Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

Healthcare disparities and pelvic organ prolapse operative complications: a nationwide analysis.

INTRODUCTION AND HYPOTHESIS: The objective of this study was to evaluate the differences in the incidence of peri-operative complications at the time of pelvic organ prolapse (POP) repair based on health care disparities such as race and socioeconomic status. METHODS: The National Inpatient Sample (NIS) database was queried using ICD-9/-10 codes for patients aged >18 years undergoing POP repair in 2008-2018. Demographic information, Elixhauser Comorbidity Index (ECI), insurance status, and peri-operative complications were extracted. Multivariate weighted logistic regression using the discharge weights from NIS were constructed on binary outcomes. Complications with at least 1% incidence were included in the analysis. RESULTS: A total of 172,483 POP repair patients were analyzed: 130,022 (75.4%) were white, 10,561 (6.1%) were Black, 21,915 (12.7%) were Hispanic, and 9,985 (5.8%) were of other races. Patients with Medicaid as well as Black, Hispanic, and other races had higher odds of developing postoperative complications such as urinary tract infections, sepsis, and acute renal failure (p value <0.001-0.02). These were also more common in smaller, rural hospitals and with patients with an annual income of $45,999 or less (p value <0.001-0.03). Black and Hispanic patients had lower odds of intraoperative complications such as hemorrhage (aOR 0.77, 95% CI 0.71-0.84; aOR 0.75, 95% CI 0.7-0.8 respectively) or abdominopelvic injury (aOR 0.86, 95% CI 0.81-0.92; aOR 0.93, 95% CI 0.79-0.88 respectively) compared with white patients. CONCLUSION: Nonwhite patients with lower socioeconomic status had increased postoperative complications and fewer intraoperative complications from POP surgery, whereas white patients with higher socioeconomic status had more intraoperative complications.

Rate of Mesh Erosion After Sacrocolpopexy With Concurrent Supracervical Compared With Total Hysterectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the effect of concomitant supracervical hysterectomy compared with total hysterectomy during abdominal sacrocolpopexy on the rate of mesh erosion by performing a systematic review and meta-analysis of the existing literature. DATA SOURCES: From database inception through January 2022, we explored MEDLINE, Web of Science, EMBASE, CINAHL, ClinicalTrials.gov , and Cochrane Central Register of Controlled Trials. Studies comparing the rate of mesh erosion in women undergoing abdominal sacrocolpopexy who had concomitant supracervical hysterectomy compared with total hysterectomy were included. DATA EXTRACTION AND SYNTHESIS: Two reviewers separately ascertained studies, obtained data, and gauged study quality. The rate of mesh erosion was compared, and odds ratios (ORs) with 95% CIs were estimated. TABULATION, INTEGRATION, AND RESULTS: Nineteen studies with 10,572 women who underwent abdominal sacrocolpopexy were identified, including 4,285 women in the supracervical group and 6,287 women in the total hysterectomy group. The overall mean postprocedure follow-up time was 30.7±15.1 months (median 12.4, range 1.5-44.2). The median (95% CI) point prevalence of mesh erosion was 0.36% (0-1.9%) in women who had supracervical hysterectomy compared with 3.8% (1.8-8.7%) in women who had total hysterectomy. The overall rate of mesh erosion in women who had supracervical hysterectomy was lower compared with women who had total hysterectomy (pooled OR 0.26, 95% CI 0.18-0.38, I 2 0%). CONCLUSION: In women with symptomatic apical pelvic organ prolapse who undergo abdominal sacrocolpopexy with concomitant hysterectomy, supracervical hysterectomy is associated with a lower risk of mesh erosion compared with total hysterectomy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022301862.

Health Care Disparities in Surgical Management of Pelvic Organ Prolapse: A Contemporary Nationwide Analysis.

