The Risk of Sympathetic Ophthalmia Associated with Open-Globe Injury Management Strategies: A Meta-analysis.

TOPIC: Sympathetic ophthalmia (SO) is a sight-threatening granulomatous panuveitis caused by a sensitizing event. Primary enucleation or primary evisceration, versus primary repair, as a risk management strategy after open-globe injury (OGI) remains controversial. CLINICAL RELEVANCE: This systematic review was conducted to report the incidence of SO after primary repair compared with that of after primary enucleation or primary evisceration. This enabled the reporting of an estimated number needed to treat. METHODS: Five journal databases were searched. This review was registered with International Prospective Register of Systematic Reviews (identifier, CRD42021262616). Searches were carried out on June 29, 2021, and were updated on December 10, 2022. Prospective or retrospective studies that reported outcomes (including SO or lack of SO) in a patient population who underwent either primary repair and primary enucleation or primary evisceration were included. A systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Random effects modelling was used to estimate pooled SO rates and absolute risk reduction (ARR). RESULTS: Eight studies reporting SO as an outcome were included in total. The included studies contained 7500 patients and 7635 OGIs. In total, 7620 OGIs met the criteria for inclusion in this analysis; SO developed in 21 patients with OGI. When all included studies were pooled, the estimated SO rate was 0.12% (95% confidence interval [CI], 0.00%-0.25%) after OGI. Of 779 patients who underwent primary enucleation or primary evisceration, no SO cases were reported, resulting in a pooled SO estimate of 0.05% (95% CI, 0.00%-0.21%). For primary repair, the pooled estimate of SO rate was 0.15% (95% CI, 0.00%-0.33%). The ARR using a random effects model was -0.0010 (in favour of eye removal; 95% CI, -0.0031 [in favor of eye removal] to 0.0011 [in favor of primary repair]). Grading of Recommendations, Assessment, Development, and Evaluations analysis highlighted a low certainty of evidence because the included studies were observational, and a risk of bias resulted from missing data. DISCUSSION: Based on the available data, no evidence exists that primary enucleation or primary evisceration reduce the risk of secondary SO. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of amnioinfusion volume at the time of surgery for twin-twin transfusion syndrome and latency to delivery.

OBJECTIVE: To evaluate the impact of amnioinfusion and other peri-operative factors on pregnancy outcomes in the setting of Twin-twin transfusion syndrome (TTTS) treated via fetoscopic laser photocoagulation (FLP). METHODS: Retrospective study of TTTS treated via FLP from 2010 to 2019. Pregnancies were grouped by amnioinfusion volume during FLP (<1 L vs. ≥1 L). The primary outcome was latency from surgery to delivery. An amnioinfusion statistic (AIstat) was created for each surgery based on the volume of fluid infused and removed and the preoperative deepest vertical pocket. Regression analysis was planned to assess the association of AIstat with latency. RESULTS: Patients with amnioinfusion of ≥1 L at the time of FLP had decreased latency from surgery to delivery (61 ± 29.4 vs. 73 ± 28.8 days with amnioinfusion <1 L, p < 0.001) and increased preterm prelabor rupture of membranes (PPROM) <34 weeks (44.7% vs. 33.5%, p = 0.042). Amnioinfusion ≥1 L was associated with an increased risk of delivery <32 weeks (aRR 2.6, 95% CI 1.5-4.5), 30 weeks (aRR 2.4, 95% CI 1.5-3.8), and 28 weeks (aRR 1.9, 95% CI 1.1-2.3). Cox-proportional regression revealed that AIstat was inversely associated with latency (HR 1.1, 95% CI 1.1-1.2). CONCLUSION: Amnioinfusion ≥1 L during FLP was associated with decreased latency after surgery and increased PPROM <34 weeks.

The Use of Preoperative Prophylactic Systemic Antibiotics for the Prevention of Endopthalmitis in Open Globe Injuries: A Meta-Analysis.

