Metal-insulator-semiconductor photoelectrodes for enhanced photoelectrochemical water splitting.

Photoelectrochemical (PEC) water splitting provides a scalable and integrated platform to harness renewable solar energy for green hydrogen production. The practical implementation of PEC systems hinges on addressing three critical challenges: enhancing energy conversion efficiency, ensuring long-term stability, and achieving economic viability. Metal-insulator-semiconductor (MIS) heterojunction photoelectrodes have gained significant attention over the last decade for their ability to efficiently segregate photogenerated carriers and mitigate corrosion-induced semiconductor degradation. This review discusses the structural composition and interfacial intricacies of MIS photoelectrodes tailored for PEC water splitting. The application of MIS heterostructures across various semiconductor light-absorbing layers, including traditional photovoltaic-grade semiconductors, metal oxides, and emerging materials, is presented first. Subsequently, this review elucidates the reaction mechanisms and respective merits of vacuum and non-vacuum deposition techniques in the fabrication of the insulator layers. In the context of the metal layers, this review extends beyond the conventional scope, not only by introducing metal-based cocatalysts, but also by exploring the latest advancements in molecular and single-atom catalysts integrated within MIS photoelectrodes. Furthermore, a systematic summary of carrier transfer mechanisms and interface design principles of MIS photoelectrodes is presented, which are pivotal for optimizing energy band alignment and enhancing solar-to-chemical conversion efficiency within the PEC system. Finally, this review explores innovative derivative configurations of MIS photoelectrodes, including back-illuminated MIS photoelectrodes, inverted MIS photoelectrodes, tandem MIS photoelectrodes, and monolithically integrated wireless MIS photoelectrodes. These novel architectures address the limitations of traditional MIS structures by effectively coupling different functional modules, minimizing optical and ohmic losses, and mitigating recombination losses.

Irregular Cycles, Ovulatory Disorders, and Cardiometabolic Conditions in a US-Based Digital Cohort.

Importance: Polycystic ovary syndrome (PCOS), characterized by irregular menstrual cycles and hyperandrogenism, is a common ovulatory disorder. Having an irregular cycle is a potential marker for cardiometabolic conditions, but data are limited on whether the associations differ by PCOS status or potential interventions. Objective: To evaluate the association of PCOS, time to regularity since menarche (adolescence), and irregular cycles (adulthood) with cardiometabolic conditions. Design, Setting, and Participants: This cross-sectional study used a large, US-based digital cohort of users of the Apple Research application on their iPhone. Eligibility criteria were having ever menstruated, living in the US, being at age of consent of at least 18 years (or 19 years in Alabama and Nebraska or 21 years in Puerto Rico), and being able to communicate in English. Participants were enrolled between November 14, 2019, and December 13, 2022, and completed relevant surveys. Exposures: Self-reported PCOS diagnosis, prolonged time to regularity (not spontaneously establishing regularity within 5 years of menarche), and irregular cycles. Main Outcomes and Measures: The primary outcome was self-reported cardiometabolic conditions, including obesity, prediabetes, type 1 and 2 diabetes, high cholesterol, hypertension, metabolic syndrome, arrhythmia, congestive heart failure, coronary artery disease, heart attack, heart valve disease, stroke, transient ischemic attack (TIA), deep vein thrombosis, and pulmonary embolism measured using descriptive statistics and logistic regression to estimate prevalence odds ratios (PORs) and 95% CIs. Effect modification by lifestyle factors was also estimated. Results: The study sample (N = 60 789) had a mean (SD) age of 34.5 (11.1) years, with 12.3% having PCOS and 26.3% having prolonged time to regularity. Among a subset of 25 399 participants who completed the hormonal symptoms survey, 25.6% reported irregular cycles. In covariate-adjusted logistic regression models, PCOS was associated with a higher prevalence of all metabolic and several cardiovascular conditions, eg, arrhythmia (POR, 1.37; 95% CI, 1.20-1.55), coronary artery disease (POR, 2.92; 95% CI, 1.95-4.29), heart attack (POR, 1.79; 95% CI, 1.23-2.54), and stroke (POR, 1.66; 95% CI, 1.21-2.24). Among participants without PCOS, prolonged time to regularity was associated with type 2 diabetes (POR, 1.24; 95% CI, 1.05-1.46), hypertension (POR, 1.09; 95% CI, 1.01-1.19), arrhythmia (POR, 1.20; 95% CI, 1.06-1.35), and TIA (POR, 1.33; 95% CI, 1.01-1.73), and having irregular cycles was associated with type 2 diabetes (POR, 1.36; 95% CI, 1.08-1.69), high cholesterol (POR, 1.17; 95% CI, 1.05-1.30), arrhythmia (POR, 1.21; 95% CI, 1.02-1.43), and TIA (POR, 1.56; 95% CI, 1.06-2.26). Some of these associations were modified by high vs low body mass index or low vs high physical activity. Conclusions and Relevance: These findings suggest that PCOS and irregular cycles may be independent markers for cardiometabolic conditions. Early screening and intervention among individuals with irregular menstrual cycles may be beneficial.