OBJECTIVES: Our objective was to compare the rate of native tissue repair (NTR) versus sacrocolpopexy (SCP) and reconstructive (RECON) versus obliterative repair (OBR) for the treatment of pelvic organ prolapse (POP), evaluating for health care disparities based on race, socioeconomic, and geographic factors. METHODS: The National Inpatient Sample database was queried for patients older than 18 years undergoing POP surgery from 2008 to 2018. Baseline demographics, comorbidity index, socioeconomic, and hospital variables were extracted. The weighted t test, Wilcoxon test, and χ2 test were used to compare the rate of (1) NTR versus SCP and (2) RECON vs OBR. Multivariate weighted logistic regression was used to compare while controlling for confounders. Reference groups were White race, Medicare patients, northeast region, small hospital size, and rural location. RESULTS: Of 71,262 patients, 67,382 (94.6%) underwent RECON. Patients undergoing OBR were older and had a higher comorbidity score. Multivariate analysis showed the following: (1) Black, Hispanic, and other races; (2) Medicaid patients; (3) patients at urban teaching hospitals are less likely to receive RECON. Patients in the midwest were more likely to receive RECON. Among 68,401 patients, 23,808 (34.8%), and 44,593 (65.19%) underwent SCP and NTR, respectively. Hysterectomy was more common in the NTR group. Multivariate analysis showed the following:(1) Black, Hispanic, and "other" races; (2) uninsured and Medicaid patients; (3) patients in the midwest, south, and west were at higher odds of receiving NTR. Patients in large and urban hospitals were less likely to undergo NTR. CONCLUSIONS: Racial, socioeconomic, and geographic disparities exist in surgical management for POP warranting further study to seek to eliminate these disparities.

COVID-19 and its effect on Instagram adoption by #OBGYN residency programs.

OBJECTIVES: Instagram (IG) is becoming one of the larger resource tools within medicine. Since the onset of the COVID-19 pandemic, it is becoming important for programs to improve virtual presence and outreach. We evaluated the adoption of IG by OB/GYN residency programs in the United States and aimed to see if highly ranked programs had higher utilization rates. METHODS: IG presence and engagement metrics were extracted for all ACGME accredited OB/GYN programs. Doximity residency navigator tool was used to obtain nationwide program rankings, and statistical analysis was performed to prove any significant correlation. Mann-Whitney U test, Cochran-Armitage test and Analysis of variance were used for analysis. IRB exemption was obtained. RESULTS: Seventy percent of programs (202/287) have IG presence, with the majority creating presence after the COVID pandemic began (115/202; 57%). Seventy-two percent (83/115) of these programs created their IG account once virtual interviews were announced. The top 25% of programs, as ranked on Doximity, have a higher number of posts, followers and likes when compared to the rest of the programs. CONCLUSIONS: The COVID-19 pandemic has led to increased adoption of IG by residency programs. Highly ranked and reputed programs have higher rates of activity, popularity, and engagement on IG.

Neonatal and maternal outcomes among twin pregnancies stratified by mode of conception in the United States.

OBJECTIVE: To compare neonatal and maternal outcomes among twin pregnancies conceived as a result of different types of fertility treatments with those of spontaneously conceived twin pregnancies. DESIGN: Retrospective Cohort. SETTING: Population-based analysis. PATIENT(S): Population-based analysis of twin pregnancies in the United States based on their mode of conception using the natality data from the National Center for Health Statistics from the Centers for Disease Control and Prevention (from January 2015 through December 2017). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Adverse neonatal and maternal outcomes. RESULT(S): The overall prevalence of early adverse maternal outcomes and medical complications and obstetric complications including the risk of unplanned hysterectomy, intensive care unit admission, maternal blood transfusion, and perineal laceration were significantly higher in the fertility treatment group (including both ovulation induction/intrauterine insemination and assisted reproductive technology groups) compared with those of the spontaneous conception group, even after adjusting for several potential confounders. The risk of adverse composite neonatal outcomes was slightly lower in the spontaneous conception live twin birth group even after adjustment for several potential confounders. CONCLUSION(S): The rate of maternal and neonatal morbidity in twins conceived via different fertility treatments was slightly increased compared with those of twins conceived spontaneously. Because the absolute risks of maternal and neonatal morbidity were low, overall reassurance regarding these outcomes can be provided to the patients undergoing all types of fertility treatments.

