Genome-wide association study of male sexual orientation

Family and twin studies suggest that genes play a role in male sexual orientation. We conducted a genome-wide association study (GWAS) of male sexual orientation on a primarily European ancestry sample of 1,077 homosexual men and 1,231 heterosexual men using Affymetrix single nucleotide polymorphism (SNP) arrays. We identified several SNPs with p < 10 -5 , including regions of multiple supporting SNPs on chromosomes 13 (minimum p = 7.5 × 10 -7 ) and 14 (p = 4.7 × 10 -7 ). The genes nearest to these peaks have functions plausibly relevant to the development of sexual orientation. On chromosome 13, SLITRK6 is a neurodevelopmental gene mostly expressed in the diencephalon, which contains a region previously reported as differing in size in men by sexual orientation. On chromosome 14, TSHR genetic variants in intron 1 could conceivably help explain past findings relating familial atypical thyroid function and male homosexuality. Furthermore, skewed X chromosome inactivation has been found in the thyroid condition, Graves' disease, as well as in mothers of homosexual men. On pericentromeric chromosome 8 within our previously reported linkage peak, we found support (p = 4.1 × 10 -3 ) for a SNP association previously reported (rs77013977, p = 7.1 × 10 -8 ), with the combined analysis yielding p = 6.7 × 10 -9 , i.e., a genome-wide significant association

Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections

The Biodiversity of the Mediterranean Sea: Estimates, Patterns, and Threats

The Mediterranean Sea is a marine biodiversity hot spot. Here we combined an extensive literature analysis with expert opinions to update publicly available estimates of major taxa in this marine ecosystem and to revise and update several species lists. We also assessed overall spatial and temporal patterns of species diversity and identified major changes and threats. Our results listed approximately 17,000 marine species occurring in the Mediterranean Sea. However, our estimates of marine diversity are still incomplete as yet—undescribed species will be added in the future. Diversity for microbes is substantially underestimated, and the deep-sea areas and portions of the southern and eastern region are still poorly known. In addition, the invasion of alien species is a crucial factor that will continue to change the biodiversity of the Mediterranean, mainly in its eastern basin that can spread rapidly northwards and westwards due to the warming of the Mediterranean Sea. Spatial patterns showed a general decrease in biodiversity from northwestern to southeastern regions following a gradient of production, with some exceptions and caution due to gaps in our knowledge of the biota along the southern and eastern rims. Biodiversity was also generally higher in coastal areas and continental shelves, and decreases with depth. Temporal trends indicated that overexploitation and habitat loss have been the main human drivers of historical changes in biodiversity. At present, habitat loss and degradation, followed by fishing impacts, pollution, climate change, eutrophication, and the establishment of alien species are the most important threats and affect the greatest number of taxonomic groups. All these impacts are expected to grow in importance in the future, especially climate change and habitat degradation. The spatial identification of hot spots highlighted the ecological importance of most of the western Mediterranean shelves (and in particular, the Strait of Gibraltar and the adjacent Alboran Sea), western African coast, the Adriatic, and the Aegean Sea, which show high concentrations of endangered, threatened, or vulnerable species. The Levantine Basin, severely impacted by the invasion of species, is endangered as well

Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity.

Immune responses are initiated by HLA-DR+ cells, which present antigen to T cells. Observations that HLA-DR may be experimentally induced on thyroid epithelium and that HLA-DR occurs on thyrocytes in autoimmune thyroid diseases suggest a mechanism of autoimmunity with special relevance to organ-specific diseases. This involves the local aberrant expression of HLA-DR antigens by epithelial cells and their subsequent capacity to present autoantigens occurring on their surfaces to T lymphocytes. For autoantigens which T cells recognise infrequently because of their restricted tissue location and low concentration in the circulation, T-cell tolerance is unlikely, and so induction of autoreactive T cells would occur. Because interferon is the best known inducer of DR antigen expression and viral infections may predate endocrine autoimmunity, the following sequence seems likely: local viral infection which causes interferon production, or other local environmental factors which would induce DR expression, presentation of autoantigens, and subsequent autoimmune T-cell induction. These T cells would activate effector B and T cells. Whether the initial induction of autoimmune T cells leads to autoimmune disease would depend on factors such as abnormalities of the suppressor T-cell pathway, reported to coexist with autoimmunity and necessary to induce autoimmune disease in mice. This mechanism of autoimmune disease induction explains vague associations with viral infections and long latency periods before disease becomes manifest and gives a simple explanation for the well-documented association between HLA-DR and autoimmune diseases in man

Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity.

Immune responses are initiated by HLA-DR+ cells, which present antigen to T cells. Observations that HLA-DR may be experimentally induced on thyroid epithelium and that HLA-DR occurs on thyrocytes in autoimmune thyroid diseases suggest a mechanism of autoimmunity with special relevance to organ-specific diseases. This involves the local aberrant expression of HLA-DR antigens by epithelial cells and their subsequent capacity to present autoantigens occurring on their surfaces to T lymphocytes. For autoantigens which T cells recognise infrequently because of their restricted tissue location and low concentration in the circulation, T-cell tolerance is unlikely, and so induction of autoreactive T cells would occur. Because interferon is the best known inducer of DR antigen expression and viral infections may predate endocrine autoimmunity, the following sequence seems likely: local viral infection which causes interferon production, or other local environmental factors which would induce DR expression, presentation of autoantigens, and subsequent autoimmune T-cell induction. These T cells would activate effector B and T cells. Whether the initial induction of autoimmune T cells leads to autoimmune disease would depend on factors such as abnormalities of the suppressor T-cell pathway, reported to coexist with autoimmunity and necessary to induce autoimmune disease in mice. This mechanism of autoimmune disease induction explains vague associations with viral infections and long latency periods before disease becomes manifest and gives a simple explanation for the well-documented association between HLA-DR and autoimmune diseases in man