EEG Ictal Power Dynamics, Function-Structure Associations, and Epilepsy Surgical Outcomes.

BACKGROUND AND OBJECTIVES: Postoperative seizure control in drug-resistant temporal lobe epilepsy (TLE) remains variable, and the causes for this variability are not well understood. One contributing factor could be the extensive spread of synchronized ictal activity across networks. Our study used novel quantifiable assessments from intracranial EEG (iEEG) to test this hypothesis and investigated how the spread of seizures is determined by underlying structural network topological properties. METHODS: We evaluated iEEG data from 157 seizures in 27 patients with TLE: 100 seizures from 17 patients with postoperative seizure control (Engel score I) vs 57 seizures from 10 patients with unfavorable surgical outcomes (Engel score II-IV). We introduced a quantifiable method to measure seizure power dynamics within anatomical regions, refining existing seizure imaging frameworks and minimizing reliance on subjective human decision-making. Time-frequency power representations were obtained in 6 frequency bands ranging from theta to gamma. Ictal power spectrums were normalized against a baseline clip taken at least 6 hours away from ictal events. Electrodes' time-frequency power spectrums were then mapped onto individual T1-weighted MRIs and grouped based on a standard brain atlas. We compared spatiotemporal dynamics for seizures between groups with favorable and unfavorable surgical outcomes. This comparison included examining the range of activated brain regions and the spreading rate of ictal activities. We then evaluated whether regional iEEG power values were a function of fractional anisotropy (FA) from diffusion tensor imaging across regions over time. RESULTS: Seizures from patients with unfavorable outcomes exhibited significantly higher maximum activation sizes in various frequency bands. Notably, we provided quantifiable evidence that in seizures associated with unfavorable surgical outcomes, the spread of beta-band power across brain regions is significantly faster, detectable as early as the first second after seizure onset. There was a significant correlation between beta power during seizures and FA in the corresponding areas, particularly in the unfavorable outcome group. Our findings further suggest that integrating structural and functional features could improve the prediction of epilepsy surgical outcomes. DISCUSSION: Our findings suggest that ictal iEEG power dynamics and the structural-functional relationship are mechanistic factors associated with surgical outcomes in TLE.

Menarche and Time to Cycle Regularity Among Individuals Born Between 1950 and 2005 in the US.

Importance: Early menarche is associated with adverse health outcomes. Trends toward earlier menarche have been observed in the US, but data remain limited on differences by sociodemographic factors and body mass index (BMI). Time from menarche to cycle regularity is another understudied early-life characteristic with health implications. Objectives: To evaluate the temporal trends and disparities in menarche and time to regularity and explore early-life BMI as a mediator. Design, Setting, and Participants: This ongoing cohort study enrolled participants from an ongoing mobile application-based US cohort from November 14, 2019, to March 20, 2023. Exposures: Birth year (categorized as 1950-1969, 1970-1979, 1980-1989, 1990-1999, and 2000-2005). Main Outcomes and Measures: Main outcomes were age at menarche and time to regularity, which were self-recalled at enrollment. In addition, early (aged <11 years), very early (aged <9 years), and late (aged ≥16 years) age at menarche was assessed. Results: Among the 71 341 female individuals who were analyzed (mean [SD] age at menarche, 12.2 [1.6] years; 2228 [3.1%] Asian, 3665 [5.1%] non-Hispanic Black, 4918 [6.9%] Hispanic, 49 518 [69.4%] non-Hispanic White, and 8461 [11.9%] other or multiple races or ethnicities), 5223 were born in 1950 to 1969, 12 226 in 1970 to 1979, 22 086 in 1980 to 1989, 23 894 in 1990 to 1999, and 7912 in 2000 to 2005. The mean (SD) age at menarche decreased from 12.5 (1.6) years in 1950 to 1969 to 11.9 (1.5) years in 2000 to 2005. The number of individuals experiencing early menarche increased from 449 (8.6%) to 1223 (15.5%), the number of individuals experiencing very early menarche increased from 31 (0.6%) to 110 (1.4%), and the number of individuals experiencing late menarche decreased from 286 (5.5%) to 137 (1.7%). For 61 932 participants with reported time to regularity, the number reaching regularity within 2 years decreased from 3463 (76.3%) to 4075 (56.0%), and the number not yet in regular cycles increased from 153 (3.4%) to 1375 (18.9%). The magnitude of the trend toward earlier menarche was greater among participants who self-identified as Asian, non-Hispanic Black, or other or multiple races (vs non-Hispanic White) (P = .003 for interaction) and among participants self-rated with low (vs high) socioeconomic status (P < .001 for interaction). Within a subset of 9865 participants with data on BMI at menarche, exploratory mediation analysis estimated that 46% (95% CI, 35%-61%) of the temporal trend in age at menarche was explained by BMI. Conclusions and Relevance: In this cohort study of 71 341 individuals in the US, as birth year increased, mean age at menarche decreased and time to regularity increased. The trends were stronger among racial and ethnic minority groups and individuals of low self-rated socioeconomic status. These trends may contribute to the increase in adverse health outcomes and disparities in the US.

