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Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted owing to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole-genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice, and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of AN. By combining whole-genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

Reports on the association between the prevalence of atopic diseases and neurodevelopmental disabilities (NDs) have been inconsistent in the literature. We investigated whether autism spectrum disorder (ASD), attention deficit-hyperactivity disorders (ADHD), and other NDs are more prevalent in children with asthma, atopic dermatitis (AD) and allergic rhinitis (AR) compared to those without specific atopic conditions. A total of 2580 children enrolled at birth were followed prospectively, of which 119 have ASD, 423 have ADHD, 765 have other NDs, and 1273 have no NDs. Atopic diseases and NDs were defined based on physician diagnoses in electronic medical records. Logistic regressions adjusting for maternal and child characteristics estimated the associations between NDs (i.e., ASD, ADHD, and other NDs) and asthma, AD and AR, respectively. Children with asthma, AD or AR had a greater likelihood of having ADHD or other NDs compared with children without specific atopic conditions. The association between ASD and asthma diminished after adjusting for maternal and child factors. Either mothers or children having atopic conditions and both mothers and children with atopic conditions were associated with a higher prevalence of ADHD in children, compared with neither mothers nor children having atopic conditions. Children diagnosed with multiple atopic diseases were more likely to have NDs compared with those without or with only one type of atopic disease. In conclusion, in this U.S. urban birth cohort, children with atopic diseases had a higher co-morbidity of NDs. The findings have implications for etiologic research that searches for common early life antecedents of NDs and atopic conditions. Findings from this study also should raise awareness among health care providers and parents about the possible co-occurrence of both NDs and atopic conditions, which calls for coordinated efforts to screen, prevent and manage NDs and atopic conditions.

Background: “Epigenetic clocks” have been developed to accurately predict chronologic gestational age and have been associated with child health outcomes in prior work. Methods:We meta-analyzed results from four prospective U.S cohorts investigating the association between epigenetic age acceleration estimated using blood DNA methylation collected at birth and preschool age Childhood Behavior Checklist (CBCL) scores. Results:Epigenetic aging was not significantly associated with CBCL total problem scores (β= 0.33, 95% CI: -0.95, 0.28) and DSM-oriented pervasive development problem scores (β=-0.23, 95% CI: -0.61, 0.15). No associations were observed for other DSM-oriented subscales. Conclusions:These findings may relate to our sample size or sample characteristics; future work should address the role of epigenetic age in child health in other study populations.

The attempt of this work is to evaluate the three options (BSE-1979, AMTB-2013, SHU-2015) embedded in IRI-2016 for the F2 layer peak height (hmF2) estimation under low and high solar flux levels. We compare the model hmF2 with digisonde observations from Qaanaaq, Milllstone Hill, Ramey, Jicamarca and Port Stanley as well as Constellation Observing System for Meteorology, Ionosphere and Climate (COSMIC) ionospheric radio occultation data over the five stations spanning from northern hemisphere to southern hemisphere. In the case of Millstone Hill, we also use incoherent scatter radar (ISR) measurements. For the comparison with digisonde data, SHU-2015 is the most accurate option for reproducing hmF2 at low and middle latitude stations (Milllstone Hill, Ramey, Jicamarca) with the smallest Root-Mean-Square-Error and the highest correlation with observations. At high latitude (Qaanaaq and Port Stanley), BSE-1979 becomes the best option. This is true for both low and high solar flux conditions. Similar results are obtained for the comparison between ISR and IRI-2016 hmF2 model options over Millstone Hill, where SHU-2015 option has the smallest deviations from the observation data in both low and high solar activity conditions. As for the comparison with COSMIC data, SHU-2015 edges out the other two options under low solar activity level with better performance at three stations. There is no optimal option under high solar activity level, which is to our surprise, cause SHU-2015 was developed based on a large amount of radio occultation data. At Jicamarca, all options show dramatic deviations from COSMIC observations, showing even negative correlations. We propose that the performance of the three options do not vary much with solar condition, while they differ a lot with location, for example, latitude.

