Allen R. Kunselman

Purpose: To characterize quality of life (QoL) and depressive symptoms among caregivers of children with optic nerve hypoplasia (ONH), identify associated demographic and clinical factors, and explore the measurement properties of a modified caregiver QoL instrument. Patients and Methods: This cross-sectional survey included 20 primary caregivers of children with ONH who completed a modified 20-item Caregiver’s Congenital Glaucoma Quality of Life (CarCGQoL) questionnaire (0– 40; higher scores indicate better self-reported QoL), the Patient Health Questionnaire-9 (PHQ-9; 0– 27), and a demographic and clinical survey. CarCGQoL analyses required completion of ≥ 16 of 20 items; clinical and demographic associations and measurement properties were explored. Results: Caregivers had a mean age of 42.7± 11.7 years, and 75% were mothers. In primary CarCGQoL analyses (n=19), scores were strongly inversely associated with PHQ-9 scores (r_s=− 0.73, p< 0.001); 50% of the full cohort reported at least mild depressive symptoms and 25% moderate-or-greater symptoms. CarCGQoL scores were lower among caregivers of children with bilateral vs unilateral ONH (19.8± 7.6 vs 29.9± 10.3, p=0.03) and were associated with nystagmus (r_pβ=− 0.55, p=0.01); nystagmus was also associated with higher PHQ-9 scores (r_pβ=0.63, p=0.003). Internal consistency was high among complete responders (Cronbach’s α=0.93), although exploratory Rasch analysis identified greatest misfit for the modified item addressing the child’s ability to see. Conclusion: Depressive symptoms were common and closely associated with lower modified CarCGQoL scores, while bilateral ONH and nystagmus were associated with poorer caregiver-reported outcomes. These findings support greater attention to caregiver well-being in ONH care and further evaluation of the modified CarCGQoL in larger cohorts.

Background: The Fontan operation is the final stage of palliation for single-ventricle patients. While operative survival has improved, pleural effusions remain a common postoperative complication, increasing morbidity and hospitalization. Our aim was to investigate the incidence and risk factors for unplanned readmissions due to post-Fontan pleural effusion. Methods: A retrospective review of all single ventricle patients who underwent the Fontan procedure from 2012–2023 was performed. This case-control study compared post-Fontan patients readmitted to the hospital due to pleural effusion with those who were not. Readmission was defined as rehospitalization for recurrent pleural effusion requiring intravenous diuretics and/or chest tube placement. Demographics, baseline clinical features, pre-Fontan hemodynamics, type of Fontan surgery, presence of fenestration, cardiac medications and doses, perioperative and post-discharge factors were analyzed between groups. Results: Sixty-one patients who were 42 ± 12.4 months of age underwent the Fontan operation. Of these, 31/61 (51%) had a diagnosis of hypoplastic left heart syndrome, 32/61 (52%) underwent extracardiac Fontan surgery, and 33/61 (54%) had a Fontan fenestration. Nine of 66 (14.7%) patients were readmitted for pleural effusion at a median of 7 days (IQR 5-15) post-discharge. Readmitted patients were older at Fontan (50.4 ± 13 vs 40.5 ± 11.8 months, P = .025), had increased chylothorax incidence (33.3% [3/9] vs 5.8% [3/52], P = .04), absent or restrictive fenestration at discharge (88.9% [8/9] vs 44.2% [23/52], P = .03) and were more likely to have pleural effusion at the first postoperative clinic visit (100% [9/9] vs 13.5% [7/52], P < .01). When comparing maximal diuretic usage, the readmitted patients required more diuretics (median 3 vs 2, P = .01). There were no significant differences in race, gender, weight at Fontan, cardiac anatomy, pre-Fontan hemodynamics, Fontan type, initial fenestration status, cardiopulmonary bypass duration time, supplemental oxygen duration, chest tube duration, number and doses of cardiac medications prior to and at Fontan discharge, or length of hospital stay. No patient required catheter-based intervention or surgery within 3 months post-Fontan discharge. Conclusion: Older age at Fontan, chylothorax, absent/restrictive fenestration at discharge, and detection of pleural effusion at the first postoperative clinic visit are risk factors for readmission due to pleural effusion. Earlier Fontan timing, optimizing diuretic management, and ensuring Fontan fenestration patency may reduce readmissions.

