Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

An evaluation of a pilot of daily testing of SARS-CoV-2 contacts in acute hospital and ambulance trusts in England.

OBJECTIVES: Healthcare worker (HCW) SARS-CoV-2 contacts in England have been required to quarantine, creating staff shortages. We piloted daily contact testing (DCT) to assess its feasibility as an alternative. STUDY DESIGN: Observational service evaluation. METHODS: We conducted an observational service evaluation of 7-day DCT using antigen lateral flow devices (LFDs) at four acute hospital trusts and one ambulance trust in England. Mixed methods were used, using aggregate and individual-level test monitoring data, semi-structured interviews, and a survey of eligible contacts. RESULTS: In total, 138 HCWs were identified as contacts of a confirmed SARS-CoV-2 case. Of these, 111 (80%) consented to daily LFD testing, of whom 82 (74%) completed the required programme without interruption and 12 (11%) completed with interruption. Fifty-eight participants (52%) and two non-participants (7.4%) completed the survey. In total, 28 interviews were conducted with participants, site and infection control leads, and union representatives. One participant tested positive on LFD and polymerase chain reaction (PCR) test. Three participants tested positive on PCR but not LFD. DCT was well-accepted by trusts and staff. Participants reported no relaxation of their infection prevention and control behaviours. No incidents of transmission were detected. An estimated 729 potential days of work absence were averted. CONCLUSIONS: DCT can be acceptably operated in a healthcare setting, averting quarantine-related work absences in HCW SARS-CoV-2 contacts.

Estimating the incubation period of acute Q fever, a systematic review.

Estimates of the incubation period for Q fever vary substantially between different reviews and expert advice documents. We systematically reviewed and quality appraised the literature to provide an evidence-based estimate of the incubation period of the Q fever by the aerosolised infection route. Medline (OVIDSP) and EMBASE were searched with the search limited to human studies and English language. Eligible studies included persons with symptomatic, acute Q fever, and defined exposure to Coxiella burnetti. After review of 7115 titles and abstracts, 320 records were screened at full-text level. Of these, 23 studies contained potentially useful data and were quality assessed, with eight studies (with 403 individual cases where the derivation of incubation period was possible) being of sufficient quality and providing individual-level data to produce a pooled summary. We found a median incubation period of 18 days, with 95% of cases expected to occur between 7 and 32 days after exposure.

A compendium of developmental gene expression in Lake Malawi cichlid fishes.

BACKGROUND: Lake Malawi cichlids represent one of a growing number of vertebrate models used to uncover the genetic and developmental basis of trait diversity. Rapid evolutionary radiation has resulted in species that share similar genomes but differ markedly in phenotypes including brains and behavior, nuptial coloration and the craniofacial skeleton. Research has begun to identify the genes, as well as the molecular and developmental pathways that underlie trait divergence. RESULTS: We assemble a compendium of gene expression for Lake Malawi cichlids, across pharyngula (the phylotypic stage) and larval stages of development, encompassing hundreds of gene transcripts. We chart patterns of expression in Bone morphogenetic protein (BMP), Fibroblast growth factor (FGF), Hedgehog (Hh), Notch and Wingless (Wnt) signaling pathways, as well as genes involved in neurogenesis, calcium and endocrine signaling, stem cell biology, and numerous homeobox (Hox) factors-in three planes using whole-mount in situ hybridization. Because of low sequence divergence across the Malawi cichlid assemblage, the probes we employ are broadly applicable in hundreds of species. We tabulate gene expression across general tissue domains, and highlight examples of unexpected expression patterns. CONCLUSIONS: On the heels of recently published genomes, this compendium of developmental gene expression in Lake Malawi cichlids provides a valuable resource for those interested in the relationship between evolution and development.

Association between use of proton pump inhibitors and non-typhoidal salmonellosis identified following investigation into an outbreak of Salmonella Mikawasima in the UK, 2013.