Infantile nystagmus syndrome (INS) denominates early-onset, involuntary oscillatory eye movements with different etiologies. Nystagmus is also one of the symptoms in oculocutaneus albinism (OCA), a heterogeneous disease mainly caused by defects in melanin synthesis or melanosome biogenesis. Dopachrome tautomerase (DCT, also called TYRP2) together with tyrosinase (TYR) and tyrosin-related protein 1 (TYRP1) is one of the key enzymes in melanin synthesis. Although DCT´s role in pigmentation has been proven in different species, until now only mutations in TYR and TYRP1 have been found in patients with OCA. Detailed ophthalmological and orthoptic investigations identified a consanguineous family with two individuals with isolated infantile nystagmus and one family member with subtle signs of albinism. By whole-exome sequencing and segregation analysis, we identified the missense mutation c.176G > T (p.Gly59Val) in DCT in a homozygous state in all three affected family members. We show that this mutation results in incomplete protein maturation and targeting in vitro compatible with a partial or total loss of function. Subsequent screening of a cohort of patients with OCA (n = 85) and INS (n = 25) revealed two heterozygous truncating mutations, namely c.876C > A (p.Tyr292*) and c.1407G > A (p.Trp469*), in an independent patient with OCA. Taken together, our data suggest that mutations in DCT can cause a phenotypic spectrum ranging from isolated infantile nystagmus to oculocutaneous albinism.

Aim Inhaled nitric oxide (iNO) during cardiopulmonary resuscitation (CPR) improved systemic hemodynamics and outcomes in a preclinical model of adult in-hospital cardiac arrest (IHCA) and may also have a neuroprotective role following cardiac arrest. The primary objectives of this study were to determine if iNO during CPR would improve cerebral hemodynamics and mitochondrial function in a pediatric model of lipopolysaccharide-induced shock-associated IHCA. Methods After lipopolysaccharide infusion and ventricular fibrillation induction, 20 1-month-old piglets received hemodynamic-directed CPR and were randomized to blinded treatment with or without iNO (80 ppm) during and after CPR. Defibrillation attempts began at 10 min with a 20-min maximum CPR duration. Cerebral tissue from animals surviving 1-h post-arrest underwent high-resolution respirometry to evaluate the mitochondrial electron transport system and immunohistochemical analyses to assess neuropathology. Results During CPR, the iNO group had higher mean aortic pressure (41.6 ± 2.0 vs. 36.0 ± 1.4 mmHg; p = 0.005); diastolic BP (32.4 ± 2.4 vs. 27.1 ± 1.7 mmHg; p = 0.03); cerebral perfusion pressure (25.0 ± 2.6 vs. 19.1 ± 1.8 mmHg; p = 0.02); and cerebral blood flow relative to baseline (rCBF: 243.2 ± 54.1 vs. 115.5 ± 37.2%; p = 0.02). Among the 8/10 survivors in each group, the iNO group had higher mitochondrial Complex I oxidative phosphorylation in the cerebral cortex (3.60 [3.56, 3.99] vs. 3.23 [2.44, 3.46] pmol O2/s mg; p = 0.01) and hippocampus (4.79 [4.35, 5.18] vs. 3.17 [2.75, 4.58] pmol O2/s mg; p = 0.02). There were no other differences in mitochondrial respiration or brain injury between groups. Conclusions Treatment with iNO during CPR resulted in superior systemic hemodynamics, rCBF, and cerebral mitochondrial Complex I respiration in this pediatric cardiac arrest model.

Background In prior work we observed differences in morphology features in placentas from an autism-enriched cohort as compared to those from a general population sample. Here we sought to examine whether these differences associate with ASD-related outcomes in the child. Methods Participants (n = 101) were drawn from the Early Autism Risk Longitudinal Investigation (EARLI), a cohort following younger siblings of children with autism spectrum disorder (ASD). ASD-related outcomes, including the Social Responsiveness Scale (SRS), Mullen Scales of Early Learning (MSEL) Early Learning Composite, and ASD diagnosis, were assessed at age 3. Crude and adjusted linear regression was used to examine associations between placental morphological features (parametrized continuously and in quartiles) and SRS and MSEL scores; comparisons by ASD case status were explored as secondary analyses due to the small number of cases (n = 20). Results In adjusted analyses, we observed a modest positive association between umbilical cord eccentricity, defined as the ratio of the maximum:minimum radius from the cord insertion point, and SRS scores (Beta = 1.68, 95%CI = 0.45, 2.9). Positive associations were also suggested between placental maximum thickness and cord centrality and SRS scores, though these were estimated with little precision. Associations between other placental morphological features and outcomes were not observed. Conclusions Our analyses suggested a potential association between umbilical cord features and ASD-related traits, of interest as non-central cord insertion may reflect reduced placenta efficiency. Future studies with larger sample sizes are needed to further examine these and other placental features in association with ASD-related outcomes.

