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STUDY QUESTION To what extent is male fatty acid intake associated with fecundability among couples planning pregnancy? SUMMARY ANSWER We observed weak positive associations of male dietary intakes of total and saturated fatty acids with fecundability; no other fatty acid subtypes were appreciably associated with fecundability. WHAT IS KNOWN ALREADY Male fatty acid intake has been associated with semen quality in previous studies. However, little is known about the extent to which male fatty acid intake is associated with fecundability among couples attempting spontaneous conception. STUDY DESIGN, SIZE, DURATION We conducted an internet-based preconception prospective cohort study of 697 couples who enrolled during 2015–2022. During 12 cycles of observation, 53 couples (7.6%) were lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were residents of the USA or Canada, aged 21–45 years, and not using fertility treatment at enrollment. At baseline, male participants completed a food frequency questionnaire from which we estimated intakes of total fat and fatty acid subtypes. We ascertained time to pregnancy using questionnaires completed every 8 weeks by female participants until conception or up to 12 months. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs for the associations of fat intakes with fecundability, adjusting for male and female partner characteristics. We used the multivariate nutrient density method to account for energy intake, allowing for interpretation of results as fat intake replacing carbohydrate intake. We conducted several sensitivity analyses to assess the potential for confounding, selection bias, and reverse causation. MAIN RESULTS AND THE ROLE OF CHANCE Among 697 couples, we observed 465 pregnancies during 2970 menstrual cycles of follow-up. The cumulative incidence of pregnancy during 12 cycles of follow-up after accounting for censoring was 76%. Intakes of total and saturated fatty acids were weakly, positively associated with fecundability. Fully adjusted FRs for quartiles of total fat intake were 1.32 (95% CI 1.01–1.71), 1.16 (95% CI 0.88–1.51), and 1.43 (95% CI 1.09–1.88) for the second, third, and fourth vs the first quartile, respectively. Fully adjusted FRs for saturated fatty acid intake were 1.21 (95% CI 0.94–1.55), 1.16 (95% CI 0.89–1.51), and 1.23 (95% CI 0.94–1.62) for the second, third, and fourth vs the first quartile, respectively. Intakes of monounsaturated, polyunsaturated, trans-, omega-3, and omega-6 fatty acids were not strongly associated with fecundability. Results were similar after adjustment for the female partner’s intakes of trans- and omega-3 fats. LIMITATIONS, REASONS FOR CAUTION Dietary intakes estimated from the food frequency questionnaire may be subject to non-differential misclassification, which is expected to bias results toward the null in the extreme categories when exposures are modeled as quartiles. There may be residual confounding by unmeasured dietary, lifestyle, or environmental factors. Sample size was limited, especially in subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS Our results do not support a strong causal effect of male fatty acid intakes on fecundability among couples attempting to conceive spontaneously. The weak positive associations we observed between male dietary fat intakes and fecundability may reflect a combination of causal associations, measurement error, chance, and residual confounding. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the National Institutes of Health, grant numbers R01HD086742 and R01HD105863. In the last 3 years, PRESTO has received in-kind donations from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility app). L.A.W. is a consultant for AbbVie, Inc. M.L.E. is an advisor to Sandstone, Ro, Underdog, Dadi, Hannah, Doveras, and VSeat. The other authors have no competing interests to report. TRIAL REGISTRATION NUMBER N/A.

Purpose To report real-world complications associated with femtosecond laser-assisted cataract surgery (FLACS). Setting De-identified database. Design Retrospective review of adverse events associated with FLACS reported to the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. Methods The MAUDE database was culled for adverse events involving ophthalmic femtosecond laser during cataract surgery from January 2010 to January 2020. Reports in which the narrative description was inadequate to determine the nature of the complication were excluded. Each report was reviewed for complications, which were subsequently assigned to a complication category as determined by these authors. The number of events per year was determined and compared. Results Between January 2010 and January 2020, the MAUDE database search yielded 2,927 reports involving femtosecond laser, of which 1,927 met inclusion criteria and were included for analysis. These reports revealed 2,704 complications: 1,115 capsule tears (41.2%), 329 of which required vitrectomy, 372 instances of suction loss, 321 other capsulotomy-related complications, and 432 corneal or incisional complications. Rare complications included 54 reports of miosis, 16 reports of endophthalmitis, and 4 reports of toxic anterior segment syndrome. The number of events in the MAUDE database increased year over year between 2011 and 2017, peaking in 2017 at 303 events. Conclusions By drawing on real-world data in the MAUDE database, this study identifies the complications of greatest importance in clinical practice. Surgeons should be aware of the spectrum of possible complications in order to best prepare for all potential outcomes and to effectively counsel patients.