In November 2013, national public health agencies in England and Scotland identified an increase in laboratory-confirmed Salmonella Mikawasima. The role of proton pump inhibitors (PPIs) as a risk factor for salmonellosis is unclear; we therefore captured information on PPI usage as part of our outbreak investigation. We conducted a case-control study, comparing each case with two controls. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Thirty-nine of 61 eligible cases were included in the study. The median age of cases was 45 years; 56% were female. Of these, 33% were admitted to hospital and 31% reported taking PPIs. We identified an association between PPIs and non-typhoidal salmonellosis (aOR 8·8, 95% CI 2·0-38·3). There is increasing evidence supporting the existence of an association between salmonellosis and PPIs; however, biological studies are needed to understand the effect of PPIs in the pathogenesis of Salmonella. We recommend future outbreak studies investigate PPI usage to strengthen evidence on the relevance of PPIs in Salmonella infection. These findings should be used to support the development of guidelines for patients and prescribers on the risk of gastrointestinal infection and PPI usage.

Biomechanical Evaluation of 6.5-mm Cannulated Screws.

Although biomechanical and clinical evidence exists regarding smaller compression screws, biomechanical data regarding the larger headless screws are not currently available. Headed and headless 6.5-mm cannulated compression screws were examined, with analysis of interfragmentary compression, insertion torque, and resistance of the construct to a shear force. No significant differences were seen between the maximum insertion torque of the headless or headed screws. Maximum and steady-state compression forces were also not significantly different between groups. Countersinking the headless model 2 mm led to a 77.01% decrease in steady-state compression levels. Shear testing did not reveal any significant differences in peak load at ultimate failure, specimen stiffness, or final block displacement, although a trend to increased peak load and stiffness was seen with the headless specimens.

Four-month outbreak of invasive meningococcal disease caused by a rare serogroup B strain, identified through the use of molecular PorA subtyping, England, 2013.

Molecular PorA subtyping provides information that increasingly requires the adaptation of standard public health approaches to outbreak management. We report an outbreak of a rare subtype of meningococcal infection not previously identified in the United Kingdom (UK). The outbreak occurred in the Warwickshire area in England between February and June 2013. Molecular subtyping allowed the identification of additional cases, prompting an enhanced public health response that included efforts to identify potential social networks that might benefit from chemoprophylaxis. It also prompted swabbing to define nasopharyngeal carriage in the focal nursery and helped explain the unusual epidemiological pattern. Without subtyping to identify a link, the additional cases would have been managed as sporadic cases in accordance with current UK guidance.

Low bone turnover and low bone density in a cohort of adults with Down syndrome.

UNLABELLED: Increased incidence of osteoporosis in Down syndrome has been reported, but etiology is not established. We report low bone turnover markers and bone mineral density (BMD) in a cohort of people with Down syndrome without consistent clinical risk factors. Our results should guide future studies and treatments for this common problem. INTRODUCTION: To better understand the etiology for osteoporosis in Down syndrome (DS), we measured bone density by dual-energy X-ray absorptiometry (DXA) and circulating biochemical markers of bone formation and resorption in a cohort of 30 community-dwelling DS adults. METHODS: Seventeen males and 13 females followed in the University of Arkansas Down Syndrome Clinic were evaluated by DXA to estimate BMD and underwent phlebotomy to measure serum procollagen type-1 intact N-terminal propeptide (P1NP) to evaluate bone formation, and serum C-terminal peptide of type-I collagen (CTx) to evaluate bone resorption. RESULTS: Seven of 13 DS females and 12 of 17 DS males had low bone mass at one of measured sites (z≤-2.0). When data were grouped by age, males had apparent osteopenia earlier than females. The mean P1NP in the normal group was 19.2±5.2 ng/ml vs. 2.2±0.9 ng/ml in the DS group (P=0.002). Serum CTx levels in the normal group were 0.4±0.1 ng/ml vs. 0.3±0.1 ng/ml (P=0.369). CONCLUSIONS: Low BMD in adults with DS is correlated with a significant decrease in bone formation markers, compared to controls without DS, and is independent of gender. These data suggest that diminished osteoblastic bone formation and inadequate accrual of bone mass, with no significant differences in bone resorption, are responsible for the low bone mass in DS. These observations question the use of antiresorptive therapy in this population and focus attention on increasing bone mass by other interventions.

Induced membrane technique for reconstruction to manage bone loss.

Multiple surgeries are often required to manage segmental bone loss because of the complex mechanics and biology involved in reconstruction. These procedures can lead to prolonged recovery times, poor patient outcomes, and even delayed amputation. A two-stage technique uses induced biologic membranes with delayed placement of bone graft to manage this clinical challenge. In the first stage, a polymethyl methacrylate spacer is placed in the defect to produce a bioactive membrane, which appears to mature biochemically and physically 4 to 8 weeks after spacer placement. In the second, cancellous autograft is placed within this membrane and, via elution of several growth factors, the membrane appears to prevent graft resorption and promote revascularization and consolidation of new bone. Excellent clinical results have been reported, with successful reconstruction of segmental bone defects >20 cm.

