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Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

Seborrheic dermatitis is a common, chronic relapsing skin condition that predominantly affects areas of the body that are rich in sebaceous glands. Clinically, seborrheic dermatitis presents as symmetric, poorly defined erythematous patches with yellow, oily scales and fine, superficial desquamation (flaking). In people who have darker skin, erythema may be less apparent, and postinflammatory pigmentary changes might be a presenting sign with hypopigmented, slightly scaly areas. Seborrheic dermatitis of the scalp can be effectively treated with topical over-the-counter antifungal shampoos and prescription-strength antifungal or corticosteroid solutions, foams, or oils. Thick, scaly areas can be treated with keratolytic shampoos and lotions. Seborrheic dermatitis of the face and body can be treated with over-the-counter and prescription-strength antifungal creams, over-the-counter and prescription-strength corticosteroid creams and ointments, and calcineurin inhibitor cream or ointment. Neonatal seborrheic dermatitis is common and typically self-resolves by 6 months of age. Mild cases of the scalp (cradle cap) may be treated conservatively with mineral oil to loosen scale and gentle combing. More severe cases may overlap with atopic dermatitis and can be treated with topical antifungals or topical corticosteroids.

Dystocia (abnormally slow or protracted labor) accounts for 25% to 55% of primary cesarean deliveries. The latent phase of labor begins with onset of regular, painful contractions and continues until 6 cm of cervical dilation. Current recommendations are to avoid admission to labor and delivery during the latent phase, assuming maternal/fetal status is reassuring. The active phase begins at 6 cm. An arrested active phase is defined as more than four hours without cervical change despite rupture of membranes and adequate contractions and more than six hours of no cervical change without adequate contractions. Managing a protracted active phase includes oxytocin augmentation with or without amniotomy. The second stage of labor begins at complete cervical dilation and continues to delivery. This stage is considered protracted if it lasts three hours or more in nulliparous patients without an epidural or four hours or more in nulliparous patients with an epidural. Primary interventions for a protracted second stage include use of oxytocin and manual rotation if the fetus is in the occiput posterior position. When contractions or pushing is inadequate, vacuum or forceps delivery may be needed. Effective measures for preventing dystocia and subsequent cesarean delivery include avoiding admission during latent labor, providing cervical ripening agents for induction in patients with an unfavorable cervix, encouraging the use of continuous labor support (e.g., a doula), walking or upright positioning in the first stage, and not diagnosing failed induction during the latent phase until oxytocin has been given for 12 to 18 hours after membrane rupture. Elective induction at 39 weeks' gestation in low-risk nulliparous patients may reduce the risk of cesarean delivery.

Placebo or No Intervention for Patients with Suspected or Confirmed MI Outcomes Probable outcome with beta-blocker administration Probable outcome with placebo or no treatment NNT (95% CI) Participants (studies) Evidence quality Short-term MI risk (within three months) 23 per 1,000 (98% CI, 21 to 25) 28 per 1,000 196 (143 to 333) 67,562 (18 RCTs) Moderate Long-term MI risk (six to 60 months) 83 per 1,000 (98% CI, 69 to 99) 92 per 1,000 NA 6,825 (14 RCTs) Low Long-term cardiovascular mortality risk (six to 24 months) 112 per 1,000 (98% CI, 103 to 122) 124 per 1,000 83 (48 to 500) 22,457 (14 RCTs) Moderate Long-term all-cause mortality risk (six to 60 months) 138 per 1,000 (97.5% CI, 127 to 147) 148 per 1,000 91 (48 to 1,000) 25,210 (21 RCTs) Moderate MI = myocardial infarction; NA = not applicable (no statistical difference in outcomes); NNT = number needed to treat; RCT = randomized controlled trial. There are no significant harms.1 (Strength of Recommendation: A, based on consistent, good-quality patient-oriented evidence.) Practice Pointers Heart disease was the leading cause of death in the United States in 2018, according to data from the Centers for Disease Control and Prevention.2 Among the contributors to death from heart disease are the acute coronary syndromes, which include ST elevation MI (STEMI), non–ST elevation MI (NSTEMI), and unstable angina. Use of beta blockers did not reduce the risk of angina, and there was insufficient evidence to determine if their use altered quality-of-life scores, MACE, or other serious adverse events.