Chemical hair straighteners (“relaxers”) are used by millions of North Americans, particularly women of color. Hair relaxers may contain endocrine-disrupting compounds, which can harm fertility. We evaluated the association between hair relaxer use and fecundability among 11,274 participants from Pregnancy Study Online (PRESTO), a North American preconception cohort study. During 2014–2022, participants completed a baseline questionnaire in which they reported their history of relaxer use and completed follow-up questionnaires every 8 weeks for 12 months or until pregnancy, whichever came first. We used multivariable-adjusted proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs). Relative to never use, fecundability was lower among current (FR = 0.81, 95% CI: 0.64, 1.03) and former (FR = 0.89, 95% CI: 0.81, 0.98) users of hair relaxers. FRs for first use of hair relaxers at ages

Zika virus (ZIKV) can be transmitted vertically from mother to fetus during pregnancy, resulting in a range of outcomes, including severe birth defects and fetal/infant death. Potential pathways of vertical transmissionin uterohave been proposed but remain undefined. Identifying the timing and routes of vertical transmission of ZIKV may help us identify when interventions would be most effective. Furthermore, understanding what barriers ZIKV overcomes to effect vertical transmission may help improve models for evaluating infection by other pathogens during pregnancy. To determine the pathways of vertical transmission, we inoculated 12 pregnant rhesus macaques with an African-lineage ZIKV at gestational day 30 (term is 165 days). Eight pregnancies were surgically terminated at either seven or 14 days post-maternal infection. Maternal-fetal interface and fetal tissues and fluids were collected and evaluated with RT-qPCR,in situhybridization for ZIKV RNA, immunohistochemistry, and plaque assays. Four additional pregnant macaques were inoculated and terminally perfused with 4% paraformaldehyde at three, six, nine, or ten days post-maternal inoculation. For these four cases, the entire fixed pregnant uterus was evaluated within situhybridization for ZIKV RNA. We determined that ZIKV can reach the MFI by six days post-infection and infect the fetus by ten days. Infection of the chorionic membrane and the extraembryonic coelomic fluid preceded infection of the fetus and the mesenchymal tissue of the placental villi. We did not find evidence to support a transplacental route of ZIKV vertical transmission via infection of syncytiotrophoblasts or villous cytotrophoblasts. The pattern of infection observed in the maternal-fetal interface provides evidence of vertical ZIKV transmission through the fetal membranes.Author’s SummaryZika virus (ZIKV) can be vertically transmitted from mother to fetus during pregnancy resulting in adverse pregnancy outcomes. For vertical transmission to occur, ZIKV must overcome the barriers of the maternal-fetal interface, yet the exact pathway ZIKV takes remains undefined. The maternal-fetal interface consists of the maternal decidua, the placenta, and the fetal membranes. ZIKV could reach the fetus through the placenta if it can infect the layer of cells that are directly exposed to maternal blood. ZIKV could also reach the fetus by infecting the decidua and then the adjacent fetal membranes. To determine the pathways of ZIKV vertical transmission, we infected pregnant macaques and evaluated ZIKV burden in the maternal-fetal interface and fetus shortly after maternal infection. The pattern of infection observed suggests that ZIKV vertically transmits through the fetal membranes, not the placenta. This finding is significant because it challenges the assumption that vertical transmission occurs exclusively across the placenta. By including the fetal membranes in our models of vertical transmission, we can more accurately determine which pathogens can be vertically transmitted. Ultimately, this study demonstrates that fetal membranes are an essential barrier to pathogens that warrant further investigation.