Background: The risk-to-benefit ratio of using combined oral contraceptive pills (COCPs) and/or metformin for comprehensive management of polycystic ovary syndrome (PCOS) in women with obesity is unclear. As there is a lack of robust evidence on the impact of these first-line medications on cardiovascular disease (CVD) risk, we compared the effect of COCPs, metformin or both on prevalence of metabolic syndrome (MetS) in participants with hyperandrogenic PCOS and hypothesized that COCPs would increase prevalence of MetS while metformin would decrease prevalence of MetS. Methods and findings: We conducted a multicenter, double-blind, double-dummy, randomized trial (COMET-PCOS) in participants between ages ≥18 and ≤40 years and body mass index (BMI) ≥25 kg/m ² and ≤ 48 kg/m ² with hyperandrogenic PCOS (defined by the Rotterdam criteria). Participants were randomized 1:1:1 to 24 weeks of low-dose COCPs (20 μg ethinyl estradiol/0.15 mg desogestrol), metforminXR (2,000 mg), or both (Combined). The primary outcome, assessed by intention-to-treat analysis, was the effect of the different treatment groups on the prevalence of MetS at the end of study. The analytical model included site, race, and the presence or absence of MetS at the screening visit as covariates. The secondary outcomes included changes in each component of MetS (TG, HDL-C, BP, WC, and fasting glucose levels) over the study period. Of the 240 participants randomly assigned, 20 out of 79 in the COCP group, 16 out of 81 in the metformin group, and 17 out of 80 in the combined group dropped out of the study. A total of 169 participants (70.4%) completed the trial between January 2018 and June 2023 (mean age: 29.5 years; mean BMI: 35.6 kg/m ² ; 70% were White and 23% were Black). The overall prevalence of MetS was 31% at baseline and comparable across groups. At the end of the study, the prevalence of MetS was 26.2% (17/65) in the metformin group, 28.6% (17/59) in the Combined group, and 28.8% (17/59) in COCP group with no significant difference in trend of MetS prevalence between groups (adjusted p = 0.26). Waist circumference (mean change (MC) −2.23 cm; 95% CI [−3.98, −0.49]; p = 0.01), BMI (MC −0.49 kg/m ² ; 95% CI [−0.88, −0.10]; p = 0.01), and android fat mass measured by DXA (MC −167 g; 95% CI [−264, −71[; p < 0.001) decreased in the COCP group over the study period whilst there was no statistically significant changes in these parameters in the metformin only group when compared to baseline.. In the metformin and Combined groups, the majority of participants (>64%) reported diarrhea, while 24.1% in the COCP group reported uterine bleeding. The main methodologic limitation of the study is the potential lack of power to detect differences in secondary outcomes. Conclusions: In participants with hyperandrogenic PCOS and overweight/obesity, low-dose COCPs effectively managed PCOS symptoms without increasing prevalence of MetS. Our findings challenge the current practice of using metformin alone or with COCPs for lowering cardiometabolic risk. Trial registration: ClinicalTrials.Gov Identifier: NCT03229057.

Polycystic ovary syndrome (PCOS) is a complex, multi-system, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive-aged women. While insulin resistance (IR) is not a diagnostic feature, it is widespread in women with PCOS, and often more severe than in women of similar age and BMI. Conversely, women with rare Mendelian disorders of IR also present with features of PCOS. We hypothesize that PCOS is driven by underlying IR, which can be evaluated through a genetic approach. We curated and stratified 310 genes related to three mechanisms of IR using molecular and clinical criteria. We evaluated protein-altering genetic variation in 102 insulin signaling genes, 29 obesity genes, and 22 dyslipidemia genes from whole-exome sequencing data from 675 PCOS patients. 40 insulin signaling genes, 12 obesity genes, and 10 dyslipidemia genes were significantly enriched for protein-altering variation in PCOS cases compared to healthy population controls. Variants in these 62 significantly enriched genes affected 51% of PCOS cases in our study cohort. The 15 highest ranked genes were selected for follow-up: LMNA, LEPR, KCNJ11, BSCL2, ACACA, NTRK2, GCK, ABCC8, SLC2A2, POMC, MC4R, TBC1D4, INSR, NR0B2, and GCKR . 50% of variants identified in these 15 genes were pathogenic, 35% were likely pathogenic, and only 15% were variants of uncertain significance. These findings support IR as a central pathway in PCOS. Furthermore, this study demonstrates that a candidate pathway approach with sufficient pre-processing can successfully identify functionally relevant variants and genes underlying complex traits.