TOPIC: This study reports the effect of systemic prophylactic antibiotics (and their route) on the risk of endophthalmitis after open globe injury (OGI). CLINICAL RELEVANCE: Endophthalmitis is a major complication of OGI; it can lead to rapid sight loss in the affected eye. The administration of systemic antibiotic prophylaxis is common practice in some health care systems, although there is no consensus on their use. METHODS: PubMed, CENTRAL, Web of Science, CINAHL, and Embase were searched. This was completed July 6, 2021 and updated December 10, 2022. We included randomized and nonrandomized prospective studies which reported the rate of post-OGI endophthalmitis when systemic preoperative antibiotic prophylaxis (via the oral or IV route) was given. The Cochrane Risk of Bias tool and ROBINS-I tool were used for assessing the risk of bias. Where meta-analysis was performed, results were reported as an odds ratio. PROSPERO registration: CRD42021271271. RESULTS: Three studies were included. One prospective observational study compared outcomes of patients who had received systemic or no systemic preoperative antibiotics. The endophthalmitis rates reported were 3.75% and 4.91% in the systemic and no systemic preoperative antibiotics groups, a nonsignificant difference (P = 0.68). Two randomized controlled trials were included (1555 patients). The rates of endophthalmitis were 17 events in 751 patients (2.26%) and 17 events in 804 patients (2.11%) in the oral antibiotics and IV (± oral) antibiotics groups, respectively. Meta-analysis demonstrated no significant differences between groups (odds ratio, 1.07; 95% confidence interval, 0.54-2.12). CONCLUSIONS: The incidences of endophthalmitis after OGI were low with and without systemic antibiotic prophylaxis, although high-risk cases were excluded in the included studies. When antibiotic prophylaxis is considered, there is moderate evidence that oral antibiotic administration is noninferior to IV. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Effect of allograft patch closure on incidence of spinal inclusion cyst formation following open fetal myelomeningocele repair.

OBJECTIVE: The aim of this study was to evaluate the incidence of spinal inclusion cyst (sIC) formation after open fetal myelomeningocele (fMMC) repair and the effect of dural patch closure. METHODS: The authors conducted a retrospective review of patients who underwent open fMMC repair at their institution between March 2011 and June 2020. All patients met the criteria for intervention defined by the Management of Myelomeningocele Study (MOMS). The primary outcomes investigated were development of sIC and need for surgical intervention. Secondary outcomes included need for CSF diversion, extent of reversal of hindbrain herniation, and ambulatory status. RESULTS: Of 56 patients who underwent open fMMC repair, 52 had adequate spinal imaging for review. Twelve of these patients (23%) developed sIC (95% CI 0.11-0.35). Six patients experienced symptoms and required surgical detethering with sIC resection. Six additional patients had evidence of sIC on surveillance MRI but remained asymptomatic. The authors found a statistically significant relationship between the use of a dural allograft patch and sIC formation (p = 0.05). In terms of sIC development, there was no statistically significant difference between patients who underwent primary closure and those who received an allograft at the level of the fascia (p = 0.34) or skin (p = 0.26). The rate of hydrocephalus requiring CSF diversion was 52%. Interestingly, 98% of patients had improvement in extent of hindbrain herniation. Dural patch closure did not have any effect on the rate of progressive hydrocephalus (p = 0.33) or degree of reversal of hindbrain herniation (p > 0.99). CONCLUSIONS: This study suggested that children with prenatally repaired MMC are at higher risk for development of sIC and associated symptoms than those who undergo postnatal repair. The presentation of symptoms was also earlier in these patients than previously reported after postnatal repair. The use of a dural allograft patch appears to have a positive correlation with sIC formation. Future investigations evaluating the incidence of sIC after fetoscopic MMC repair, in which primary dural closure typically cannot be achieved and a dural patch is most often utilized, will be helpful in facilitating prenatal counseling for patients considering fetal intervention.

Comparison of Pregnancy Outcomes of Previable and Periviable Rupture of Membranes After Laser Photocoagulation for Twin-Twin Transfusion Syndrome.