Gender differences in illicit drug access, use and use disorder: Analysis of National Survey on Drug Use and Health data.

Although gender differences in the prevalence of substance use disorders (SUD) have been well-characterized, little is known about when gender differences emerge along the continuum of substance use. Understanding the contribution of gender to risk at key transition points across this continuum is needed to identify potential mechanisms underlying gender differences and to inform improved gender-responsive interventions. To characterize gender differences in the progression of cannabis, cocaine, and heroin use, the current study used data from the United States-based 2015-2019 National Survey on Drug Use and Health to quantify gender differences in: (1) perceived access to drugs, (2) lifetime drug use among individuals with at least some access, and (3) past-year SUD among those who had ever used each drug. Logistic regressions were conducted for each drug to examine gender differences across all three stages, controlling for sociodemographic factors and survey year. Compared to women, men had higher odds of reporting access to and lifetime use of all three drug types. Men also had higher odds of past-year cannabis and cocaine use disorders compared to women. Results suggest gender differences emerge in the earliest stage of drug use (access) and may accumulate across the stages of use. The magnitude of gender differences varied across stages, with the largest differences observed for odds of drug initiation among those with perceived access to each drug. Longitudinal data will be needed to confirm these findings and to provide insight into potential contributors to gender-specific risk and intervention targets across the continuum of drug use severity.

A randomized controlled trial to compare the effects of time-restricted eating versus Mediterranean diet on symptoms and quality of life in bipolar disorder.

BACKGROUND: The primary objective of this randomized controlled trial (RCT) is to establish the effectiveness of time-restricted eating (TRE) compared with the Mediterranean diet for people with bipolar disorder (BD) who have symptoms of sleep disorders or circadian rhythm sleep-wake disruption. This work builds on the growing evidence that TRE has benefits for improving circadian rhythms. TRE and Mediterranean diet guidance will be offered remotely using self-help materials and an app, with coaching support. METHODS: This study is an international RCT to compare the effectiveness of TRE and the Mediterranean diet. Three hundred participants will be recruited primarily via social media. Main inclusion criteria are: receiving treatment for a diagnosis of BD I or II (confirmed via DIAMOND structured diagnostic interview), endorsement of sleep or circadian problems, self-reported eating window of ≥ 12 h, and no current mood episode, acute suicidality, eating disorder, psychosis, alcohol or substance use disorder, or other health conditions that would interfere with or limit the safety of following the dietary guidance. Participants will be asked to complete baseline daily food logging for two weeks and then will be randomly allocated to follow TRE or the Mediterranean diet for 8 weeks, during which time, they will continue to complete daily food logging. Intervention content will be delivered via an app. Symptom severity interviews will be conducted at baseline; mid-intervention (4 weeks after the intervention begins); end of intervention; and at 6, 9, and 15 months post-baseline by phone or videoconference. Self-rated symptom severity and quality of life data will be gathered at those timepoints, as well as at 16 weeks post baseline. To provide a more refined index of whether TRE successfully decreases emotional lability and improves sleep, participants will be asked to complete a sleep diary (core CSD) each morning and complete six mood assessments per day for eight days at baseline and again at mid-intervention. DISCUSSION: The planned research will provide novel and important information on whether TRE is more beneficial than the Mediterranean diet for reducing mood symptoms and improving quality of life in individuals with BD who also experience sleep or circadian problems. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06188754.