Background: Regulating gestational weight gain (GWG) in pregnant women with overweight or obesity is difficult, particularly because of the narrow range of recommended GWG for optimal health outcomes. Given that many pregnant women show excessive GWG and considering the lack of a “gold standard” intervention to manage GWG, there is a timely need for effective and efficient approaches to regulate GWG. We have enhanced the Healthy Mom Zone (HMZ) 2.0 intervention with a novel digital platform, automated dosage changes, and personalized strategies to regulate GWG, and our pilot study demonstrated successful recruitment, compliance, and utility of our new control system and digital platform. Objective: The goal of this paper is to describe the study protocol for a randomized controlled optimization trial to examine the efficacy of the enhanced HMZ 2.0 intervention with the new automated control system and digital platform to regulate GWG and influence secondary maternal and infant outcomes while collecting implementation data to inform future scalability. Methods: This is an efficacy study using a randomized controlled trial design. HMZ 2.0 is a multidosage, theoretically based, and individually tailored adaptive intervention that is delivered through a novel digital platform with an automated link of participant data to a new model-based predictive control algorithm to predict GWG. Our new control system computes individual dosage changes and produces personalized physical activity (PA) and energy intake (EI) strategies to deliver just-in-time dosage change recommendations to regulate GWG. Participants are 144 pregnant women with overweight or obesity randomized to an intervention (n=72) or attention control (n=72) group, stratified by prepregnancy BMI (<29.9 vs ≥30 kg/m2), and they will participate from approximately 8 to 36 weeks of gestation. The sample size is based on GWG (primary outcome) and informed by our feasibility trial showing a 21% reduction in GWG in the intervention group compared to the control group, with 3% dropout. Secondary outcomes include PA, EI, sedentary and sleep behaviors, social cognitive determinants, adverse pregnancy and delivery outcomes, infant birth weight, and implementation outcomes. Analyses will include descriptive statistics, time series and fixed effects meta-analytic approaches, and mixed effects models. Results: Recruitment started in April 2024, and enrollment will continue through May 2027. The primary (GWG) and secondary (eg, maternal and infant health) outcome results will be analyzed, posted on ClinicalTrials.gov, and published after January 2028. Conclusions: Examining the efficacy of the novel HMZ 2.0 intervention in terms of GWG and secondary outcomes expands the boundaries of current GWG interventions and has high clinical and public health impact. There is excellent potential to further refine HMZ 2.0 to scale-up use of the novel digital platform by clinicians as an adjunct treatment in prenatal care to regulate GWG in all pregnant women. International Registered Report Identifier (IRRID): DERR1-10.2196/66637

Context Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS. Objective We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and selects a lipodystrophy-like subtype of PCOS. Design, Setting, and Participants We sequenced LMNA by targeted sequencing a discovery cohort of 811 PCOS patients and 164 healthy controls. We then analyzed LMNA from whole-exome sequencing (WES) of a replication cohort of 718 PCOS patients and 281 healthy controls. Main Outcome Measures Variation in the LMNA gene, hormone and lipid profiles of participants Results In the discovery cohort, we identified 8 missense variants in 15/811 cases, and 1 variant in 1/172 reproductively healthy controls. There is strong evidence for association between the variants and PCOS compared to gnomAD non-Finnish European population controls (χ²=17, p=3.7x10^-5, OR=2.9). In the replication cohort, we identified 11 unique variants in 15/718 cases, and 1 variant in 281 reproductively healthy controls. Again, there is strong evidence for association with population controls (χ²=30.5, p=3.4x10^-8, OR= 4.0). In both the discovery and replication cohorts, variants in LMNA identify women with PCOS with high triglycerides and extreme insulin resistance. Conclusions Rare missense variation in LMNA is reproducibly associated with PCOS and identifies some individuals with lipodystrophy-like features. The overlap between this PCOS phenotype and genetic partial lipodystrophy syndromes warrants further investigation into additional lipodystrophy genes and their potential in PCOS etiology.