BACKGROUND Even preceding the Supreme Court’s 2022 Dobbs v. Jackson Women’s Health Organization decision, patients in the United States faced exceptional barriers to reaching abortion providers, and abortion access was highly unequal. Presently, clinics in states where abortion remains legal are experiencing an influx of out-of-state patients and wait times are increasing. Direct-to-patient telehealth for abortion care was introduced in the United States in 2020 and since then has expanded to many states, however, the role of telehealth abortion care in addressing geographic barriers to and inequities in abortion access remains unclear. OBJECTIVE We sought to examine the amount of travel patients averted by using telehealth for abortion care, and the role of telehealth in mitigating inequities in abortion access. METHODS Using geospatial analyses and data from patients in 31 states and Washington D.C., we documented the travel to the nearest abortion facility that patients averted by using telehealth abortion services from April 2021 to January 2022, prior to the Dobbs decision. We examined whether telehealth made it possible for patients to have an abortion in a timely manner and whether this varied by patient characteristics and travel averted. RESULTS The 6,027 patients averted a median of 10 miles and 25 minutes of round-trip driving, and 1 hour and 25 minutes of round-trip public transit time. Across the sample, patients averted a total of 162,663 driving miles and 4,195 driving hours, and 11,720 hours of public transit time. Among 1,586 patients surveyed, 43% reported that telehealth made it possible to obtain timely abortion care. Telehealth was more likely to make it possible to have a timely abortion for younger patients; rural patients; those experiencing food insecurity; patients of color; and those who averted over 100 driving miles. CONCLUSIONS Telehealth is a powerful tool to reduce abortion-related travel in states where abortion remains legally accessible, especially among patient populations who already face structural barriers to abortion care. Restrictions on telehealth abortion threaten health equity.

•The COVID-19 pandemic suppressed fertility desires among US women.•Impacts on fertility preferences persisted from summer 2020 to early 2021.•The fertility preferences of younger women, women of color and those facing financial stress were most impacted.

Current methods to detect post-translational modifications (PTMs) of proteins, such as phosphate groups, cannot measure single molecules and often cannot differentiate between closely spaced phosphorylation sites. Using a nanopore sequencing approach, we here report detection of PTMs at the single-molecule level on immunopeptide sequences with cancer-associated phosphate variants. We reliably discriminate peptide sequences with one or two closely spaced phosphates with 95% accuracy for individual reads of single molecules.

Purpose To report the clinical and refractive outcomes of a modified Yamane technique for scleral fixation of the CT Lucia 602 lens. Design Retrospective case series. Patients One hundred twenty-one eyes with dislocated posterior chamber lens implants, surgical aphakia, subluxed crystalline lenses, capsular tear, anterior chamber, or iris sutured posterior chamber lens intolerance were included. Methods Secondary implantation of the Zeiss CT Lucia 602 lens was performed by a single surgeon using a modified Yamane technique employing a single needle, rather than the double-needle approach. One hundred twelve eyes underwent simultaneous 3 port pars plana vitrectomy and 9 eyes had previously undergone posterior vitrectomy surgery. Exclusion criteria were age

Nonhuman primates are excellent models for studying human placentation as experimental manipulations in vitro can be translated to in vivo pregnancy. Our objective was to develop macaque trophoblast stem cells (TSCs) as an in vitro platform for future assessment of primate trophoblast development and function. Macaque TSC lines were generated by isolating first and second trimester placental villous cytotrophoblasts followed by culture in TSC medium to maintain cellular proliferation. TSCs grew as mononuclear colonies, whereas upon induction of syncytiotrophoblast (ST) differentiation multinuclear structures appeared, indicative of syncytium formation. Chorionic gonadotropin secretion was > 4000-fold higher in ST culture media compared to TSC media. The secretion of chorionic gonadotropin by TSC-derived ST reflects a reprogramming of macaque TSCs to an earlier pregnancy phenotype. Characteristic trophoblast hallmarks were defined in TSCs and ST including expression of C19MC miRNAs and the macaque placental nonclassical MHC class I molecule, Mamu-AG. Extravillous trophoblasts (EVTs) were derived that express macaque EVT markers Mamu-AG and CD56, and also secrete high levels of MMP2. Our analyses of macaque TSCs suggests that these cells represent a proliferative, self-renewing population capable of differentiating to STs and EVTs in vitro thereby establishing an experimental model of primate placentation.