IL-13 protects from C. difficile Colitis.

OBJECTIVES: Clostridioides difficile infection (CDI) is the leading hospital-acquired infection in North America. We have previously discovered that antibiotic disruption of the gut microbiota decreases intestinal IL-33 and IL-25 and increases susceptibility to CDI. We further found that IL-33 promotes protection through type 2 Innate Lymphoid Cells (ILC2s), which produce IL-13. However, the contribution of IL-13 to disease has never been explored. METHODS: We used a validated model of CDI in mice, in which we neutralized via blocking antibodies, or administered recombinant protein, IL-13 to assess the role of this cytokine during infection using weight and clinical scores. Fluorescent activated cell sorting (FACS) was used to characterize myeloid cell population changes in response to IL-13 manipulation. RESULTS: We found that administration of IL-13 protected, and anti-IL-13 exacerbated CDI. Additionally, we observe alterations to the monocyte/macrophage cells following neutralization of IL-13 as early as day three post infection. We also observed elevated accumulation of myeloid cells by day four post-infection following IL-13 neutralization. Neutralization of the decoy receptor, IL-13Rα2, resulted in protection from disease, likely through increased available endogenous IL-13. CONCLUSIONS: Our data highlight the protective role of IL-13 in protecting from more severe CDI and the association of poor responses with a dysregulated monocyte-macrophage compartment. These results increase our understanding of type 2 immunity in CDI and may have implications for treating disease in patients.

Relationship between FEV1/FVC and age in children with asthma.

INTRODUCTION: Forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) normally decreases through childhood, increases briefly during early adolescence, and then declines throughout life. The physiology behind this temporary increase during early adolescence is not well understood. The objective of this study was to determine if this pattern occurs in children with asthma. DESIGN: Single-center, cross-sectional, retrospective analysis of pulmonary function tests obtained over a 5-year period in children 5-18 years of age with persistent asthma. RESULTS: A total of 1793 patients satisfied all inclusion and exclusion criteria. The mean age (±SD) was 10.4 ± 3.8 years. Forty-eight percent were female. Mean FEV1/FVC was 0.83 ± 0.09. FEV1/FVC was lower at 5 years of age than in healthy children, declined from age 5 to 11 by 5.7% compared to 7.3% in healthy girls, and 5.8% compared to 9.4% in healthy boys. FEV1/FVC increased in early adolescence, but at age 16, was 5.6% lower in male children compared to healthy children, and 5.4% lower in females. The ratio was lower in obese children at all ages but demonstrated the same curvilinear shape as healthy children. In absolute terms, FEV1 grew proportionately more than FVC during early adolescence, so the ratio of FEV1/FVC increased during that period. The curvilinear shape of the curve remained in postbronchodilator testing, though significantly blunted. CONCLUSIONS: FEV1/FVC is lower in children with persistent asthma than healthy children, but the "Shepherd's Hook" pattern is preserved. This was true in obese patients with asthma, although their FEV1/FVC ratios were lower throughout all stages of childhood and adolescence.

Protocol for harmonization of randomized trials testing the addition of behavioral therapy to buprenorphine for opioid use disorder.

Background: Although buprenorphine is an effective treatment for opioid use disorder (OUD), much remains to be understood about treatment non-response and methods for improving treatment retention. The addition of behavioral therapies to buprenorphine has not yielded consistent benefits for opioid outcomes, on average. However, several studies suggest that certain subgroups may benefit from the combination of buprenorphine and behavioral therapy, highlighting the potential for personalized approaches to treatment. Furthermore, little is known about whether behavioral therapies improve buprenorphine retention or non-opioid (e.g., functional) outcomes. Methods: The objective of this project is to harmonize four previously conducted clinical trials testing the addition of behavioral therapy to buprenorphine maintenance for OUD and to use this larger dataset to answer critical clinical questions about the role of behavioral therapy in this population. Study aims include identifying potential moderators of the effect of the addition of behavioral therapy and quantifying the effect of behavioral therapy on buprenorphine retention and functional outcomes. Results: Analyses will consider outcomes of weeks of opioid use, weeks of retention in buprenorphine treatment, and functional outcomes as measured by the Addiction Severity Index. Analyses will include an indicator for each study to account for heterogeneity of samples and design. Conclusion: Results will help to inform clinical and research efforts to optimize the use of behavioral therapies in the treatment of OUD.