OBJECTIVES: A variable pitch locking screw is intended to provide interfragmentary compression combined with fixed angle stability of locking plate constructs. The objective of this study was to compare variable pitch locking screws (3.5-mm KreuLock Ti locking compression screws, Arthrex Inc., Naples, FL) with standard locking screws (from the same manufacturer) in bicortical fixation scenarios in cadaver bone by assessing (1) interfragmentary compression and plate-bone compression and (2) construct biomechanical stability. METHODS: Nine matched pairs of fresh-frozen cadaveric specimens with an average age of 67.2 years (range, 37–83) were used. Interfragmentary compression and plate-bone compression associated with insertion of single bicortical screws were compared between the variable pitch and standard locking screws at increasing levels of torque. The specimens tested were distal tibiae having a simulated longitudinal fracture. Additionally, fibulae were osteotomized to create a stable longitudinal fracture pattern and were fixed with a 5-screw plate construct with either all variable pitch or all standard locking screws. One of the 5 screws was placed across the osteotomy without lagging. Fibulae were tested cyclically with axial with torsional loading to compare displacements, rotation, and loads at failure or tested in 4-point bending to compare construct stiffness and maximum force to failure. RESULTS: Interfragmentary and plate-bone compression forces in the distal tibia model varied across specimens but were significantly higher with variable pitch locking screws compared with standard locking screws [512 N (SD = 324 N) vs. 79 N (SD = 64 N), P = 0.002, and 242 N (SD = 119 N) vs. 104 N (SD = 123 N), P = 0.028, respectively]. In cyclic loading of fibula constructs, no significant differences were detected in construct axial displacement or angular displacement (P > 0.05). In 4-point bending, no differences were detected in maximum force or bending stiffness (P > 0.05). CONCLUSIONS: Variable pitch locking screws produced interfragmentary compression between cortices and plate-bone compression that was greater than that produced by standard locking screws. In a stable bicortical fibula fixation scenario under external loading, the stability of variable pitch locking screw constructs was similar to constructs with standard locking screws.

BACKGROUND Regulating gestational weight gain (GWG) in pregnant women with overweight or obesity is difficult, particularly because of the narrow range of recommended GWG for optimal health outcomes. Given that many pregnant women show excessive GWG and considering the lack of a “gold standard” intervention to manage GWG, there is a timely need for effective and efficient approaches to regulate GWG. We have enhanced the Healthy Mom Zone (HMZ) 2.0 intervention with a novel digital platform, automated dosage changes, and personalized strategies to regulate GWG, and our pilot study demonstrated successful recruitment, compliance, and utility of our new control system and digital platform. OBJECTIVE The goal of this paper is to describe the study protocol for a randomized controlled optimization trial to examine the efficacy of the enhanced HMZ 2.0 intervention with the new automated control system and digital platform to regulate GWG and influence secondary maternal and infant outcomes while collecting implementation data to inform future scalability. METHODS This is an efficacy study using a randomized controlled trial design. HMZ 2.0 is a multidosage, theoretically based, and individually tailored adaptive intervention that is delivered through a novel digital platform with an automated link of participant data to a new model-based predictive control algorithm to predict GWG. Our new control system computes individual dosage changes and produces personalized physical activity (PA) and energy intake (EI) strategies to deliver just-in-time dosage change recommendations to regulate GWG. Participants are 144 pregnant women with overweight or obesity randomized to an intervention (n=72) or attention control (n=72) group, stratified by prepregnancy BMI (<29.9 vs ≥30 kg/m2), and they will participate from approximately 8 to 36 weeks of gestation. The sample size is based on GWG (primary outcome) and informed by our feasibility trial showing a 21% reduction in GWG in the intervention group compared to the control group, with 3% dropout. Secondary outcomes include PA, EI, sedentary and sleep behaviors, social cognitive determinants, adverse pregnancy and delivery outcomes, infant birth weight, and implementation outcomes. Analyses will include descriptive statistics, time series and fixed effects meta-analytic approaches, and mixed effects models. RESULTS Recruitment started in April 2024, and enrollment will continue through May 2027. The primary (GWG) and secondary (eg, maternal and infant health) outcome results will be analyzed, posted on ClinicalTrials.gov, and published after January 2028. CONCLUSIONS Examining the efficacy of the novel HMZ 2.0 intervention in terms of GWG and secondary outcomes expands the boundaries of current GWG interventions and has high clinical and public health impact. There is excellent potential to further refine HMZ 2.0 to scale-up use of the novel digital platform by clinicians as an adjunct treatment in prenatal care to regulate GWG in all pregnant women. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/66637