OBJECTIVE: To describe the pregnancy outcomes of patients who experienced previable and periviable prelabor rupture of membranes (PROM) after the treatment of twin-twin transfusion syndrome. METHODS: We conducted a retrospective cohort study of patients whose pregnancies were complicated by twin-twin transfusion syndrome who were treated with fetoscopic laser photocoagulation at a single fetal center and subsequently experienced PROM from April 2010 to June 2019. Outcomes were infant survival and latency from PROM to delivery. Patients were grouped by gestational age at PROM (before 26 weeks of gestation and 26 weeks or later). The group with PROM before 26 weeks of gestation was stratified by gestational age at PROM for further description of outcomes. RESULTS: Two-hundred fifty of 653 patients (38%) developed PROM, 81 before 26 weeks of gestation and 169 after 26 weeks of gestation. In the setting of PROM before 26 weeks of gestation, the rate of survival of both twins to neonatal intensive care unit (NICU) discharge was 46.3%, compared with 76.9% in the setting of PROM at 26 weeks of gestation or later ( P <.001); the survival rate of at least one twin was 61.2% and 98.5%, respectively ( P <.001). Fourteen, 22, and 45 patients experienced PROM at 16-19 6/7, 20-22 6/7, and 23-25 6/7 weeks of gestation, respectively. Survival of both twins and at least one twin to NICU discharge was 25.0%, 47.4%, 52.8% (for two) and 33.3%, 47.4%, and 77.8% (for at least one), respectively, among those groups. Fifty-seven of the 81 patients with PROM before 26 weeks of gestation experienced a latency longer than 48 hours. In the setting of PROM before 26 weeks of gestation, when latency lasted longer than 48 hours, overall survival was improved (69.6% vs 53.7%, respectively, P =.017). With latency longer than 48 hours and PROM at 16-19 6/7, 20-22 6/7, and 23-25 6/7 weeks of gestation, survival of both twins to NICU discharge was 60.0%, 61.5%, and 60.7%, respectively, and survival of at least one twin was 80.0%, 61.5%, and 85.7%, respectively. CONCLUSION: Earlier gestational age at PROM after laser photocoagulation is associated with longer latency but lower rates of survival. When PROM occurs before 26 weeks of gestation and latency exceeds 48 hours, rates of neonatal survival are significantly improved.

Whole Exome Sequencing in a Population With Severe Congenital Anomalies of Kidney and Urinary Tract.

Fetal and neonatal interventions (e.g., amnioinfusions, amniotic shunting, and infant dialysis) have increased survival of infants with severe Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), however, outcomes vary dramatically. Our aim was to perform Whole Exome Sequencing (WES) in a unique severe CAKUT population with the goal to identify new variants that will enhance prediction of postnatal outcomes. We performed trio WES on five infants with severe CAKUT (undergoing fetal interventions and/or those who initiated renal replacement therapy (RRT) within 1 month of life) and their parents as well as three singletons. We identified three potential candidate gene variants (NSUN7, MTMR3, CEP162) and validated two variants in known CAKUT genes (GATA3 and FRAS1) showing strong enrichment in this severe phenotype population. Based on our small pilot study of a unique severe CAKUT population, WES appears to be a potential tool to help predict the course of infants with severe CAKUT prenatally.

Maternal age-specific drivers of severe maternal morbidity.

BACKGROUND: The maternal age influences the risk of adverse pregnancy outcomes, including severe maternal morbidity. However, the leading drivers of severe maternal morbidity may differ between the maternal age groups. OBJECTIVE: To compare the contribution of different risk factors to the risk of severe maternal morbidity between various maternal age groups and estimate their population-attributable risks. STUDY DESIGN: This was a retrospective, population-based cohort study of all US live births from 2012 to 2016 using birth certificate records. The demographic, medical, and pregnancy factors were compared between the 4 maternal age strata (<18 years, 18-34 years, 35-39 years, and ≥40 years). The primary outcome was composite severe maternal morbidity, defined as having maternal intensive care unit admission, eclampsia, unplanned hysterectomy, or a ruptured uterus. Multivariate logistic regression estimated the relative influence of the risk factors associated with severe maternal morbidity among the maternal age categories. Population-attributable fraction calculations assessed the contribution of the individual risk factors to overall severe maternal morbidity. RESULTS: Of 19,473,910 births in the United States from 2012 to 2016, 80,553 (41 cases per 10,000 delivery hospitalizations) experienced severe maternal morbidity. The highest rates of severe maternal morbidity were observed at the extremes of maternal age: 45 per 10,000 at <18 years (risk ratio, 1.31; 95% confidence interval, [1.16-1.48]) and 73 per 10,000 (risk ratio, 2.02; 95% confidence interval, [1.96-2.09]) for ≥40 years. In all the age groups, preterm delivery, cesarean delivery, chronic hypertension, and preeclampsia were significantly associated with an increased adjusted relative risk of severe maternal morbidity. Cesarean delivery and preeclampsia increased the severe maternal morbidity risk among all the age groups and were more influential among the youngest mothers. The risk factors with the greatest population-attributable fractions were non-Hispanic Black race (5.4%), preeclampsia (10.9%), preterm delivery (29.4%), and cesarean delivery (38.1%). On the basis of these estimates, the births occurring in mothers at the extremes of maternal age (<18 and ≥35 years) contributed 4 severe maternal morbidity cases per 10,000 live births. Preterm birth and cesarean delivery contributed 12 and 15 cases of severe maternal morbidity per 10,000 live births, respectively. CONCLUSION: Both adolescent and advanced-age pregnancies have an increased risk of severe maternal morbidity. However, there are age-specific differences in the drivers of severe maternal morbidity. This information may allow for better identification of those at a higher risk of severe maternal morbidity and may ultimately aid in patient counseling. KEY WORDS: adolescents, advanced-age pregnancy, maternal morbidity, population-attributable fraction.