BackgroundCongenital Zika virus (ZIKV) infection can result in birth defects, including malformations in the fetal brain and visual system. There are two distinct genetic lineages of ZIKV: African and Asian. Asian lineage ZIKVs have been associated with adverse pregnancy outcomes in humans; however, recent evidence from experimental models suggests that African-lineage viruses can also be vertically transmitted and cause fetal harm.Methodology/Principal FindingsTo evaluate the potential for vertical transmission of African-lineage ZIKV, we inoculated nine pregnant rhesus macaques (Macaca mulatta) subcutaneously with 44 plaque- forming units of a ZIKV strain from Senegal, (ZIKV-DAK). Dams were inoculated either at gestational day 30 or 45. Following maternal inoculation, pregnancies were surgically terminated seven or 14 days later and fetal and maternal-fetal interface tissues were collected and evaluated. Infection in the dams was evaluated via plasma viremia and neutralizing antibody titers pre- and post- ZIKV inoculation. All dams became productively infected and developed strong neutralizing antibody responses. ZIKV RNA was detected in maternal-fetal interface tissues (placenta, decidua, and fetal membranes) by RT-qPCR and in situ hybridization. In situ hybridization detected ZIKV predominantly in the decidua and revealed that the fetal membranes may play a role in ZIKV vertical transmission. Infectious ZIKV was detected in the amniotic fluid of three pregnancies and one fetus had ZIKV RNA detected in multiple tissues. No significant pathology was observed in any fetus; however, we did find an increase in the occurrence of decidual vasculitis and necrosis in ZIKV-exposed pregnancies compared to gestational-age-matched controls.Conclusions/SignificanceThis study demonstrates that African-lineage ZIKV, like Asian-lineage ZIKV, can be vertically transmitted to the macaque fetus during pregnancy. The low inoculating dose used in this study suggests a low minimal infectious dose for rhesus macaques. Vertical transmission with a low dose in macaques further supports the high epidemic potential of African ZIKV strains.Author SummaryZika virus infection during pregnancy can result in adverse pregnancy outcomes including birth defects and miscarriage. There are two distinct genetic backgrounds of Zika virus: Asian-lineage and African-lineage. Currently, only Asian-lineage Zika virus is causally associated with adverse pregnancy outcomes in people. However, experimental studies have shown that African-lineage Zika virus can infect the fetus during pregnancy and cause adverse outcomes. Adverse pregnancy outcomes may not be associated with infection in people until there is an outbreak in a naive population. Thus, as African-lineage Zika virus continues to spread globally, the risk that it may pose to pregnant people remains a public health concern. In this study, we demonstrate that African-lineage Zika virus can be transmitted from the mother to the fetus during pregnancy. This study is significant because we used rhesus macaques, an animal that shares many key elements of Zika virus infection in pregnant people. This study is also significant because we inoculated pregnant macaques with a very small amount of virus, suggesting that fetal infection reported in previously published macaque studies is not limited to high-dose inoculation.

Screening for medication abortion eligibility typically includes ultrasonography or pelvic examination. To reduce physical contact during the COVID-19 pandemic, many clinicians stopped requiring tests before medication abortion and instead screened patients for pregnancy duration and ectopic pregnancy risk by history alone. However, few US-based studies have been conducted on the outcomes and safety of this novel model of care.To evaluate the outcomes and safety of a history-based screening, no-test approach to medication abortion care.This retrospective cohort study included patients obtaining a medication abortion without preabortion ultrasonography or pelvic examination between February 1, 2020, and January 31, 2021, at 14 independent, Planned Parenthood, academic-affiliated, and online-only clinics throughout the US.Medications for abortion provided without preabortion ultrasonography or pelvic examination and dispensed to patients in person or by mail.Effectiveness, defined as complete abortion after 200 μg of mifepristone and up to 1600 μg of misoprostol without additional intervention, and major abortion-related adverse events, defined as hospital admission, major surgery, or blood transfusion.The study included data on 3779 patients with eligible abortions. The study participants were racially and ethnically diverse and included 870 (23.0%) Black patients, 533 (14.1%) Latinx/Hispanic patients, 1623 (42.9%) White patients, and 327 (8.7%) who identified as multiracial or with other racial or ethnic groups. For most (2626 [69.5%]), it was their first medication abortion. Patients lived in 34 states, and 2785 (73.7%) lived in urban areas. In 2511 (66.4%) abortions, the medications were dispensed in person; in the other 1268 (33.6%), they were mailed to the patient. Follow-up data were obtained for 2825 abortions (74.8%), and multiple imputation was used to account for missing data. Across the sample, 12 abortions (0.54%; 95% CI, 0.18%-0.90%) were followed by major abortion-related adverse events, and 4 patients (0.22%; 95% CI, 0.00%-0.45%) were treated for ectopic pregnancies. Follow-up identified 9 (0.40%; 95% CI, 0.00%-0.84%) patients who had pregnancy durations of greater than 70 days on the date the mifepristone was dispensed that were not identified at screening. The adjusted effectiveness rate was 94.8% (95% CI, 93.6%-95.9%). Effectiveness was similar when medications were dispensed in person (95.4%; 95% CI, 94.1%-96.7%) or mailed (93.3%; 95% CI, 90.7%-95.9%).In this cohort study, screening for medication abortion eligibility by history alone was effective and safe with either in-person dispensing or mailing of medications, resulting in outcomes similar to published rates of models involving ultrasonography or pelvic examination. This approach may facilitate more equitable access to this essential service by increasing the types of clinicians and locations offering abortion care.