A Comparison of Perioperative Outcomes, Readmission, and Reoperation for Sacrospinous Ligament Fixation, Uterosacral Ligament Suspension, and Minimally Invasive Sacrocolpopexy.

OBJECTIVES: Sacrospinous ligament fixation (SSLF), uterosacral ligament suspension (USLS), and minimally invasive sacrocolpopexy (MISC) are common routes for vaginal apical suspension. Comparative data analyzing perioperative adverse events among these 3 routes are sparse. Perioperative morbidity was compared among these 3 approaches. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients older than 18 years undergoing these surgical procedures from 2012 to 2018. Baseline characteristics, postoperative complications, and rates and timing of readmission/reoperation with identification of causes for either were extracted. Logistic regression was used to compare the odds of readmission or reoperation, adjusting for concurrent hysterectomy and the American Society of Anesthesiologists (ASA) score. RESULTS: There were 1,881 SSLFs, 975 USLSs, and 4,559 MISCs that were performed from 2012 to 2018. Vaginal approaches were more common in older, non-White women; women with comorbidities; and women with higher ASA scores and performed more often by gynecologists (vs urologists). More concomitant hysterectomies were performed with USLS and MISC than with SSLF (22% and 26% vs 5%). Increased postoperative blood transfusions, urinary tract infections, and overall complications were noted in the vaginal approaches (7% and 7% vs 5%). Minimally invasive sacrocolpopexy had longer operative times. More same-day discharges were observed in USLS and SSLF. Readmission (2%-3%) and reoperation (1%-2%) rates were similar across all routes when adjusted for concomitant hysterectomy and ASA class. The most common indications for readmission were related to bleeding, infection, or bowel issues (MISC). Hemorrhage/hematoma followed by intestinal obstruction was the most common indication for reoperation. CONCLUSIONS: Overall perioperative safety is comparable in 3 common vaginal apical suspension routes. Readmission and reoperation remain rare after operative colpopexy regardless of route.

Perioperative outcomes of reconstructive surgery for apical prolapse in the very elderly: a national contemporary analysis.

INTRODUCTION AND HYPOTHESIS: It is predicted that the number of women aged 80 years or older will more than triple by 2050. In the US, women have a 13% lifetime risk of undergoing pelvic organ prolapse surgery. Our aim was to compare the perioperative outcomes following various reconstructive approaches for apical prolapse surgery in the very elderly. METHODS: The National Surgical Quality Improvement Program database was used to identify women age ≥ 80 years of age who underwent reconstructive apical prolapse surgery from 2010 to 2017. Perioperative morbidity of vaginal colpopexy, minimally invasive sacrocolpopexy (MISC) and abdominal sacrocolpopexy (ASC) were compared. The primary outcome was the rate of composite serious complications. Univariate and multivariate logistic regression was used to identify independent predictors of serious complications. RESULTS: A total of 1012 patients were identified: vaginal (n = 792), MISC (n = 151) and ASC (n = 69). The composite serious complication rate was higher in the ASC group compared to vaginal/MISC groups (18.8% vs. 9.3% and 9.3%, p < 0.05). ASC had higher rates of blood transfusion, thromboembolism and reintubation. Life-threatening complications, readmission, pneumonia, stroke and 30-day mortality were lowest in the vaginal group. ASC (aOR 2.27), age > 85 years (aOR 1.98), operative time > 3 h (aOR 2.02), baseline dyspnea (aOR 2.17), "other race" (aOR 2.04), preoperative coagulopathy (aOR 2.92) and ASA (aOR 1.47) were associated with composite serious complications. CONCLUSION: ASC is associated with higher perioperative morbidity in the very elderly population. MISC and vaginal colpopexy have similar rates of composite serious complications; however, vaginal colpopexy is overall the safest approach in this population.