New antibiotics with unique biological targets are desperately needed to combat the growing number of resistant bacterial pathogens. ATP synthase, a critical protein found in all life, has recently become a target of interest for antibiotic development due to the success of the anti-tuberculosis drug bedaquiline, and while many groups have worked on developing drugs to target bacterial ATP synthase, few have been successful at inhibiting

Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with 6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N=65). Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p=0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients’ progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.

OBJECTIVES Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is unclear. This study examines the impact of CPB on cerebral mitochondrial reactive oxygen species (ROS) generation and mitochondrial bioenergetics. METHODS Twenty-three piglets (mean weight 4.2 ± 0.5 kg) were placed on CPB for either 1, 2, 3 or 4 h (n = 5 per group) or underwent anaesthesia without CPB (sham, n = 3). Microdialysis was used to measure metabolic markers of ischaemia. At the conclusion of CPB or 4 h of sham, brain tissue was harvested. Utilizing high-resolution respirometry, with simultaneous fluorometric analysis, mitochondrial respiration and ROS were measured. RESULTS There were no significant differences in markers of ischaemia between sham and experimental groups. Sham animals had significantly higher mitochondrial respiration than experimental animals, including maximal oxidative phosphorylation capacity of complex I (OXPHOSCI) (3.25 ± 0.18 vs 4-h CPB: 1.68 ± 0.10, P CONCLUSIONS Even in the absence of local markers of ischaemia, CPB is associated with decreased mitochondrial respiration relative to shams irrespective of duration. Exposure to 4 h of CPB resulted in a significant increase in cerebral mitochondrial ROS formation compared to shorter durations. Further study is needed to improve the understanding of cerebral mitochondrial health and its effects on the pathophysiology of neurological injury following exposure to CPB.

Hypophosphatasia (HPP) is a rare inborn error of metabolism due to a decreased activity of tissue nonspecific alkaline phosphatase (TNSALP). As the onset and severity of HPP are heterogenous, it can be challenging to determine the pathogenicity of detected rare ALPL variants in symptomatic patients. We aimed to characterize patients with rare ALPL variants to propose which patients can be diagnosed with adult HPP. We included 72 patients with (1) clinical symptoms of adult HPP or positive family history and (2) low TNSALP activity and/or high pyridoxal 5′-phosphate (PLP) levels, who underwent ALPL gene sequencing. The patients were analyzed and divided into three groups depending on ALPL variant pathogenicity according to the classification of the American College of Medical Genetics and Genomics (ACMG). Reported pathogenic (n = 34 patients), rare (n = 17) and common (n = 21) ALPL variants only were found. Muscular complaints were the most frequent symptoms (> 80%), followed by bone affection (> 50%). Tooth involvement was significantly more common in patients with pathogenic or rare ALPL variants. Seven rare variants could be classified as likely pathogenic (ACMG class 4) of which five have not yet been described. Inconclusive genetic findings and less specific symptoms make diagnosis difficult in cases where adult HPP is not obvious. As not every pathogenic or rare ALPL variant leads to a manifestation of HPP, only patients with bone complications and at least one additional complication concerning teeth, muscle, central nervous and mental system, repeated low TNSALP activity and high PLP levels should be diagnosed as adult HPP if rare ALPL gene variants of ACMG class 4 or higher support the diagnosis.

Prior work proposed a shortened version of the Social Responsiveness Scale (SRS), a commonly used quantitative measure of social communication traits. We used data from 3,031 participants (including 190 ASD cases) from the Environmental Influences on Child Health Outcomes (ECHO) Program to compare distributional properties and criterion validity of 16-item “short” to 65-item “full” SRS scores. Results demonstrated highly overlapping distributions of short and full scores. Both scores separated case from non-case individuals by approximately two standard deviations. ASD prediction was nearly identical for short and full scores (area under the curve values of 0.87, 0.86 respectively). Findings support comparability of shortened and full scores, suggesting opportunities to increase efficiency. Future work should confirm additional psychometric properties of short scores.