Differences in hepatitis B infection rate between ethnic groups in antenatal women in Birmingham, United Kingdom, May 2004 to December 2008.

Hepatitis B virus (HBV) is a major cause of morbidity and mortality worldwide. Although the United Kingdom (UK) prevalence of HBV is low, it is increasing. There is some evidence that the rate of infection is much higher in some populations living in Britain of non-white ethnicity or who were not born in Britain, compared with the British-born white population. We examined the prevalence of HBV infection in pregnant women through hepatitis B surface antigen (HBsAg) or e-antigen (HBeAg) in Birmingham UK between May 2004 and December 2008 and the effect of ethnicity on the relative risk of infection. There was a significant increase in the number of antenatal HBV infections detected over the study period from 106 cases in 2005 to 161 cases in 2008 (p=0.037). Women who define themselves as of black African, non-British white and Pakistani ethnicity had a markedly elevated rate of HBV infection (relative risk (RR): 11.25, 5.87 and 2.33 respectively) compared to the England average. Health organisations that serve populations with a high or increasing proportion of women originating from intermediate and high HBV prevalence areas of the world such as Africa, some parts of Europe and Asia, should anticipate a need for perinatal and postnatal prophylaxis to children born to HBV infected mothers.

Previous history of gonococcal infection as a risk factor in patients presenting with gonorrhoea.

Recidivism is common in patients infected with gonorrhoea. Identifying the factors most closely associated with recurrent gonococcal infection can help to target health promotion and disease prevention interventions. A case-control study design was used to quantify the importance of past infection as a risk marker for gonorrhoea while controlling for other demographic and behavioural factors. Data were available for 134 cases of gonorrhoea and 150 controls. A history of gonorrhoea (odds ratio [OR] 4.36 [95% CI 1.78-10.71]) was the strongest predictor of current infection. The number of partners in the last month (OR 2.19 [95% CI 1.20-4.02]) was also significantly associated with a diagnosis of gonorrhoea. Patients presenting with gonorrhoea are a specific high-risk group who require additional interventions and should be prioritized for evidence-based, enhanced and interactive counselling.

Risk of developing tuberculosis from a school contact: retrospective cohort study, United Kingdom, 2009.

To quantify the risk of developing tuberculosis (TB) following school contact with a student with smear positive respiratory TB in a population with a high background rate of tuberculosis, a retrospective cohort study was conducted. This study included all students and staff (n=1,065) at an inner city secondary school in Birmingham, United Kingdom (UK). Being in the same school year as the index case resulted in a significantly higher risk of being diagnosed with active TB (odds ratio (OR) 6.11) and either active or latent TB (OR 10.52) compared to the risk for pupils in other school years. Neither lower level classroom exposure in tutoring groups nor being a staff member resulted in significantly increased risk of infection. The number of cases detected in the school was significantly higher than compared with the TB notification rate for the respective age groups in the population in the area. This study is consistent with the small body of evidence that already exists suggesting that greater levels of classroom contact with a student with smear positive active TB significantly increases the risk of contracting active and latent TB. It also suggests that staff may be at a lower risk of active TB than students. It does not appear that being in an area with high TB incidence substantially alters the epidemiology of the outbreak or risk of transmission between students in comparison to other populations.

An empirical test of recruitment limitation in a coral reef fish.

A long-term, large-scale empirical test of the recruitment limitation hypothesis was done by sampling fish populations from the southern Great Barrier Reef after having monitored their recruitment histories for 9 years. After adjustment for demographic differences, recruitment patterns explained over 90 percent of the spatial variation in abundance of a common damselfish among seven coral reefs. The age structures from individual reefs also preserved major temporal variations in the recruitment signal over at least 10 years. Abundance and demography of this small fish at these spatial and temporal scales can be explained almost entirely as variable recruitment interacting with density-independent mortality.

Comparison of adult HIV prevalence from national population-based surveys and antenatal clinic surveillance in countries with generalised epidemics: implications for calibrating surveillance data.