Prescribed medical cannabis in women with gynecologic malignancies: A single-institution survey-based study.

Research within a gynecologic oncology population has lagged behind the uptake in use of medical cannabis for symptom control. This study seeks to evaluate patient experience with prescribed medical cannabis obtained through licensed dispensaries in women with gynecologic malignancies. A 43-item survey exploring patient experience with medical cannabis was administered to women with gynecologic malignancies who used medical cannabis prescribed by a gynecologic oncologist. Thirty-six eligible patients were approached for consent, and 31 patients returned completed surveys (86%). Ninety-three percent had advanced or recurrent disease; 74% were receiving chemotherapy or immunotherapy. Eighty-three percent reported medical cannabis provided relief from cancer or treatment-related symptoms including decreased appetite (41%), insomnia (41%), neuropathy (41%), anxiety (35%), nausea (29%), joint pain (29%), bone pain (29%), abdominal pain (25%), and depression (19%). Eighty percent of patients reported medical cannabis worked the same or better than other traditional medications for management of their cancer or treatment-related symptoms, and 83% reported medical cannabis had an equivalent or better side effect profile. Of the subset of patients using medical cannabis for pain, 63% reported a reduction in opioid use. Patients perceive that medical cannabis was useful for relief of cancer and treatment-related symptoms, suggesting medical cannabis may be a reasonable alternative or adjunct therapy. Medical cannabis was well tolerated and may have the potential to improve neuropathic pain and decrease opioid use.

Academic tweeting in #ObGyn. Where do we stand?

Objective To describe the scenario of academic tweeting and utilization of Twitter by editorial board members of the leading journal in obstetrics and gynecology. Methods The Twitter presence of an editorial board members of obstetrics and gynecology journal with an impact factor greater than 4 was determined. Details of their Twitter activity, year of graduation from medical school and gender were analyzed. Median SparkScore™, an online influence measure, of journals was compared to the highest impact factor journals in medicine (New England Journal of Medicine, The Lancet, The British Medical Journal and Journal of the American Medical Association). Results In the six highest impact factor journals in obstetrics and gynecology, 92 of 240 (38.3%) editorial board members had an active Twitter account. The Twitter presence of editorial members of Obstetrics and Gynecology was statistically less when compared to all other journals (P < 0.01). The median number of tweets in the last 24 h and 7 days were 0. Median SparkScore™ for the highest impact factor obstetrics and gynecology journals (24) were lower compared to the highest impact journals in medicine (66) (P = 0.03). Conclusion Editorial board members of the six highest impact factor journals in obstetrics and gynecology are not capitalizing on the dynamic nature of Twitter and its instant convenient access from our smartphones to further academia, when compared to specialties in medicine. There is a need for increased adoption of Twitter among physician leaders in the specialty.

Evacuation of a large traumatic vulvar haematoma with an intravaginal cosmetic approach.

A healthy youngwoman presented 3 days after a jet ski accident with a large left vulvar haematoma measuring 12 cm. Immediately postinjury, she was managed conservatively in the emergency room of another hospital. However, the haematoma continued to slowly expand. She presented to our clinic with difficulty walking and severe discomfort. Decision was made to drain the haematoma surgically. The patient was sceptical to have scarring on her vulva. Thus, the haematoma was evacuated by a vertical incision on the left vaginal sidewall. After evacuation and achieving haemostasis, the was closed with two interrupted sutures. Edges of the incision were secured similar to marsupialisation with five interrupted sutures to allow continual drainage. Her discomfort resolved immediately postsurgery and she had an uncomplicated postoperative course. The intravaginal approach yielded superior aesthetic result with no scarring on the external vulva.

Phosphorylation Modulates Catalytic Activity of Mycobacterial Sirtuins.