Gestational exposure to air pollution increases the risk of autism spectrum disorder and cognitive impairments with unresolved molecular mechanisms. This study exposed C57BL/6J mice throughout gestation to urban-derived nanosized particulate matter (nPM). Young adult male and female offspring were studied for behavioral and metabolic changes using forced swim test, fat gain, glucose tolerance, and hippocampal transcriptome. Gestational nPM exposure caused increased depressive behaviors, decreased neurogenesis in the dentate gyrus, and increased glucose tolerance in adult male offspring. Both sexes gained fat and body weight. Gestational nPM exposure induced 29 differentially expressed genes (DEGs) in adult hippocampus related to cytokine production, IL17a signaling, and dopamine degradation in both sexes. Stratification by sex showed twofold more DEGs in males than females (69 vs 37), as well as male-specific enrichment of DEGs mediating serotonin signaling, endocytosis, Gαi, and cAMP signaling. Gene co-expression analysis (WCGNA) identified a module of 43 genes with divergent responses to nPM between the sexes. Chronic changes in 14 DEGs (e.g., microRNA9-1) were associated with depressive behaviors, adiposity and glucose intolerance. These genes enriched neuroimmune pathways such as HMGB1 and TLR4. Based on cerebral cortex transcriptome data of neonates, we traced the initial nPM responses of HMGB1 pathway. In vitro, mixed glia responded to 24 h nPM with lower HMGB1 protein and increased proinflammatory cytokines. This response was ameliorated by TLR4 knockdown. In sum, we identified transcriptional changes that could be associated with air pollution-mediated behavioral and phenotypic changes. These identified genes merit further mechanistic studies for therapeutic intervention development.

Background Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1–3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer. Case presentation A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient’s young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient’s father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy. Conclusion Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.

PURPOSE OF REVIEW: Environmental chemicals and toxins have been associated with increased risk of impaired neurodevelopment and specific conditions like autism spectrum disorder (ASD). Prenatal diet is an individually modifiable factor that may alter associations with such environmental factors. The purpose of this review is to summarize studies examining prenatal dietary factors as potential modifiers of the relationship between environmental exposures and ASD or related neurodevelopmental outcomes. RECENT FINDINGS: Twelve studies were identified; five examined ASD diagnosis or ASD-related traits as the outcome (age at assessment range: 2–5 years) while the remainder addressed associations with neurodevelopmental scores (age at assessment range: 6 months to 6 years). Most studies focused on folic acid, prenatal vitamins, or omega-3 fatty acids as potentially beneficial effect modifiers. Environmental risk factors examined included air pollutants, endocrine disrupting chemicals, pesticides, and heavy metals. Most studies took place in North America. In 10/12 studies, the prenatal dietary factor under study was identified as a significant modifier, generally attenuating the association between the environmental exposure and ASD or neurodevelopment. SUMMARY: Prenatal diet may be a promising target to mitigate adverse effects of environmental exposures on neurodevelopmental outcomes. Further research focused on joint effects is needed that encompasses a broader variety of dietary factors, guided by our understanding of mechanisms linking environmental exposures with neurodevelopment. Future studies should also aim to include diverse populations, utilize advanced methods to optimize detection of novel joint effects, incorporate consideration of timing, and consider both synergistic and antagonistic potential of diet.

Children with autism spectrum disorder (ASD) have a higher prevalence of pain compared to those without ASD. Pain is a leading cause of morbidity and disability worldwide and may contribute to adverse health outcomes in people with ASD, thus warranting further research on this special population. The present study used data from 1,423 children with ASD and 46,023 children without ASD and their mothers from the combined 2016-2017 National Survey of Children’s Health. Mothers reported child pain and ASD status and their own mental health status. Mothers reporting a status of “Fair or Poor” were considered as having maternal mental health conditions (MMHCs) for the purposes of this study. Children with and without ASD who had mothers with MMHCs had higher odds of pain compared to children with mothers without MMHCs. These increased odds did not attenuate as a result of controlling for co-occurring neurological conditions, which have been associated with increased pain in children with ASD. Thus, parent mental health may alter perception and/or reports of pain on behalf of children with and without ASD. Future research should include more detailed assessments of parent mental health and clinical assessments of children in order to explore the role of parent mental health in the experiences of pain and other symptoms present in children with ASD.