BACKGROUND: Estimates of the impact of HIV in countries with generalised epidemics are generally based on antenatal clinic surveillance data collected over time. In an attempt to obtain geographically more representative estimates of HIV prevalence, many countries are now also conducting national population-based surveys in which HIV testing is included. We compare adult HIV prevalence estimates from antenatal clinic surveillance to those from national population-based surveys to assess the implications for calibrating surveillance data. METHODS: HIV prevalence estimates derived from fitting prevalence curves to antenatal clinic surveillance data are statistically compared to prevalence from national population-based surveys using data from 26 countries with generalised epidemics for the year in which the survey was conducted. Appropriate transformations are applied to inform the correction factors needed to adjust prevalence in countries where population-based surveys have not been conducted. RESULTS: HIV prevalence derived from antenatal clinic surveillance data generally overestimate population-based survey prevalence by about 20% (95% confidence interval: 10% to 30%) in both urban and rural areas. CONCLUSIONS: In countries where national population-based HIV surveys have been conducted, survey estimates of HIV prevalence (adjusted for potential survey biases as appropriate) can be used directly to calibrate antenatal clinic surveillance data. In countries where national HIV surveys have not been conducted, HIV prevalence derived from antenatal clinic surveillance data should be multiplied by about 0.8 to adjust for overestimation.

Estimating the number of HIV infections averted: an approach and its issues.

OBJECTIVE: To propose a methodology to estimate the number of new HIV infections averted. Knowledge of HIV infection has increased tremendously and modelling tools to project current epidemics into the future have greatly improved. Different types of models can be used to estimate HIV infections averted, although the number of new HIV infections averted cannot be measured directly. METHOD: Using cohort-component population projections, a disease modelling-based approach was used to compare the observed epidemiology of a disease after programme initiation with an expected epidemiology from past trends before programme initiation. The concept of modelling infections averted in a disease modelling-based approach involves a comparison between an "expected" or baseline epidemic with an "estimated" one. A hypothetical example was featured in order to demonstrate the proposed methodology. Using both the Estimation and Projection Package (EPP) and the Spectrum demographic modelling program, the underlying annual incidence levels implied by both the baseline and estimated epidemics were examined. RESULTS: The difference between baseline and estimated incidence levels is interpreted as "infections averted". Strengths and limitations of the approach are discussed. CONCLUSIONS: In this study an expected epidemiological approach was compared to one based on observation. Once sufficient data become available, the validation of various country data including HIV prevalence, mortality, and behaviour must be done. Additional information related to behaviour change may be critical to further support arguments for a change in disease trend. It is therefore important to use all available data, consequently strengthening findings from a disease modelling-based approach on HIV infections averted.

Preoperative magnetic resonance imaging cross-sectional area for the measurement of hamstring autograft diameter for reconstruction of the adolescent anterior cruciate ligament.

PURPOSE: We conducted this study to determine if preoperative magnetic resonance imaging (MRI) cross-sectional area measurements would correlate with intraoperative graft size in hamstring anterior cruciate ligament (ACL) reconstructions. METHODS: We retrospectively reviewed ACL reconstructions performed by a single surgeon using a quadruple-looped hamstring allograft. Preoperative MRI axial images were used to determine the combined cross-sectional area of the semitendinosis and gracilis tendons. These cross-sectional areas were correlated to the intraoperative graft size. RESULTS: We found a strong correlation between the MRI cross-sectional areas and graft size. If the combined cross-sectional areas were >or=18 mm(2), there was an 88% probability of obtaining a graft of sufficient size at the time of surgery. CONCLUSIONS: We conclude that our technique is a reliable option to assist the surgeon with preoperative determination of graft size. This is valuable to the orthopaedist to more accurately discuss graft options with the patient and improve preoperative preparation with respect to graft choice. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria on the basis of consecutive patients with universally applied gold standard.

Surgical Fixation of Geriatric Sacral U-Type Insufficiency Fractures: A Retrospective Analysis.