Molecular basis for substrate recruitment to the PRMT5 methylosome.

PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5. We demonstrate that PRMT5 uses modular adaptor proteins containing a common binding motif for substrate recruitment, comparable with other enzyme classes such as kinases and E3 ligases. We structurally resolve the interface with PRMT5 and show via genetic perturbation that it is required for methylation of adaptor-recruited substrates including the spliceosome, histones, and ribosomal complexes. Furthermore, disruption of this site affects Sm spliceosome activity, leading to intron retention. Genetic disruption of the PRMT5-substrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development of therapeutic inhibitors of PRMT5.

Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction.

PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action studies revealed the formation of a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts PRMT5-RIOK1 complexes, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive inhibitor that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.

Trialkylammonium salt degradation: implications for methylation and cross-coupling.

Trialkylammonium (most notably N,N,N-trimethylanilinium) salts are known to display dual reactivity through both the aryl group and the N-methyl groups. These salts have thus been widely applied in cross-coupling, aryl etherification, fluorine radiolabelling, phase-transfer catalysis, supramolecular recognition, polymer design, and (more recently) methylation. However, their application as electrophilic methylating reagents remains somewhat underexplored, and an understanding of their arylation versus methylation reactivities is lacking. This study presents a mechanistic degradation analysis of N,N,N-trimethylanilinium salts and highlights the implications for synthetic applications of this important class of salts. Kinetic degradation studies, in both solid and solution phases, have delivered insights into the physical and chemical parameters affecting anilinium salt stability. 1H NMR kinetic analysis of salt degradation has evidenced thermal degradation to methyl iodide and the parent aniline, consistent with a closed-shell SN2-centred degradative pathway, and methyl iodide being the key reactive species in applied methylation procedures. Furthermore, the effect of halide and non-nucleophilic counterions on salt degradation has been investigated, along with deuterium isotope and solvent effects. New mechanistic insights have enabled the investigation of the use of trimethylanilinium salts in O-methylation and in improved cross-coupling strategies. Finally, detailed computational studies have helped highlight limitations in the current state-of-the-art of solvation modelling of reaction in which the bulk medium undergoes experimentally observable changes over the reaction timecourse.

EXIT-to-airway: Fundamentals, prenatal work-up, and technical aspects.

Ex-utero intrapartum treatment (EXIT) is a delivery strategy developed to manage a variety of prenatally diagnosed conditions in the transition to newborn life. This procedure allows control and provides time for intervention in otherwise life-threatening malformations, such as congenital upper airway obstructions. EXIT-to-airway has changed the outcome of fetuses with these anomalies. The main purpose of this intervention is to improve the safety of establishing a reliable airway at birth. Maximal but controlled uterine relaxation to maintain feto-maternal perfusion and thus gas exchange, while keeping the fetal and maternal well-being are the paradigms of any type of EXIT. The most important aspect of fetal airway management is to consolidate a highly trained, well-coordinated, multidisciplinary team that is prepared for every contingency. A comprehensive prenatal assessment, including ultrasound, fetal echocardiogram, fetal MRI, and genetic testing is imperative for patient selection. Extensive preoperative planning, ad-hoc team meetings, and surgical simulations for challenging cases are critical strategies to achieve the best outcomes. This article outlines the prenatal work-up, decision making, technical aspects, and principles for a successful EXIT-to-airway procedure.