Aneuploidy is the presence of one or more extra chromosomes or the absence of one or more chromosomes. The risk of fetal aneuploidy rises with increasing maternal age. Because fetal aneuploidy can affect any pregnancy, all pregnant women should be offered screening. First-trimester combined screening performed between 10 and 13 weeks' gestation detects 82% to 87% of trisomy 21 (Down syndrome) cases. Second-trimester serum quadruple screening performed between 15 and 22 weeks' gestation detects 81% of trisomy 21 cases. Combinations of these tests include integrated or serum integrated, stepwise sequential, and contingent sequential screenings, all of which improve detection rates compared with each test alone. Fetal cell-free DNA testing (noninvasive prenatal testing) performed at or after 10 weeks' gestation detects more than 99% of trisomy 21 cases, with a lower false-positive rate than traditional first- or second-trimester screening methods. Fetal cell-free DNA testing has similar detection rates in high- and low-risk populations but has lower positive predictive values in younger women. It may be performed as primary screening or as a follow-up test to abnormal findings on first- or second-trimester screenings. Second-trimester ultrasonography has limited utility in aneuploidy screening in women who have already been screened with a first- or second-trimester serum test. Diagnostic tests following a positive screening result include chorionic villus sampling performed between 10 and 13 weeks' gestation or amniocentesis performed after 15 weeks' gestation.

Methylation of specific lysine residues in core histone proteins is essential for embryonic development and can impart active and inactive epigenetic marks on chromatin domains. The ubiquitous nuclear protein PTIP is encoded by the Paxip1 gene and is an essential component of a histone H3 lysine 4 (H3K4) methyltransferase complex conserved in metazoans. In order to determine if PTIP and its associated complexes are necessary for maintaining stable gene expression patterns in a terminally differentiated, non-dividing cell, we conditionally deleted PTIP in glomerular podocytes in mice. Renal development and function were not impaired in young mice. However, older animals progressively exhibited proteinuria and podocyte ultra structural defects similar to chronic glomerular disease. Loss of PTIP resulted in subtle changes in gene expression patterns prior to the onset of a renal disease phenotype. Chromatin immunoprecipitation showed a loss of PTIP binding and lower H3K4 methylation at the Ntrk3 (neurotrophic tyrosine kinase receptor, type 3) locus, whose expression was significantly reduced and whose function may be essential for podocyte foot process patterning. These data demonstrate that alterations or mutations in an epigenetic regulatory pathway can alter the phenotypes of differentiated cells and lead to a chronic disease state.

Measurement of vitamin D levels and supplementation with oral vitamin D have become commonplace, although clinical trials have not demonstrated health benefits. The usefulness of serum 25-hydroxyvitamin D levels to assess adequate exposure to vitamin D is hampered by variations in measurement technique and precision. Serum levels less than 12 ng per mL reflect inadequate vitamin D intake for bone health. Levels greater than 20 ng per mL are adequate for 97.5% of the population. Routine vitamin D supplementation does not prolong life, decrease the incidence of cancer or cardiovascular disease, or decrease fracture rates. Screening asymptomatic individuals for vitamin D deficiency and treating those considered to be deficient do not reduce the risk of cancer, type 2 diabetes mellitus, or death in community-dwelling adults, or fractures in persons not at high risk of fractures. Randomized controlled trials of vitamin D supplementation in the treatment of depression, fatigue, osteoarthritis, and chronic pain show no benefit, even in persons with low levels at baseline.