There are currently no approved drugs to treat Zika virus (ZIKV) infection during pregnancy. Hyperimmune globulin products such as VARIZIG and WinRho are FDA-approved to treat conditions during pregnancy such as Varicella Zoster virus infection and Rh-incompatibility. We administered ZIKV-specific human immune globulin as a treatment in pregnant rhesus macaques one day after subcutaneous ZIKV infection. All animals controlled ZIKV viremia following the treatment and generated robust levels of anti-Zika virus antibodies in their blood. No adverse fetal or infant outcomes were identified in the treated animals, yet the placebo control treated animals also did not have signs related to congenital Zika syndrome (CZS). Human immune globulin may be a viable prophylaxis and treatment option for ZIKV infection during pregnancy, however, more studies are required to fully assess the impact of this treatment to prevent CZS.

To facilitate the estimation of heat loads on plasma-facing components in fusion devices in various different magnetic geometries, a heat load proxy model was developed based on anisotropic diffusion. In this work, this model is compared to the so-called field-line diffusion approach. To facilitate the evaluation of these models, a novel synthetic camera-based approach for obtaining heat load distributions from Monte Carlo samples was also developed and implemented. With the assistance of this synthetic camera, heat load predictions for the Wendelstein 7-X divertor were obtained and compared with infrared camera observations. It was found that the anisotropic diffusion-based model achieved a closer match to infrared camera observations, while still being suitable in computational effort for large magnetic configuration database scans.

The voltage-gated sodium channel Na

[Image: see text] Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure–activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.

Purpose There are limited and conflicting data regarding the impact of comorbid hepatitis C virus (HCV) infection on diabetic retinopathy (DR). This study sought to compare the prevalence and severity of DR among patients with diabetes mellitus (DM) with and without HCV. Patients and methods This was a retrospective, case-control study of patients with DM comparing 120 patients with comorbid HCV and 120 age-matched controls. DR prevalence and several measures of severity were compared between groups. Subgroup analyses were performed among HCV patients with cirrhosis, comorbid HIV, or history of treatment with interferon. Statistical analysis for between-group comparisons utilized both univariate and multivariate analyses. Results Cases and controls exhibited similar baseline characteristics: average hemoglobin A1c, DM duration, and age (p>0.05). Among cases and controls, there was no difference in DR prevalence (35.8% versus 42.5%, respectively, p=0.29) or severity (p>0.05). Within the HCV subgroup, DR severity was reduced in patients with HIV or cirrhosis. However, multivariate analysis identified reduced DM duration in these subgroups as the primary contributor to lesser DR severity, rather than HIV or cirrhosis. Conclusion In this study, comorbid HCV did not modulate the prevalence or severity of DR among patients with DM. These findings may inform clinical monitoring among HCV-positive diabetics undergoing ophthalmic evaluation.

The status of bulk superconductor magnetic levitation (Maglev) train technique is evaluated. Existing industrial magnetic trains (electromagnetic, electrodynamic) point to key performance factors as load, speed, efficiency, and environmental protection. On that basis, a feasibility analysis of trapped-field train demonstrators should be attained. HTS bulk trapped field experiments at lower temperatures up to 6.8 T were performed and the HTS mass production capability is indicated. For increasing the transport load, a new generation of robust and mobile LN 2 vacuum cryostat type is developed. The new device is designed and scaled up according to the technique and practical experience of a smaller cryostat with 250 kg load and 30-40 h operation time. A test vehicle levitated by four cryostats on a magnetic guideway is presented. It is capable of levitating more than 1 ton. The new cryostat consists of 30 tiles 3-seed YBCO bulks, it levitates up to 0.5 ton at 10 mm distance, and with 5 l LN 2 stored it achieves an operation time of up to 2 days. We report about the integration of YBCO bulks, thermal insulation, LN 2 refilling, and mechanical construction. With the new development, we obtain evidence to manage higher train forces of several tons.

