Targeting sexual health services in primary care: a systematic review of the psychosocial correlates of adverse sexual health outcomes reported in probability surveys of women of reproductive age

BACKGROUND: Women using primary care vary in need for sexually transmitted infections (STIs) testing and contraception. Psychosocial correlates of these needs may be useful for targeting services. We undertook a systematic review to identify psychosocial correlates of STI acquisition, unplanned pregnancy (UP), abortion and risky sexual behaviours in general population samples of women of reproductive age. METHODS: We searched bibliographic databases for probability surveys of women aged 16-44years in the European Union, USA, Canada, Australia, UK or New Zealand undertaken January 1994-January 2014. RESULTS: Eleven papers were included. Unplanned pregnancy was associated with smoking, depression, being single and sexual debut <16years. Abortion was associated with lack of closeness to parents, leaving home at an early age, and relationship break-up. Multiple partnerships were associated with intensity of marijuana and alcohol use, and smoking. STI diagnosis was associated with relationship break-up and younger partners. Non-use of contraception was associated with smoking, obesity, relationship status, sedentary lifestyles, fatalistic pregnancy attitudes and lower alcohol use. Condom non-use was higher (at first sex) with partners 5+years older and lower (at last sex) in less stable partnerships. CONCLUSION: Psychosocial variables, particularly relationship status and smoking, may help identify women in primary care for STI testing and contraception advice and supply

The discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition

Targeted proteolysis sustains calcineurin activation.

BACKGROUND: Calcineurin (CnA) is important in the regulation of myocardial hypertrophy. We demonstrated that targeted proteolysis of the CnA autoinhibitory domain under pathological myocardial workload leads to increased CnA activity in human myocardium. Here, we investigated the proteolytic mechanism leading to activation of CnA. METHODS AND RESULTS: In patients with diseased myocardium, we found strong nuclear translocation of CnA. In contrast, in normal human myocardium, there was a cytosolic distribution of CnA. Stimulation of rat cardiomyocytes with angiotensin (Ang) II increased calpain activity significantly (433+/-11%; P<0.01; n=6) and caused proteolysis of the autoinhibitory domain of CnA. Inhibition of calpain by a membrane-permeable calpain inhibitor prevented proteolysis. We identified the cleavage site of calpain in the human CnA sequence at amino acid 424. CnA activity was increased after Ang II stimulation (310+/-29%; P<0.01; n=6) and remained high after removal of Ang II (214+/-17%; P<0.01; n=6). Addition of a calpain inhibitor to the medium decreased CnA activity (110+/-19%; P=NS; n=6) after removal of Ang II. Ang II stimulation of cardiomyocytes also translocated CnA into the nucleus as demonstrated by immunohistochemical staining and transfection assays with GFP-tagged CnA. Calpain inhibition and therefore suppression of calpain-mediated proteolysis of CnA enabled CnA exit from the nucleus. CONCLUSIONS: Ang II stimulation of cardiomyocytes increased calpain activity, leading to proteolysis of the autoinhibitory domain of CnA. This causes an increase in CnA activity and results in nuclear translocation of CnA. Loss of the autoinhibitory domain renders CnA constitutively nuclear and active, even after removal of the hypertrophic stimulus

Sall1 is a transcriptional regulator defining microglia identity and function

Microglia are the resident macrophages of the central nervous system (CNS). Gene expression profiling has identified Sall1, which encodes a transcriptional regulator, as a microglial signature gene. We found that Sall1 was expressed by microglia but not by other members of the mononuclear phagocyte system or by other CNS-resident cells. Using Sall1 for microglia-specific gene targeting, we found that the cytokine receptor CSF1R was involved in the maintenance of adult microglia and that the receptor for the cytokine TGF-β suppressed activation of microglia. We then used the microglia-specific expression of Sall1 to inducibly inactivate the murine Sall1 locus in vivo, which resulted in the conversion of microglia from resting tissue macrophages into inflammatory phagocytes, leading to altered neurogenesis and disturbed tissue homeostasis. Collectively, our results show that transcriptional regulation by Sall1 maintains microglial identity and physiological properties in the CNS and allows microglia-specific manipulation in vivo

Reducing antibiotic exposure in suspected neonatal sepsis

Prolonged antibiotic therapy is associated with antimicrobial resistance and increased mortality in preterm infants. We evaluated the impact of an automatic stop order (ASO) and C-reactive protein (CRP) on the duration of antibiotics and level of intervention in infants screened for early-onset sepsis who had negative cultures. We introduced an ASO for low-risk infants, then, consequently, for all infants treated for suspected sepsis. We subsequently introduced a single CRP measurement at 36 hours. Between 2011 and 2014, 4 time periods were studied, at baseline and after each intervention. The proportion of infants receiving ≤48 hours of antibiotics increased from 19% to 72.5% (P &#60; .0001), whereas that of infants receiving avoidable doses (&#62;48 hours and &#60;5 days) fell from 50% to 0.8% (P &#60; .0001). The use of an ASO decreased the proportion receiving avoidable doses from 26/92 (28.3%) to 9/293 (3.1%); P &#60; .0001. There was a reduction in lumbar punctures performed, from 35% to 20%; P = .015