The application of aptamers in biomedicine is emerging as an essential technology in the field of cancer research. As small single-stranded DNA or RNA ligands with high specificity and low immunogenicity for their targets, aptamers provide many advantages in cancer therapeutics over protein-based molecules, such as antibodies. Vimentin is an intermediate filament protein that is overexpressed in endothelial cells of cancerous tissue. High expression levels of vimentin have been associated with increased capacity for migration and invasion of the tumor cells. We have selected and identified thioated aptamers with high specificity for vimentin using human ovarian cancer tissues. Tentative binding motifs were chosen for two vimentin aptamers based on predicted secondary structures. Each of these shorter, tentative binding motifs was synthesized, purified, and characterized via cell binding assays. Two vimentin binding motifs with high fidelity binding were selected and further characterized via cell and tissue binding assays, as well as flow cytometric analysis. The equilibrium binding constants of these small thioated aptamer constructs were also determined. Future applications for the vimentin binding aptamer motifs include conjugation of the aptamers to synthetic dyes for use in targeted imaging and therapy, and ultimately more detailed and precise monitoring of treatment response and tumor progression in ovarian pathology.

Key Points Question What factors are associated with gaps in the HIV preexposure prophylaxis (PrEP) continuum of care and where in the continuum do HIV infections occur? Findings In this cohort of 13 906 insured adults linked to PrEP care, individuals aged 18 to 25, African American individuals, Latinx individuals, women, individuals with lower socioeconomic status, and individuals with a substance use disorder were more likely to experience gaps in the PrEP continuum of care. Attrition along the continuum was associated with incident HIV infection. Meaning These findings suggest that comprehensive strategies are warranted to improve PrEP continuum of care outcomes in high-priority populations., This cohort study assesses factors associated with receipt and use of preexposure prophylaxis and incidence of HIV among individuals assessed for preexposure prophylaxis., Importance Long-term follow-up is needed to evaluate gaps in HIV preexposure prophylaxis (PrEP) care delivery and to identify individuals at risk for falling out of care. Objective To characterize the PrEP continuum of care, including prescription, initiation, discontinuation, and reinitiation, and evaluate incident HIV infections. Design, Setting, and Participants This retrospective cohort study used data from the electronic health records (EHR) at Kaiser Permanente Northern California to identify individuals aged 18 years and older who received PrEP care between July 2012 and March 2019. Individuals were followed up from date of linkage (defined as a PrEP referral or PrEP-coded encounter) until March 2019, HIV diagnosis, discontinuation of health plan membership, or death. Data were analyzed from December 2019 to January 2021. Exposures Sociodemographic factors included age, sex, race and ethnicity, and neighborhood deprivation index, and clinical characteristics were extracted from the EHR. Main Outcomes and Measures The primary outcomes were attrition at each step of the PrEP continuum of care and incident HIV infections. Results Among 13 906 individuals linked to PrEP care, the median (interquartile range [IQR]) age was 33 (27-43) years, 6771 individuals (48.7%) were White, and 13 227 (95.1%) were men. Total follow-up was 26 210 person-years (median [IQR], 1.6 [0.7-2.8] years). Of individuals linked to PrEP care, 88.1% (95% CI, 86.1%-89.9%) were prescribed PrEP and of these, 98.2% (95% CI, 97.2%-98.8%) initiated PrEP. After PrEP initiation, 52.2% (95% CI, 48.9%-55.7%) discontinued PrEP at least once during the study period, and 60.2% (95% CI, 52.2%-68.3%) of these individuals subsequently reinitiated. Compared with individuals aged 18 to 25 years, older individuals were more likely to receive a PrEP prescription (eg, age >45 years: hazard ratio [HR], 1.21 [95% CI, 1.14-1.29]) and initiate PrEP (eg, age >45 years: HR, 1.09 [95% CI, 1.02-1.16]) and less likely to discontinue (eg, age >45 years: HR, 0.46 [95% CI, 0.42-0.52]). Compared with White patients, African American and Latinx individuals were less likely to receive a PrEP prescription (African American: HR, 0.74 [95% CI, 0.69-0.81]; Latinx: HR, 0.88 [95% CI, 0.84-0.93]) and initiate PrEP (African American: HR, 0.87 [95% CI, 0.80-0.95]; Latinx: HR, 0.90 [95% CI, 0.86-0.95]) and more likely to discontinue (African American: HR, 1.36 [95% CI, 1.17-1.57]; Latinx: 1.33 [95% CI, 1.22-1.46]). Similarly, women, individuals with lower neighborhood-level socioeconomic status (SES), and persons with a substance use disorder (SUD) were less likely to be prescribed (women: HR, 0.56 [95% CI, 0.50-0.62]; lowest SES: HR, 0.72 [95% CI, 0.68-0.76]; SUD: HR, 0.88 [95% CI, 0.82-0.94]) and initiate PrEP (women: HR, 0.71 [95% CI, 0.64-0.80]; lower SES: HR, 0.93 [95% CI, 0.87-.0.99]; SUD: HR, 0.88 [95% CI, 0.81-0.95]) and more likely to discontinue (women: HR, 1.99 [95% CI, 1.67-2.38]); lower SES: HR, 1.40 [95% CI, 1.26-1.57]; SUD: HR, 1.23 [95% CI, 1.09-1.39]). HIV incidence was highest among individuals who discontinued PrEP and did not reinitiate PrEP (1.28 [95% CI, 0.93-1.76] infections per 100 person-years). Conclusions and Relevance These findings suggest that gaps in the PrEP care continuum were concentrated in populations disproportionately impacted by HIV, including African American individuals, Latinx individuals, young adults (aged 18-25 years), and individuals with SUD. Comprehensive strategies to improve PrEP continuum outcomes are needed to maximize PrEP impact and equity.