In the previous divertor campaign, the Wendelstein 7-X (W7-X) device injected 3.6 MW of neutral beam heating power allowing for the achievement of densities approaching 2 × 1020 m−3, and providing the first initial assessment of fast ion confinement in a drift optimized stellarator. The neutral beam injection (NBI) system on W7-X is comprised of two beam boxes with space for four radio frequency sources each. The 3.6 MW of heating reported in this work was achieved with two sources in the NI21 beam box. The effect of combined electron-cyclotron resonance heating (ECRH) and NBI was explored through a series of discharges varying both NBI and ECRH power. Discharges without ECRH saw a linear increase in the line-integrated plasma density, and strong peaking of the core density, over the discharge duration. The presence of 1 MW of ECRH power was found to be sufficient to control a continuous density rise during NBI operation. Simulations of fast ion wall loads were found to be consistent with experimental infrared camera images during operation. In general, NBI discharges were free from the presence of fast ion induced Alfvénic activity, consistent with low beam betas. These experiments provide data for future scenario development and initial assessment of fast-ion confinement in W7-X, a key topic of the project.

Purpose To describe ocular outcomes in eyes with cytomegalovirus (CMV) retinitis treated with adoptive immunotherapy using systemic administration of CMV-specific cytotoxic Tlymphocytes (CMV-specific CTLs). Design Retrospective cohort study. Participants Patients with active CMV retinitis evaluated at a tertiary care academic center. Methods Treatment of CMV retinitis with standard-of-care therapy (systemic or intravitreal antivirals) or CMV-specific CTLs (with or without concurrent standard-of-care therapies). Main Outcome Measures The electronic medical record was reviewed to determine baseline characteristics, treatment course, and ocular outcomes, including best-corrected visual acuity (BCVA), treatments administered (CMV-specific CTLs, systemic antivirals, intravitreal antivirals), resolution of CMV retinitis, any occurrence of immune recovery uveitis, cystoid macular edema, retinal detachment, or a combination thereof. Results Seven patients (3 of whom had bilateral disease [n = 10 eyes]) were treated with CMV-specific CTLs, whereas 20 patients (6 of whom had bilateral disease [n = 26 eyes]) received standard-of-care treatment. Indications for CMV-specific CTL therapy included persistent or progressive CMV retinitis (71.4% of patients); CMV UL54 or UL97 antiviral resistance mutations (42.9%); side effects or toxicity from antiviral agents (57.1%); patient intolerance to longstanding, frequent antiviral therapy for persistent retinitis (28.6%); or a combination thereof. Two patients (28.6%; 4 eyes [40%]) received CMV-specific CTL therapy without concurrent systemic or intravitreal antiviral therapy for active CMV retinitis, whereas 5 patients (71.4%; 6 eyes [60%]) continued to receive concurrent antiviral therapies. Resolution of CMV retinitis was achieved in 9 eyes (90%) treated with CMV-specific CTLs, with BCVA stabilizing (4 eyes [40%]) or improving (4 eyes [40%]) in 80% of eyes over an average follow-up of 33.4 months. Rates of immune recovery uveitis, new-onset cystoid macular edema, and retinal detachment were 0%, 10% (1 eye), and 20% (2 eyes), respectively. These outcomes compared favorably with a nonrandomized cohort of eyes treated with standard-of-care therapy alone, despite potentially worse baseline characteristics. Conclusions CMV-specific CTL therapy may represent a novel monotherapy or adjunctive therapy, or both, for CMV retinitis, especially in eyes that are resistant, refractory, or intolerant of standard-of-care antiviral therapies. More generally, adoptive cell transfer and adoptive immunotherapy may have a role in refractory CMV retinitis. Larger prospective, randomized trials are necessary.