The HelioClim-3 database (HC3v3) provides records of surface solar irradiation every 15 min, estimated by processing images from the geostationary meteorological Meteosat satellites using climatological data sets of the atmospheric Linke turbidity factor. This technical note proposes a method to improve a posteriori HC3v3 by combining it with data records of the irradiation under clear skies from the new McClear clear-sky model, whose inputs are the advanced global aerosol property forecasts and physically consistent total column content in water vapour and ozone produced by the MACC (Monitoring Atmosphere Composition and Climate) projects. The method is validated by comparison with a series of ground measurements for 15 min and 1 h for 6 stations and for daily irradiation for 23 stations. The correlation coefficient is large, greater than respectively 0.92, 0.94, and 0.97, for 15 min, 1 h and daily irradiation. The bias ranges from −4 to 4% of the mean observed irradiation for most sites. The relative root mean square difference (RMSD) varies between 14 and 38% for 15 min, 12 and 33% for 1 h irradiation, and 6 and 20% for daily irradiation. As a rule of thumb, the farther from the nadir of the Meteosat satellite located at latitude 0° and longitude 0°, and the greater the occurrence of fragmented cloud cover, the greater the relative RMSD. The method improves HC3v3 in most cases, and with no degradation in the others. A systematic correction of HC3v3 with McClear is recommended.

Background/Objectives: Extrinsic phytosterols supplemented to the diet reduce intestinal cholesterol absorption and plasma low-density lipoprotein (LDL)-cholesterol. However, little is known about their effects on cholesterol metabolism when given in native, unpurified form and in amounts achievable in the diet. The objective of this investigation was to test the hypothesis that intrinsic phytosterols present in unmodified foods alter whole-body cholesterol metabolism. Subjects/Methods: In all, 20 out of 24 subjects completed a randomized, crossover feeding trial wherein all meals were provided by a metabolic kitchen. Each subject consumed two diets for 4 weeks each. The diets differed in phytosterol content (phytosterol-poor diet, 126 mg phytosterols/2000 kcal; phytosterol-abundant diet, 449 mg phytosterols/2000 kcal), but were otherwise matched for nutrient content. Cholesterol absorption and excretion were determined by gas chromatography/mass spectrometry after oral administration of stable isotopic tracers. Results: The phytosterol-abundant diet resulted in lower cholesterol absorption (54.2±2.2% (95% confidence interval 50.5%, 57.9%) vs 73.2±1.3% (69.5%, 76.9%), P <0.0001) and 79% higher fecal cholesterol excretion (1322±112 (1083.2, 1483.3) vs 739±97 mg/day (530.1, 930.2), P <0.0001) relative to the phytosterol-poor diet. Plasma lathosterol/cholesterol ratio rose by 82% (from 0.71±0.11 (0.41, 0.96) to 1.29±0.14 μg/mg (0.98, 1.53), P <0.0001). LDL-cholesterol was similar between diets. Conclusions: Intrinsic phytosterols at levels present in a healthy diet are biologically active and have large effects on whole-body cholesterol metabolism not reflected in circulating LDL. More work is needed to assess the effects of phytosterol-mediated fecal cholesterol excretion on coronary heart disease risk in humans.

Stress is known to modulate sensitisation to repeated psychostimulant exposure. However, there is no direct evidence linking glucocorticoids and sensitisation achieved by repeated administration of the NMDA receptor antagonist MK-801. We tested the hypothesis that co-administration of RU486, a glucocorticoid receptor (GR) antagonist, prior to repeated daily MK-801 injections would block the expression of locomotor sensitisation due to its dual effects on corticosterone and dopamine. We employed a repeated MK-801 administration locomotor sensitisation paradigm in male Sprague Dawley rats. RU486 or a dimethyl sulfoxide (DMSO) vehicle was co-administered with MK-801 or saline during the induction phase. Subsequent to withdrawal, rats were challenged with MK-801 alone to test for the expression of sensitisation. In a separate cohort of rats, plasma corticosterone levels were quantified from blood samples taken on the 1st, 4th and 7th day of induction and at expression. One day after challenge, nucleus accumbens tissue levels of dopamine and its metabolites DOPAC and HVA were measured. During the induction phase, RU486 progressively enhanced locomotor sensitisation to MK-801. RU486 and MK-801 both showed stimulatory effects on corticosterone levels and this was further augmented when given in combination. Contrary to our hypothesis, RU486 did not block the expression of locomotor sensitisation to MK-801 and actually increased levels of dopamine, DOPAC and HVA in nucleus accumbens tissue. Our results showed that RU486 has augmentative rather than inhibitory effects on MK-801-induced sensitisation. This study indicates a divergent role for glucocorticoids in sensitisation to MK-801 compared to sensitisation with other psychostimulants.