Among 279 patients within a large healthcare system in San Francisco, event-driven HIV pre-exposure prophylaxis using a 2–1–1 regimen was a desirable alternative to daily dosing. Problems with adherence, planning sex in advance, or side effects were infrequent (13.9%). We found no new HIV infections over 136 person-years of follow-up.

Zusammenfassung Die Hypophosphatasie (HPP) ist eine erbliche metabolische Multisystemerkrankung, deren klinische Hauptcharakteristika Mineralisierungsstörungen von Knochen und Zähnen sowie Muskel- und Gelenkschmerzen sind. Die klinische Symptomatik ist vom Erkrankungsalter abhängig und gestaltet sich sowohl interindividuell als auch intrafamiliär sehr variabel. Es werden sechs Unterformen der HPP abgegrenzt, wobei die Übergänge fließend sind. Sie reichen von der schweren perinatalen Form, die früher aufgrund fehlender Skelettmineralisierung meist tödlich war, bis hin zur adulten Form mit typischen Symptomen wie Frakturheilungsstörungen oder Stressfrakturen. Unspezifische Symptome wie Muskelschmerzen und -schwäche, Migräne oder Depressionen können ebenfalls Teil der HPP sein. Während schwere Formen mit einer Prävalenz zwischen 1/100.000 und 1/300.000 selten sind, kommen milde Formen der HPP deutlich häufiger vor. Perinatale und frühkindliche Formen sind meist autosomal-rezessiv vererbt, hingegen werden später auftretende Formen autosomal-rezessiv oder -dominant vererbt. Ursache der HPP ist eine reduzierte oder fehlende Aktivität der gewebeunspezifischen alkalischen Phosphatase (AP), welche durch das ALPL-Gen kodiert wird. Laborchemisch lassen sich im Serum eine alters- und geschlechtsspezifisch erniedrigte AP-Aktivität und eine konsekutive Erhöhung der AP-Substrate, z. B. des Pyridoxal-5-Phosphats (PLP), feststellen. Seit der Erstbeschreibung der Erkrankung 1948 haben sich die Diagnostik und Therapie der HPP dramatisch verbessert. Vor 4 Jahren ist eine Enzymersatztherapie mit Asfotase alfa (Strensiq®) für schwer betroffene HPP-Patienten mit Beginn der Erkrankung vor dem 18. Lebensjahr zugelassen worden. Dieser Artikel gibt einen Überblick über das breite klinische Spektrum der HPP, pathophysiologische Hintergründe, die laborchemische und molekulargenetische Diagnostik sowie gegenwärtige Therapieoptionen und deren Behandlungsindikationen.