Description of the first species of gall wasp (Hym., Cynipidae: Cynipini) on Quercus grahamii (Fagaceae).

A new species of oak gall wasp, Andricus coombesi Pujade-Villar & Prez-Torres n. sp. from Mexico, known only from its asexual generation that induces galls on acorns of Quercus grahamii Benth., (section Lobatae) is described. Its presence causes the complete disappearance of the acorn. Diagnosis, distribution and biological data of the new species are given. Andricus coombesi Pujade-Villar & Prez-Torres n. sp. represents the first gall wasp species mentioned from this host.

Novel RAB39B loss-of-function mutation in patient with typical early-onset Parkinson's disease.

RAB39B mutations have been identified in X-linked developmental delays. Recently, RAB39B mutations were identified in males with early-onset parkinsonism and intellectual disability. A novel loss-of-function RAB39B mutation was found in a female patient with typical early-onset Parkinson's disease (EOPD). RAB39B mutations may cause EOPD, potentially due to a-synuclein homeostasis disruption.

MCU-independent Ca2+ uptake mediates mitochondrial Ca2+ overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo.

Measurement invariance of the Revised-Green Paranoid Thought Scale across Black and White Americans.

Given the culturally diverse landscape of mental healthcare and research, ensuring that our psychological constructs are measured equivalently across diverse populations is critical. One construct for which there is significant potential for inequitable assessment is paranoia, a prominent feature in psychotic disorders that can also be driven by culture and racial marginalization. This study examined measurement invariance-an analytic technique to rigorously investigate whether a given construct is being measured similarly across groups-of the Revised-Green Paranoid Thought Scale (R-GPTS; Freeman et al., 2021) across Black and White Americans in the general population. Racial group differences in self-reported paranoia were also examined. The analytic sample consisted of 480 non-Hispanic White and 459 non-Hispanic Black Americans. Analyses demonstrated full invariance (i.e., configural, metric, and scalar invariance) of the R-GPTS across groups, indicating that the R-GPTS appropriately captures self-reported paranoia between Black and White Americans. Accordingly, it is reasonable to compare group endorsement: Black participants endorsed significantly higher scores on both the ideas of reference and ideas of persecution subscales of the R-GPTS (Mean ± SD = 10.91 ± 7.12 versus 8.21 ± 7.17 and Mean ± SD = 10.18 ± 10.03 versus 6.35 ± 8.35, for these subscales respectively). Generalized linear modeling revealed that race remained a large and statistically significant predictor of R-GPTS total score (ß = -0.38756, p < 0.001) after controlling for relevant demographic factors (e.g., sex, age). This study addresses a critical gap within the existing literature as it establishes that elevations in paranoia exhibited by Black Americans in the R-GPTS reflect actual differences between groups rather than measurement artifacts.

Association of Demographic Characteristics and Laboratory Values in Diabetic Foot Infections Leading to Lower-Extremity Amputation.

BACKGROUND: Lower-extremity amputations are a common complication of poorly controlled diabetes and contribute to significant morbidity and mortality in diabetic patients. We sought to determine whether objective data points obtained on presentation or hospital admission, including white blood cell (WBC) count, hemoglobin A1c (HbA1c), C-reactive protein (CRP), and descriptive patient demographics allow for the ability to predict optimal amputation levels and outcomes of lower-extremity amputation in the diabetic population. METHODS: A retrospective analysis of 162 patients was performed evaluating laboratory and descriptive values on hospital presentation for lower-extremity infection during a 16-year period. Occurrence of multiple amputations and level of amputation were assessed against laboratory values to determine whether these objective values would provide clinicians with a better understanding of amputations in the diabetic patient. RESULTS: The mean patient age was 60.6 years. A significantly higher percentage of patients who underwent amputations through the tibia and fibula or of the foot midtarsal were male compared with patients who underwent amputations of the thigh through femur. Patients who had amputations through the tibia and fibula had a significantly higher WBC count compared with patients who had a transmetatarsal amputation (P = .03). There was no significant difference in type or quantity of amputations when analyzing HbA1c and CRP levels. CONCLUSIONS: An admission WBC count may be used as a predictor of lower-extremity amputation level and outcomes in diabetic infections. Although a statistically significant difference was not found for CRP or HbA1c levels between amputation procedures and number of procedures performed, these values remain useful in managing lower-extremity infections in diabetic patients.

