. Despite careful prescreening and thoughtful protocol modifications to facilitate enrollment, we closed the study early after enrolling just 7 participants over 3 years. We share lessons learned, noting the importance of feasibility studies, inclusion of biomarker outcomes, and dissemination of such findings to inform future research design and implementation successes.

Social Vulnerability and Initiation of Pharmacotherapy for Gestational Diabetes Mellitus in a Medicaid Population.

OBJECTIVE: Our study examines the association between social vulnerability index (SVI) and pharmacotherapy initiation for gestational diabetes mellitus (GDM). METHODS: We studied a retrospective cohort of pregnant patients with GDM, enrolled in Tennessee Medicaid, who gave birth between 2007 and 2019. Enrollment files were linked to birth and death certificates, state hospitalization registries, and pharmacy claims. SVI, measured at the community level and determined by residential census tract, ranged from 0 to 100 (low to high vulnerability). Multivariable logistic regression assessed the association between SVI and the odds of initiating the most common pharmacotherapies for GDM-insulin, glyburide, or metformin-and adjusted for relevant covariates. SVI was modeled with restricted cubic splines to account for nonlinear associations, using the median Tennessee SVI as a reference. Secondary analysis assessed associations with the SVI subthemes. RESULTS: Among 33,291 patients with GDM, 21.7% (7,209) initiated pharmacotherapy during pregnancy. Patients from areas with higher SVI were more likely to be non-Hispanic Black with higher body mass index, whereas those with lower SVI were more likely to be nulliparous. Multivariable modeling demonstrated a complex nonlinear association between SVI and GDM pharmacotherapy initiation, relative to the reference. Higher SVI was associated with elevated odds of GDM pharmacotherapy initiation (e.g., odds ratio 1.11 [95% confidence interval 1.02-1.22] for SVI 80) and low to medium SVI had variable nonsignificant associations with GDM pharmacotherapy initiation, relative to the reference (lower odds of initiation for values 25-50, higher odds of initiation for values < 25). Secondary analysis demonstrated a nonlinear association between subtheme 3 and the odds of GDM pharmacotherapy initiation. CONCLUSION: Social vulnerability is associated with initiation of pharmacotherapy for GDM, highlighting the possible role of social determinants of health in achieving glycemic control.

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.