Influence of Gestational Weight Gain on the Risk of Preterm Birth for Underweight Women Living in Food Deserts.

OBJECTIVE: Preterm birth (PTB) and food insecurity are two of the most significant public health crises in the United States. Effects of being underweight among populations with low food security are not well understood. We assess whether the protective effect of gestational weight gain (GWG) for women with low prepregnancy body mass index (BMI) differs by accessibility to sources of healthy food. STUDY DESIGN: Population-based retrospective cohort study using Ohio birth records analyzing all live births, 2006 to 2015. Analyses were stratified by maternal BMI (underweight, normal, overweight, and obese), Institute of Medicine (IOM) recommended GWG (under vs. met), and whether the U.S. Department of Agriculture (USDA) classified the residential census tract for each birth as a food desert. Food access data were retrieved from the USDA's 2018 Food Access Research Atlas. Covariates were selected using least absolute shrinkage and selection operator regression. Logistic regression models estimated the risk ratio (RR) of PTB for each group based on under or exceeded recommended GWG (reference = met), adjusting for coexisting risk factors. RESULTS: Analysis was performed on 1,124,299 births. PTB risk was highest for underweight women below GWG recommendations (no food desert: 21.3%, RR = 2.15, 95% confidence interval [CI]: 1.81-2.57; food desert: 21.0%, RR = 1.46, 95% CI: 0.96-2.21). Underweight women living in food deserts who exceeded GWG recommendations had lower PTB risk than those who met GWG recommendations (13.5 vs. 14.3%, RR = 0.85, 95% CI: 0.51-1.41). Factors other than GWG significantly associated with PTB included in the adjusted analysis include maternal age and race, education, marital status, interpregnancy interval, and presence of prepregnancy diabetes or hypertension. CONCLUSION: Underweight women who do not meet GWG recommendations are at high risk for PTB. Increasing pregnancy weight gain to a level that exceeds IOM recommendations was not associated with a reduction in PTB risk for underweight women who reside in food deserts compared with women who met GWG recommendations. KEY POINTS: · Women with low prepregnancy BMI are at high risk of PTB.. · Food insecurity increases the risk of PTB for underweight women.. · Excessive GWG for underweight women in food deserts does not reduce PTB risk..

Fetoscopic Multilayer, Dural Patch Closure Technique for Intrauterine Myelomeningocele Repair: 2-Dimensional Operative Video.

Myelomeningocele (MMC) is the most common open neural tube defect associated with long-term survival. In 2011, The Management of Myelomeningocele Study (MOMS) trial demonstrated that fetal repair for MMC reduced the rate of shunted hydrocephalus and improved developmental, motor, and ambulation outcomes at 30 mo compared to postnatal intervention.1 Recent studies have demonstrated the safety and feasibility of fetoscopic MMC repair as well as reduction in preterm birth, lower risk of uterine dehiscence, and the option of vaginal delivery with this approach compared to open fetal repair.2-4 The patient is a 25-yr-old female, G4 P2, who presented at 20 wk's gestation with ultrasound findings concerning for MMC and Chiari II malformation. These findings were further corroborated with fetal magnetic resonance imaging. After extensive prenatal counseling in a multidisciplinary fashion and discussion regarding risks and benefits of prenatal closure of the MMC, the patient chose to undergo prenatal repair and surgical consent was obtained. At 25 wk's gestation, the patient underwent a fetoscopic multilayer closure with dural patch repair using a standardized, 3-port, carbon dioxide insufflation technique for the intrauterine treatment of MMC without any postoperative complications. The duration of the entire procedure was 275 min. At 36 wk's and 1 d's gestational age, the patient had a spontaneous vaginal delivery, resulting in a healthy male newborn. The surgical site was well healed without complications, and follow-up radiographic imaging was reassuring. This edited, 2-dimensional operative video highlights the key steps of the fetoscopic closure with follow-up postnatal clinical and radiographic outcomes.

Workers' Compensation Elements in Different Jurisdictions in the United States.

