Luteal Phase Defects and Progesterone Supplementation.

Importance: Luteal phase defects (LPDs), or an insufficiency of progesterone production during the luteal phase of the menstrual cycle, have been identified as a potential cause of recurrent pregnancy loss (RPL), but its exact contribution to RPL is not well-defined. In addition, the role of exogenous progesterone supplementation during pregnancy remains controversial. Objective: The goal of this review is to provide an updated, evidence-based summary of LPD, including prevalence and potential pathophysiologic mechanisms, and to explore the current controversies regarding progesterone supplementation for management and treatment of RPL. Evidence Acquisition: A literature review identified relevant research using a PubMed search, Cochrane summaries, review articles, textbook chapters, databases, and society guidelines. Results: Endogenous progesterone plays a crucial role in the first trimester of pregnancy, and therefore, insufficiency may contribute to RPL. However, the precise relationship between LPD and RPL remains unclear. Luteal phase defect is primarily a clinical diagnosis based on a luteal phase less than 10 days. Although there may be a possibility of incorporating a combined clinical and biochemical approach in defining LPD, the current lack of validated diagnostic criteria creates a challenge for its routine incorporation in the workup of infertility. Moreover, no treatment modality has demonstrated efficacy in improving fertility outcomes for LPD patients, including progesterone supplementation, whose inconsistent data do not sufficiently support its routine use, despite its minimal risk. It is imperative that women diagnosed with LPD should be worked up for other potential conditions that may contribute to a shortened luteal phase. Future work needs to focus on identifying a reproducible diagnostic test for LPD to guide treatment. Conclusions and Relevance: Currently, the perceived relationship between LPD and RPL is challenged by conflicting data. Therefore, patients with an abnormal luteal phase should undergo a thorough workup to address any other potential etiologies. Although supplemental progesterone is commonly utilized for treatment of LPD and RPL, inconsistent supporting data call for exogenous hormone therapy to be only used in a research setting or after a thorough discussion of its shortcomings.

SETD2 maintains nuclear lamina stability to safeguard the genome.

Histone methyltransferases play essential roles in the organization and function of chromatin. They are also frequently mutated in human diseases including cancer1. One such often mutated methyltransferase, SETD2, associates co-transcriptionally with RNA polymerase II and catalyzes histone H3 lysine 36 trimethylation (H3K36me3) - a modification that contributes to gene transcription, splicing, and DNA repair2. While studies on SETD2 have largely focused on the consequences of its catalytic activity, the non-catalytic functions of SETD2 are largely unknown. Here we report a catalysis-independent function of SETD2 in maintaining nuclear lamina stability and genome integrity. We found that SETD2, via its intrinsically disordered N-terminus, associates with nuclear lamina proteins including lamin A/C, lamin B1, and emerin. Depletion of SETD2, or deletion of its N-terminus, resulted in widespread nuclear morphology abnormalities and genome stability defects that were reminiscent of a defective nuclear lamina. Mechanistically, the N-terminus of SETD2 facilitates the association of the mitotic kinase CDK1 with lamins, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Taken together, our findings reveal an unanticipated link between the N-terminus of SETD2 and nuclear lamina organization that may underlie how SETD2 acts as a tumor suppressor.

Race differences in iliofemoral vein stenting for chronic venous insufficiency.

INTRODUCTION: Major disparities in outcomes by race are present throughout vascular surgery, yet little has been published on iliac vein stent outcomes by race. This retrospective study assessed iliac vein stent outcomes by patient race. METHODS: Patients who underwent iliac vein stenting at a single institution for chronic venous insufficiency (CVI) from 2011 to 2021 were reviewed. Demographic, preoperative, perioperative, and postoperative data were collected. Self-reported race groups included Asian, Black, Hispanic, and White. Univariate differences were analyzed using χ2 tests for categorical variables and 1-way ANOVA for continuous variables. Outcomes included change in Venous Clinical Severity Score (VCSS) at interval timepoints relative to a preoperative baseline and reinterventions. Logistic regression models were used to determine the unadjusted and adjusted odds ratio (OR) of any minor and major reintervention. Multivariate regression models controlled for demographic and comorbidity characteristics. RESULTS: A total of 827 patients were included. Asian patients were younger and had a greater proportion of male patients, lower Body mass index (BMI), less smoking history, and fewer comorbidities. White patients were more likely to have a history of deep vein thrombosis (DVT). White patients presented with the most severe CVI symptoms as defined by both Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification and preoperative VCSS composite scores. There were no differences in acute DVT, number of stents deployed, and bilateral versus unilateral stent placement. Black patients had the longest average days of follow-up, followed sequentially by Hispanic, White, and Asian. Black patients had the most reinterventions, while Asian patients had the fewest. Asian patients were less likely to have a major reintervention. No differences in VCSS composite or change in VCSS were observed. CONCLUSIONS: In patients with CVI, Asian patients presented younger and healthier, while White patients presented with the most severe symptoms. No differences were observed in VCSS outcomes, though Black patients had the most reinterventions.

Patients with active venous leg ulcers at the time of iliac vein stenting require more reoperations.

OBJECTIVE: An active venous leg ulcer (VLU) caused by lower extremity venous insufficiency is challenging to treat and will often recur after initially healing. In the present study, we compared the symptomatic outcomes and need for reoperation after iliac vein stenting (IVS) in patients with an active VLU (VLU+) and those without an active VLU (VLU-). METHODS: A single-institution database of patients with chronic venous outflow obstruction who underwent IVS from August 2011 to June 2021 was analyzed. Symptoms were quantified using the venous clinical severity score. The patients were divided into two cohorts: those with (VLU+) and without (VLU-) VLUs. RESULTS: A total of 872 patients (71 VLU+ and 801 VLU-) were identified. Many of the demographics and comorbidities differed between the two cohorts, and these variables were included in the multivariable analysis. On univariate analysis, the VLU+ cohort was more likely to need a major reoperation (odds ratio, 1.94; 95% confidence interval, 1.01-3.52; P = .036). However, on multivariable analysis, the difference was not statistically significant (odds ratio, 1.17; 95% confidence interval, 0.55-2.40; P = .667). Additionally, the VLU+ cohort required a significantly greater mean total of reoperations (1.4 vs 1.0; P = .006) than the VLU- cohort. Comparatively, for patients who underwent at least one reoperation, the difference in the mean total number of reoperations was even greater for the VLU+ cohort (2.6 vs 1.8; P = .001). The results from the Kaplan-Meier log-rank test revealed no differences in the reintervention-free survival time (P = .980). Both cohorts experienced a durable mean reduction in the venous clinical severity score. The ulcer healing rates for the VLU+ cohort at 6, 12, 24, and 36 months were 38%, 47%, 52%, and 59%, respectively. The ulcer recurrence rates for the VLU+ cohort were 4%, 10%, 19%, and 30% at 6, 12, 24, and 36 months, respectively, with a median time to recurrence of 1.2 years. CONCLUSIONS: Patients with active VLUs who underwent a first reintervention after initial IVS, on average, required an additional reintervention.