Transcriptional regulatory network (TRN) orchestrates spatio-temporal expression of genes to generate cellular responses for survival. The transcription factors (TF) regulating expression of their target genes (TG) are the fundamental units of TRN. Several databases have been developed to catalogue human TRN based on low- and high-throughput experimental and computational studies considering their importance in understanding cellular physiology. However, literature lacks comparative assessment on the strength and weakness of each database. In this study, we compared over 2.2 million regulatory pairs between 1,379 TF and 22,518 TG assembled from 14 data resources. Our study reveals that the TF and TG were common across data resources but not their regulatory pairs. We observed that the TF and TG of the regulatory pairs showed weak expression correlation, significant gene ontology overlap, co-citations in PubMed and low numbers of TF-TG pairs representing transcriptional repression relationships. Furthermore, each TF-TG regulatory pair assigned a combined confidence score reflecting its reliability based on its presence in multiple databases and co-expression. The TRN containing 2,246,598 TF-TG pairs, of which, 44,284 with the information on TF’s activating or repressing effects on their TG is available upon request. This study brings the information about transcriptional regulation scattered over the literature and databases at one place in the form of one of the most comprehensive and complete human TRNs assembled to date, which will be a valuable resource for benchmarking TRN prediction tools, and to the scientific community working in functional genomics, gene expression and gene regulation analysis.

Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model withAtxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology. Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase ofGrn,Tlr7andRnaset2mRNA versusEif5a2,Dcp2, Uhmk1andKif5adecrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels forUnc80,Tacr1,Gnal,Ano3,Kcna2,Elovl5andCdr1contrasted withGpnmbincrease. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes includingDhcr24,Msmo1,Idi1andHmgcs1was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies.

We present a framework for training artificial neural networks (ANNs) as surrogate Bayesian models for the inference of plasma parameters from diagnostic data collected at nuclear fusion experiments, with the purpose of providing a fast approximation of conventional Bayesian inference. Because of the complexity of the models involved, conventional Bayesian inference can require tens of minutes for analyzing one single measurement, while hundreds of thousands can be collected during a single plasma discharge. The ANN surrogates can reduce the analysis time down to tens/hundreds of microseconds per single measurement. The core idea is to generate the training data by sampling them from the joint probability distribution of the parameters and observations of the original Bayesian model. The network can be trained to learn the reconstruction of plasma parameters from observations and the model joint probability distribution from plasma parameters and observations. Previous work has validated the application of such a framework to the former case at the Wendelstein 7-X and Joint European Torus experiments. Here, we first give a description of the general methodological principles allowing us to generate the training data, and then we show an example application of the reconstruction of the joint probability distribution of an effective ion charge Zeff-bremsstrahlung model from data collected at the latest W7-X experimental campaign. One key feature of such an approach is that the network is trained exclusively on data generated with the Bayesian model, requiring no experimental data. This allows us to replicate the training scheme and generate fast, surrogate ANNs for any validated Bayesian diagnostic model.

Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations on both copies of the CFTR gene. Phenylalanine deletion at position 508 of the CFTR protein (F508del-CFTR) is the most frequent mutation in CF patients. Currently, the most effective treatments of CF use a dual or triple combination of CFTR correctors and potentiators. In triple therapy, two correctors (C1 and C2) and a potentiator are employed. Herein, we describe the identification and exploration of the SAR of a series of 4-aminopyrrolidine-2-carboxylic acid C2 correctors of CFTR to be used in conjunction with our existing C1 corrector series for the treatment of CF.

This chapter reviews the contributions of the Global Early Adolescent Study (GEAS), a multi-national longitudinal study of disadvantaged urban populations, beginning in the critical early adolescent period.We highlight tools developed to capture gendered dynamics among adolescents, including empowerment and perceptions of gender norms. Initial data collected for the GEAS have contributed to several cross-national findings about adolescent well-being to date. The chapter also outlines the GEAS global research network’s experiences and challenges implementing longitudinal survey research with vulnerable young populations, including cross-cultural ethical issues and participant retention. Finally, we describe how data collected for the GEAS can contribute to the enrichment of policy indicators for vulnerable adolescent populations globally.

Aging is associated with a number of histological changes in the choroid, Bruch's membrane, RPE, and neuroretina. Outside of the normal physiologic aging spectrum of changes, abnormal deposits such as basal laminar deposits, basal linear deposits, and soft drusen are known to be associated with AMD. Progression of AMD to advanced stages involving geographic atrophy, choroidal neovascularization, and/or disciform scars can result in debilitating vision loss. Knowledge of the angiogenic pathway and its components that stimulate neovascularization has led to the development of a new paradigm of intravitreal anti-VEGF pharmacotherapy in the management of neovascular AMD. Currently however, there are no available treatments for the modification of disease progression in non-neovascular AMD, or for the treatment of geographic atrophy. Further understanding of the histopathology of AMD and the molecular mechanisms that contribute to pathogenesis of the disease may reveal additional therapeutic targets.