Summary Background The limitations of existing HIV risk prediction tools are a barrier to implementation of pre-exposure prophylaxis (PrEP). We developed and validated an HIV prediction model to identify potential PrEP candidates in a large health-care system. Methods Our study population was HIV-uninfected adult members of Kaiser Permanente Northern California, a large integrated health-care system, who were not yet using PrEP and had at least 2 years of previous health plan enrolment with at least one outpatient visit from Jan 1, 2007, to Dec 31, 2017. Using 81 electronic health record (EHR) variables, we applied least absolute shrinkage and selection operator (LASSO) regression to predict incident HIV diagnosis within 3 years on a subset of patients who entered the cohort in 2007–14 (development dataset), assessing ten-fold cross-validated area under the receiver operating characteristic curve (AUC) and 95% CIs. We compared the full model to simpler models including only men who have sex with men (MSM) status and sexually transmitted infection (STI) positivity, testing, and treatment. Models were validated prospectively with data from an independent set of patients who entered the cohort in 2015–17. We computed predicted probabilities of incident HIV diagnosis within 3 years (risk scores), categorised as low risk ( Findings Of 3 750 664 patients in 2007–17 (3 143 963 in the development dataset and 606 701 in the validation dataset), there were 784 incident HIV cases within 3 years of baseline. The LASSO procedure retained 44 predictors in the full model, with an AUC of 0·86 (95% CI 0·85–0·87) for incident HIV cases in 2007–14. Model performance remained high in the validation dataset (AUC 0·84, 0·80–0·89). The full model outperformed simpler models including only MSM status and STI positivity. For the full model, flagging 13 463 (2·2%) patients with high or very high HIV risk scores in the validation dataset identified 32 (38·6%) of the 83 incident HIV cases, including 32 (46·4%) of 69 male cases and none of the 14 female cases. The full model had equivalent sensitivity by race whereas simpler models identified fewer black than white HIV cases. Interpretation Prediction models using EHR data can identify patients at high risk of HIV acquisition who could benefit from PrEP. Future studies should optimise EHR-based HIV risk prediction tools and evaluate their effect on prescription of PrEP. Funding Kaiser Permanente Community Benefit Research Program and the US National Institutes of Health.

ObjectivesPeople with HIV (PWH) have a high burden of bacterial sexually transmitted infections (STIs). We examined the relationship of alcohol and drug use and partner pre-exposure prophylaxis (PrEP) use to STI prevalence in a cohort of PWH with a history of unhealthy alcohol use.MethodsWe analysed data from a primary care-based alcohol intervention study at Kaiser Permanente Northern California (KPNC). Participants were recruited between April 2013 and May 2015 and were followed for up to 24 months. We linked participant responses to questions from the 24 month follow-up interview, including alcohol and drug use and partner PrEP use, with STI test results (ie, syphilis, chlamydia, gonorrhoea) in the KPNC electronic health record. Prevalence ratios (PR) were estimated using Poisson models fitted with robust variance estimators to evaluate the association of substance use and partner use of PrEP with STIs.ResultsIn the analytic sample (n=465), the median age was 52 years (IQR 45–59); 67% were white; 95% were men who have sex with men. Thirty-two per cent of participants had HIV-positive partners only; 31% had HIV-negative partners with at least one on PrEP in the previous year and 37% had HIV-negative partners without any on PrEP. Twenty-three per cent reported alcohol and drug use prior to sex in the last 6 months. Eight per cent of participants had an STI. Partner PrEP use (adjusted PR (aPR) 2.99 (95% CI 1.11 to 8.08)) was independently associated with higher STI prevalence. Participants who reported use of alcohol (aPR 1.53 (0.61 to 3.83)), drugs (aPR 1.97 (0.71 to 5.51)) or both (aPR 1.93 (0.75 to 4.97)) prior to sex had a higher STI prevalence.ConclusionsThe higher prevalence of STIs among PWH with unhealthy alcohol use who have partners on PrEP suggests that this subgroup may be a high-yield focus for targeted outreach, STI screening and sexual health counselling.