Sirtuins are NAD(+)-dependent deacetylases involved in the regulation of diverse cellular processes and are conserved throughout phylogeny. Here we report about in vitro transphosphorylation of the only NAD(+)-dependent deacetylase (mDAC) present in the genome of Mycobacterium tuberculosis by eukaryotic-type Ser/Thr kinases, particularly PknA. The phosphorylated mDAC displayed decreased deacetylase activity compared to its unphosphorylated counterpart. Mass-spectrometric study identified seven phosphosites in mDAC; however, mutational analysis highlighted major contribution of Thr-214 for phosphorylation of the protein. In concordance to this observation, variants of mDAC substituting Thr-214 with either Ala (phospho-ablated) or Glu (phosphomimic) exhibited significantly reduced deacetylase activity suggesting phosphorylation mediated control of enzymatic activity. To assess the role of phosphorylation towards functionality of mDAC, we opted for a sirtuin knock-out strain of Escherichia coli (Δdac), where interference of endogenous mycobacterial kinases could be excluded. The Δdac strain in nutrient deprived acetate medium exhibited compromised growth and complementation with mDAC reversed this phenotype. The phospho-ablated or phosphomimic variant, on the other hand, was unable to restore the functionality of mDAC indicating the role of phosphorylation per se in the process. We further over-expressed mDAC or mDAC-T214A as His-tagged protein in M. smegmatis, where endogenous eukaryotic-type Ser/Thr kinases are present. Anti-phosphothreonine antibody recognized both mDAC and mDAC-T214A proteins in western blotting. However, the extent of phosphorylation as adjudged by scanning the band intensity, was significantly low in the mutant protein (mDAC-T214A) compared to that of the wild-type (mDAC). Furthermore, expression of PknA in the mDAC complemented Δdac strain was able to phosphorylate M. tuberculosis sirtuin. The growth profile of this culture in acetate medium was slow compared to that transformed with only vector. On the other hand, use of a kinase dead variant, PknA-K42N instead of PknA, did not display such behavior, which again supported phosphorylation mediated control of mDAC protein. Thus, our results ostensibly render evidence for cross-talk between two distinct post-translational modifications, phosphorylation and deacetylation, in any bacteria. Bioinformatic analysis further indicated conservation of Thr-214 among different mDAC orthologs, thereby arguing the event as mycobacteria specific.

Evidence that phosphorylation of threonine in the GT motif triggers activation of PknA, a eukaryotic-type serine/threonine kinase from Mycobacterium tuberculosis.

Phosphorylation of the activation loop in the catalytic domain of the RD family of bacterial eukaryotic-type Ser/Thr protein kinases (STPK) induces their conformational transition from an inactive to active state. However, mechanistic insights into the phosphorylation-mediated transition of these STPKs from an inactive to active state remain unknown. In the present study, we addressed this issue with PknA, an essential STPK from Mycobacterium tuberculosis. We found that the catalytic activity of PknA is confined within the N-terminal 283 amino acids (PknA-283). The crystal structure of PknA-283 in unphosphorylated form showed an ordered activation loop and existed in an inactive state preventing the phosphorylation of its cognate substrate(s). Peptide mass finger printing studies revealed that all activation loop threonines (Thr172, Thr174 and Thr180) were phosphorylated in the activated PknA-283 protein. Substitution of Thr180 with Ala/Asp (T180A/T180D) resulted in catalytically defective mutants, whereas a double mutant replacing Thr172 and Thr174 with Ala (T172A-T174A) was deficient in kinase activity. Analysis of PknA-283 structure, together with biochemical studies, revealed the possibility of phosphorylation of Thr180 via a cis mechanism, whereas that of Thr172 and Thr174 occurs via a trans mechanism. Moreover, unlike wild-type, these mutants did not show any drastic change in cell morphology in a phenotypic assay, implicating the role of all threonines in the activation loop towards the functionality of PknA. Thus, our findings offer a model for kinase activation showing that the phosphorylation of Thr180 triggers PknA to transphosphorylate Thr172/Thr174, thereby governing its functionality.