: Over the decades, the workers' compensation system has provided many injured workers with a significant guarantee of both medical and financial support when they have been injured on the job. To be effective, workers' compensation systems at a minimum should include principles that require the addressing of medical causation, determination of an individual's functional ability both pre- and post-injury to include activity restrictions, return-to-work capability and disability, meeting jurisdiction-specific reporting requirements of the workers' compensation reporting requirements, and having knowledge of other perspectives of the various authorities and jurisdictions present in the United States. ACOEM lays out a description of various aspects of workers' compensations systems in the United States, with recommendations for minimal standards and best practices. This paper limits itself to the discussion of jurisdictions within the United States and ACOEM strongly recommends that providers consult directly with the states in which they are working as there are state variations in workers' compensation.

Utilization Review in Workers' Compensation: Review of Current Status and Recommendations for Future Improvement.

: Utilization review (UR) is a process that assesses aspects of a treating provider's care plans and then provides recommendations to payors/insurance carriers, third party administrators, etc, concerning the appropriateness of the proposed care. UR has become an integral part of medical practice and has influenced medical care within the workers' compensation (WC) system and is mandated in several states and jurisdictions. This guidance statement from the American College of Occupational and Environmental Medicine (ACOEM) reviews structural elements of UR programs and proposes a possible template for operational standards. UR has a unique role in protecting patients and educating providers on evidence-based guidelines, new research, and best practices.

Reproductive Outcomes following Laser Surgery for Twin-Twin Transfusion Syndrome.

BACKGROUND: There are limited studies describing future reproductive outcomes in women who have had selective fetoscopic laser photocoagulation (SFLP) for twin-twin transfusion syndrome (TTTS). OBJECTIVE: Our study aims to compare reproductive outcomes following monochorionic multiple gestational pregnancies complicated by TTTS requiring SFLP to those not requiring SFLP. METHODS: This is a retrospective cohort study that analyzed records of patients who were evaluated at the Cincinnati Fetal Center (2007-2014) for monochorionic multiple gestations. A questionnaire regarding reproductive, obstetric, gynecologic, and psychological outcomes following the index pregnancy was administered to consented participants by electronic distribution. The data was compared between pregnancies with prior SFLP versus no prior SFLP. RESULTS: There was a higher response rate in the SFLP group (219/474, 46.2%) versus the referent group (62/187, 33.2%). The median interval between the index pregnancy and survey completion was 74 months and 46 months in the SFLP and referent groups, respectively. Approximately 38 and 37% of the women in the SFLP and referent groups attempted conception after the index pregnancy with a >90% pregnancy success rate in both groups. Use of assisted reproductive technology was highly prevalent in both the index and subsequent pregnancies, with no significant difference between the groups. Over 60% of the women in each group did not attempt future pregnancy. Of those, approximately 1 in 3 cited the outcome of the index pregnancy as the primary reason for not pursuing future conception. There were no significant differences in selected maternal-fetal complications and new-onset gynecologic problems. More than 1 in 4 women in both groups were diagnosed with a mental health disorder following the index pregnancy. CONCLUSION: SFLP does not appear to be associated with adverse reproductive, obstetric, or gynecologic outcomes. The data may help facilitate evidence-based counseling for this patient population.

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

Reconstructing sexual divisions of labor from fingerprints on Ancestral Puebloan pottery.

An understanding of the division of labor in different societies, and especially how it evolved in the human species, is fundamental to most analyses of social, political, and economic systems. The ability to reconstruct how labor was organized, however, especially in ancient societies that left behind few material remains, is challenged by the paucity of direct evidence demonstrating who was involved in production. This is particularly true for identifying divisions of labor along lines of age, sex, and gender, for which archaeological interpretations mostly rely upon inferences derived from modern examples with uncertain applicability to ancient societies. Drawing upon biometric studies of human fingerprints showing statistically distinct ridge breadth measurements for juveniles, males, and females, this study reports a method for collecting fingerprint impressions left on ancient material culture and using them to distinguish the sex of the artifacts' producers. The method is applied to a sample of 985 ceramic sherds from a 1,000-y-old Ancestral Puebloan community in the US Southwest, a period characterized by the rapid emergence of a highly influential religious and political center at Chaco Canyon. The fingerprint evidence demonstrates that both males and females were significantly involved in pottery production and further suggests that the contributions of each sex varied over time and even among different social groups in the same community. The results indicate that despite long-standing assumptions that pottery production in Ancient Puebloan societies was primarily a female activity, labor was not strictly divided and instead was likely quite dynamic.