An association between Dnmt1 and Wnt in the production of oocytes in the whitefly Bemisia tabaci.

The function of DNA methylation in insects and the DNA methyltransferase (Dnmt) genes that influence methylation remains uncertain. We used RNA interference to reduce the gene expression of Dnmt1 within the whitefly Bemisia tabaci (Hemiptera:Aleyrodidae; Gennadius), a hemipteran species that relies on Dnmt1 for proper gametogenesis. We then used RNA-seq to test an a priori hypothesis that meiosis-related genetic pathways would be perturbed. We generally did not find an overall effect on meiosis-related pathways. However, we found that genes in the Wnt pathway, genes associated with the entry into meiosis in vertebrates, were differentially expressed. Our results are consistent with Dnmt1 knockdown influencing specific pathways and not causing general transcriptional response. This is a finding that is also seen with other insect species. We also characterised the methylome of B. tabaci and assessed the influence of Dnmt1 knockdown on cytosine methylation. This species has methylome characteristics comparable to other hemipterans regarding overall level, enrichment within gene bodies, and a bimodal distribution of methylated/non-methylated genes. Very little differential methylation was observed, and difference in methylation were not associated with differences in gene expression. The effect on Wnt presents an interesting new candidate pathway for future studies.

Pregnancy History at 40 Years of Age as a Marker of Cardiovascular Risk.

BACKGROUND: Individual pregnancy complications are associated with increased maternal risk of cardiovascular disease. We assessed the link between a woman's total pregnancy history at 40 years of age and her relative risk of dying from atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS: This population-based prospective study combined several Norwegian registries covering the period 1967 to 2020. We identified 854 442 women born after 1944 or registered with a pregnancy in 1967 or later, and surviving to 40 years of age. The main outcome was the time to ASCVD mortality through age 69 years. The exposure was a woman's number of recorded pregnancies (0, 1, 2, 3, or 4) and the number of those with complications (preterm delivery <35 gestational weeks, preeclampsia, placental abruption, perinatal death, and term or near-term birth weight <2700 g). Cox models provided estimates of hazard ratios across exposure categories. The group with the lowest ASCVD mortality was that with 3 pregnancies and no complications, which served as the reference group. Among women reaching 40 years of age, risk of ASCVD mortality through 69 years of age increased with the number of complicated pregnancies in a strong dose-response fashion, reaching 23-fold increased risk (95% CI, 10-51) for women with 4 complicated pregnancies. Based on pregnancy history alone, 19% of women at 40 years of age (including nulliparous women) had an increased ASCVD mortality risk in the range of 2.5- to 5-fold. CONCLUSIONS: Pregnancy history at 40 years of age is strongly associated with ASCVD mortality. Further research should explore how much pregnancy history at 40 years of age adds to established cardiovascular disease risk factors in predicting cardiovascular disease mortality.

Optic Neuropathy and Myelopathy in a Teenager With Biotinidase Deficiency.

ABSTRACT: A 19-year-old man presented with 3 years of gradually progressive, painless vision loss in both eyes. The ophthalmic examination showed bilateral diminished visual acuity, dyschromatopsia, and temporal optic nerve pallor. The neurological examination was consistent with a mild myelopathy with decreased pin-prick sensation starting at T6-T7 and descending through the lower extremities. Hyperreflexia was also present in the lower more than upper extremities. Infectious, inflammatory, and nutritional serum workup and cerebrospinal fluid analysis were both unrevealing. MRI of the brain and spinal cord showed abnormal T2 hyperintensity of the fornix, corpus callosum, optic nerves, and lateral columns of the cervical and thoracic spine, with diffusion restriction in the inferior-posterior corpus callosum and fornix. Biotinidase serum enzyme activity was tested and showed a decreased level of activity. Biotinidase gene testing showed a homozygous pathogenic variant, c.424C>A (p.P142T), confirming the diagnosis of biotinidase deficiency and prompting oral biotin supplementation. Three months after starting treatment, the patient's visual acuity, color vision, visual fields, and MRI spine abnormalities all improved significantly. Biotinidase deficiency is an important diagnostic consideration in patients with unexplained optic neuropathy and/or myelopathy.