Unconventional natural gas development (UNGD) introduces physical and psychosocial hazards into communities, which could contribute to psychosocial stress in adolescents and an increased risk of internalizing disorders, common and impactful health outcomes.To evaluate associations between a 180-day composite UNGD activity metric and new onset of internalizing disorders, overall and separately for anxiety and depressive disorders, and effect modification by sex.We used a nested case-control design from 2008 to 2016 in 38 Pennsylvania counties using electronic health records from adolescent Geisinger subjects. Cases were defined by at least two diagnoses or medication orders indicating new onset of an internalizing disorder, and controls frequency-matched 4:1 on age, sex, and year. To evaluate associations, we used generalized estimating equations, with logit link, robust standard errors, and an exchangeable correlation structure within community.We identified 7,974 adolescents (65.9% female, mean age 15.0 years) with new onset internalizing disorders. There were no associations when we used data from the entire study period. When restricted to years with higher UNGD activity (2010-2016), comparing the highest to lowest quartile, UNGD activity was associated (odds ratio [95% confidence level]) with new onset internalizing disorders (1.15 [1.06, 1.25]). Associations were slightly stronger for depressive disorders. Associations were only present in females (p = 0.009).This is the first epidemiologic study of UNGD in relation to adolescent mental health, an important health outcome in a potentially susceptible group to the environmental and community impacts of UNGD. UNGD activity was associated with new onset internalizing disorders in females in this large sample in an area of active UNGD.

BackgroundTeeth have unique histology that make this biomatrix a time-capsule for retrospective exposure analysis of fetal and early life. However, most analytic methods require pulverizing the whole tooth, which eliminates exposure timing information. Further, the range of chemicals and endogenous exposures that can be measured in teeth has yet to be fully characterized.MethodsWe performed untargeted metabolomics on micro-dissected layers from naturally shed deciduous teeth. Using four liquid-chromatography high-resolution mass spectrometry analytical modes, we profiled small molecules (

Background: The detection of a pathogenic variant in the BRCA1 or BRCA2 gene has medical and psychological consequences for both, affected mutation carriers and their relatives. This study analyzed the psychological impact of genetic testing and mutation-positive test result as well as associated family communication processes from the perspective of BRCA1 or BRCA2 mutation carriers and their family members.Methods: We conducted a two-phase study with explanatory sequential mixed methods design to understand the perspective of psychological process regarding genetic testing more efficiently. First, we analyzed a survey data of 79 carriers of a BRCA1 or BRCA2 mutation. Second, we conducted focus group interviews of 10 family members to deepen understanding of communication processes in high-risk families.Results: The average age of the BRCA1 or BRCA2 mutation carriers was 48 years, 58% had a history of cancer. The majority (64.6%) had general psychological distress independent of cancer diagnosis in the patients’ history. The point prevalence of depression was 16.9%. The main motives for undergoing genetic testing were desire for safety, prevention and risk assessment for the own children. The mutation carriers were satisfied with the decision to undergo genetic testing. Contrary to their subjective perception, the respondents' knowledge about those mutations was moderate. The familial communication was merely partially successful. In contrast to the high rate of disclosure to at-risk relatives (100%), the reported uptake of genetic testing among informed at-risk relatives was low (45.6%). In-depth focus group interviews with 10 family members revealed significant barriers to accessing genetic counseling including anxiety, uncertainty about the benefits of testing and the own cancer risk, particulary among males.Conclusion: The detection of a BRCA1 or BRCA2 mutation has psychological impact not only on mutation carriers but also on their family members. An adequate knowledge of the genetic background is required to reduce the level of psychological distress and to support the familial communication process. Therefore, the quality of information sources for affected individuals and relatives and also the awareness of health care professionals have to be improved.

Introduction The term primary progressive aphasia (PPA) sums up the non‐fluent (nfv), the semantic (sv), and the logopenic (lv) variant. Up to now, there is only limited data available concerning magnetic resonance imaging volumetry to monitor disease progression. Methods Structural brain imaging and an extensive assessment were applied at baseline and up to 4‐year(s) follow‐up in 269 participants. With automated atlas‐based volumetry 56 brain regions were assessed. Atrophy progression served to calculate sample sizes for therapeutic trials. Results At baseline highest atrophy appeared in parts of the left frontal lobe for nfvPPA (–17%) and of the left temporal lobe for svPPA (–34%) and lvPPA (–24%). Severest progression within 1‐year follow‐up occurred in the basal ganglia in nfvPPA (–7%), in the hippocampus/amygdala in svPPA (–9%), and in (medial) temporal regions in lvPPA (–6%). Conclusion PPA presents as a left‐dominant, mostly gray matter sensitive disease with considerable atrophy at baseline that proceeds variant‐specific., publishedVersion