OBJECTIVES: To define the incidence of sacral U-type insufficiency fracture and describe management of a consecutive series of patients with this injury. DESIGN: Retrospective analysis. SETTING: Single Level II trauma center. PATIENTS/PARTICIPANTS: Sixteen adult patients with sacral U-type insufficiency fractures treated over a 36-month period. INTERVENTION: Patients were indicated for percutaneous screw fixation of the posterior pelvis if they had posterior pelvic pain that prohibited mobilization. MAIN OUTCOME MEASUREMENTS: Visual analog scale for pain, distance ambulated on postoperative day 1, and change in sacral kyphosis. RESULTS: The sacral U-type insufficiency fracture incidence was 16.7% (19/114); average patient age was 75 years. Delayed surgery was performed after primary nonoperative treatment had failed in 62.5% (10/16) at an average 83 days postinjury. Acute surgery was performed in 37.5% (6/16) at an average 5 days postinjury. Distance ambulated on postoperative day 1 was 114.4 feet [95% confidence interval (CI) (50.6, 178.2)] and 88.7 feet [95% CI (2.8, 174.6)] in the delayed and acute surgery groups, respectively, P = 0.18. Change in visual analog scale for pain was -3.2 [95% CI (-5.0, -1.4)] and -3.7 [95% CI (-7.0, -0.4)] in the delayed and acute surgery groups, respectively, P = 0.15. Change in sacral kyphosis from presentation to surgery was 12.3 degrees [95% CI (6.7, 17.9)] and 0.3 degrees [95% CI (-0.2, 0.9)] in the delayed and acute surgery groups, respectively, P < 0.01. Minimum follow-up was 12 months. CONCLUSIONS: Treatment of sacral U-type insufficiency fractures by percutaneous screw fixation permits early mobilization, provides rapid pain relief, and prevents progressive deformity. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Ebselen has lithium-like effects on central 5-HT2A receptor function.

BACKGROUND AND PURPOSE: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq -protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here, we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq -protein coupled receptor involved in lithium's actions. EXPERIMENTAL APPROACH: 5-HT2A receptor function was assessed in mice by measuring the behavioural (head-twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c-fos, Egr2) responses to 5-HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5-HT2A receptor function. Because lithium and 5-HT2A receptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. KEY RESULTS: Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2A receptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen enhanced the increase in extracellular 5-HT induced by citalopram, and also increased regional brain 5-HT synthesis. CONCLUSIONS AND IMPLICATIONS: Our data demonstrated lithium-mimetic effects of ebselen in different experimental models of 5-HT2A receptor function, probably mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent.

A transcriptional switch between the Pig-1 and Sgs-4 genes of Drosophila melanogaster.

Pig-1 and Sgs-4 are a pair of closely linked and divergently transcribed Drosophila melanogaster genes, which are both expressed in larval salivary glands but at different times during development. While Sgs-4 is expressed at high levels only at the end of the third instar, Pig-1 exhibits a major peak of expression during late second and early third instar. Thus, Pig-1 expression declines as Sgs-4 expression is induced. In this paper, we show that three adjacent elements located within the short region between these genes can account for the switch from Pig-1 to Sgs-4 expression. A 170-bp segment acts as an enhancer to direct Sgs-4 expression in late-third-instar salivary glands. A 64-bp sequence located just upstream from the enhancer can modify its temporal specificity so that it works throughout the third instar. Expression induced at mid-third instar by a combination of these two elements can be repressed by a negative regulatory sequence located still further upstream. We present evidence suggesting that the changing interactions between these regulatory elements and the Sgs-4 and Pig-1 promoters lead to the correct pattern of expression of the two genes.

Multiple sex pheromones and receptors of a mushroom-producing fungus elicit mating in yeast.

The mushroom-producing fungus Schizophyllum commune has thousands of mating types defined, in part, by numerous lipopeptide pheromones and their G protein-linked receptors. Compatible combinations of pheromones and receptors encoded by different mating types regulate a pathway of sexual development leading to mushroom formation and meiosis. A complex set of pheromone-receptor interactions maximizes the likelihood of outbreeding; for example, a single pheromone can activate more than one receptor and a single receptor can be activated by more than one pheromone. The current study demonstrates that the sex pheromones and receptors of Schizophyllum, when expressed in Saccharomyces cerevisiae, can substitute for endogenous pheromone and receptor and induce the yeast pheromone response pathway through the yeast G protein. Secretion of active Schizophyllum pheromone requires some, but not all, of the biosynthetic machinery used by the yeast lipopeptide pheromone a-factor. The specificity of interaction among pheromone-receptor pairs in Schizophyllum was reproduced in yeast, thus providing a powerful system for exploring molecular aspects of pheromone-receptor interactions for a class of seven-transmembrane-domain receptors common to a wide range of organisms.