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The exponential rise in our understanding of the aetiology and pathophysiology of genetic cystic kidney diseases can be attributed to the identification of cystogenic genes over the last three decades. The foundation of this was laid by positional cloning strategies which gradually shifted towards next-generation sequencing (NGS) based screenings. This shift has enabled the discovery of novel cystogenic genes at an accelerated pace unlike ever before and, most notably, the past decade has seen the largest increase in identification of the genes which cause nephronophthisis (NPHP). NPHP is a monogenic autosomal recessive cystic kidney disease caused by mutations in a diverse clade of over 26 identified genes and is the most common genetic cause of renal failure in children. NPHP gene types present with some common pathophysiological features alongside a diverse range of extra-renal phenotypes associated with specific syndromic presentations. This review provides a timely update on our knowledge of this disease, including epidemiology, pathophysiology, anatomical and molecular features. We delve into the diversity of the NPHP causing genes and discuss known molecular mechanisms and biochemical pathways that may have possible points of intersection with polycystic kidney disease (the most studied renal cystic pathology). We delineate the pathologies arising from extra-renal complications and co-morbidities and their impact on quality of life. Finally, we discuss the current diagnostic and therapeutic modalities available for disease management, outlining possible avenues of research to improve the prognosis for NPHP patients.

Cognitive complaints in older adults may be indicative of progressive cognitive decline including Alzheimer's disease (AD), but also occur in other age-related chronic conditions, complicating identification of early AD symptoms. To better understand cognitive complaints in aging, we systematically reviewed the evidence to determine their prevalence and characterization among older adults with the most common age-related chronic conditions. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the review protocol was prospectively registered with PROSPERO (ID: CRD42020153147). Searches were conducted in PubMed, CINAHL, PsycINFO, Web of Science, and ProQuest Dissertations & Theses A&I in June 2020. Two members of the review team independently determined article eligibility for inclusion and conducted quality appraisal. A narrative synthesis of results was used to integrate findings across studies and draw conclusions regarding the strength of the evidence in each chronic condition category. Thirty-seven articles met eligibility criteria and were included in the review. Conditions represented were diabetes (n = 20), heart disease (n = 13), hypertension (n = 10), chronic lung disease (n = 5), arthritis (n = 4), heart failure (n = 2), and hyperlipidemia (n = 2). In addition, 16 studies included a measure of multimorbidity. Overall, there was a higher prevalence of cognitive complaints in individuals with higher multimorbidity, including a potential dose-dependent relationship. Findings for specific conditions were inconsistent, but there is evidence to suggest that cross-sectionally, older adults with diabetes, heart disease, chronic lung disease, and arthritis have more cognitive complaints than those without these conditions. There is strong evidence demonstrating that cognitive complaints are more common in older adults with higher multimorbidity, but little research examining these associations over time. Improving our understanding of the longitudinal trajectory of cognitive complaints, multimorbidity, and objective cognition in older age is an important area for future research.

Nuclear receptors (NRs) and their coregulators play fundamental roles in initiating and directing gene expression influencing mammalian reproduction, development and metabolism. SRA stem Loop Interacting RNA-binding Protein (SLIRP) is a Steroid receptor RNA Activator (SRA) RNA-binding protein that is a potent repressor of NR activity. SLIRP is present in complexes associated with NR target genes in the nucleus; however, it is also abundant in mitochondria where it affects mitochondrial mRNA transcription and energy turnover. In further characterisation studies, we observed SLIRP protein in the testis where its localization pattern changes from mitochondrial in diploid cells to peri-acrosomal and the tail in mature sperm. To investigate the in vivo effects of SLIRP, we generated a SLIRP knockout (KO) mouse. This animal is viable, but sub-fertile. Specifically, when homozygous KO males are crossed with wild type (WT) females the resultant average litter size is reduced by approximately one third compared with those produced by WT males and females. Further, SLIRP KO mice produced significantly fewer progressively motile sperm than WT animals. Electron microscopy identified disruption of the mid-piece/annulus junction in homozygous KO sperm and altered mitochondrial morphology. In sum, our data implicates SLIRP in regulating male fertility, wherein its loss results in asthenozoospermia associated with compromised sperm structure and mitochondrial morphology.

Rectal diazepam and buccal midazolam are used for emergency treatment of acute febrile and afebrile (epileptic) seizures in children. We aimed to compare the safety and efficacy of these drugs. A multicentre, randomised controlled trial was undertaken to compare buccal midazolam with rectal diazepam for emergency-room treatment of children aged 6 months and older presenting to hospital with active seizures and without intravenous access. The dose varied according to age from 2·5 to 10 mg. The primary endpoint was therapeutic success: cessation of seizures within 10 min and for at least 1 hour, without respiratory depression requiring intervention. Analysis was per protocol. Consent was obtained for 219 separate episodes involving 177 patients, who had a median age of 3 years (IQR 1–5) at initial episode. Therapeutic success was 56% (61 of 109) for buccal midazolam and 27% (30 of 110) for rectal diazepam (percentage difference 29%, 95% CI 16–41). Analysing only initial episodes revealed a similar result. The rate of respiratory depression did not differ between groups. When centre, age, known diagnosis of epilepsy, use of antiepileptic drugs, prior treatment, and length of seizure before treatment were adjusted for with logistic regression, buccal midazolam was more effective than rectal diazepam. Buccal midazolam was more effective than rectal diazepam for children presenting to hospital with acute seizures and was not associated with an increased incidence of respiratory depression.