Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21.

Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants. To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10-13, odds ratio = 0.67, allele frequency = 0.52). 9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.

Venous thromboembolism chemical prophylaxis after skull base surgery.

PURPOSE: There is no guidance surrounding postoperative venous thromboembolism (VTE) prophylaxis using pharmacological agents (chemoprophylaxis) in patients undergoing skull base surgery. The aim of this study was to compare VTE and intracranial haematoma rates after skull base surgery in patients treated with/without chemoprophylaxis. METHODS: Review of prospective quaternary centre database including adults undergoing first-time skull base surgery (2009-2020). VTE was defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) within 6 months of surgery. Multivariate logistic regression was used to determine factors predictive of postoperative intracranial haematoma/VTE. Propensity score matching (PSM) was used in group comparisons. RESULTS: One thousand five hundred fifty-one patients were included with a median age of 52 years (range 16-89 years) and female predominance (62%). Postoperative chemoprophylaxis was used in 81% of patients at a median of 1 day postoperatively. There were 12 VTE events (1.2%), and the use of chemoprophylaxis did not negate the risk of VTE entirely (p > 0.99) and was highest on/after postoperative day 6 (9/12 VTE events). There were 18 intracranial haematomas (0.8%), and after PSM, chemoprophylaxis did not significantly increase the risk of an intracranial haematoma (p > 0.99). Patients administered chemoprophylaxis from postoperative days 1 and 2 had similar rates of intracranial haematomas (p = 0.60) and VTE (p = 0.60), affirmed in PSM. CONCLUSION: Postoperative chemoprophylaxis represents a relatively safe strategy in patients undergoing skull base surgery. We advocate a personalised approach to chemoprophylaxis and recommend it on postoperative days 1 or 2 when indicated.

Optimizing the role of 'lead mothers' in seasonal malaria chemoprevention (SMC) campaigns: formative research in Kano State, northern Nigeria.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a safe and effective intervention for preventing malaria in children under 5 years of age. Lead mothers are community health volunteers that help caregivers comply with monthly administration of anti-malarial drugs during SMC campaigns. The lead mother approach is used in several SMC implementing states across Nigeria, but there is lack of evidence about their roles and how effective they are. This study sought to better understand the current role of lead mothers, identify areas for improvement and ways to optimize the role of lead mothers during SMC campaigns. METHODS: This paper reports the formative phase of a three-phased intervention development study. The formative phase involved semi-structured interviews with stakeholders from national, state, local government and community levels (n = 20). Thematic analysis was used to identify key themes, forming the basis of a subsequent co-design workshop with stakeholders routinely involved in SMC campaigns. RESULTS: The findings of the formative phase converged around four overarching themes: skills and attributes required of lead mothers; factors that affect lead mother's roles; how lead mothers interact with Community Health Influencers Promoters Services (CHIPS) agents and re-imagining the role of lead mothers during SMC campaigns. CONCLUSION: This formative work in Kano state indicates that through their strong connection to communities and unique relationship with caregivers, lead mothers can and do influence caregivers to adopt healthy behaviours during SMC campaigns. However, there is room for improvement in how they are recruited, trained and supervised. There is need to improve lead mothers' knowledge and skills through adequate training and supporting materials, so they can deliver targeted health messages to caregivers. Sustainability of the lead mother approach is at risk if policymakers do not find a way of transitioning their role into the existing community health worker infrastructure, for example by using CHIPs agents, and ensuring less reliance on external donor support.

Managing aquatic habitat structure for resilient trophic interactions.

Structural habitat (the three-dimensional arrangement of physical matter, abiotic and biotic, at a location) is a foundational element for the resilience and maintenance of biodiversity, yet anthropogenic development is driving the global simplification of aquatic environments. Resource managers regularly seek to conserve aquatic food webs by increasing structural habitat complexity with expected benefits to fisheries; however, the global effectiveness of such actions is unclear. Our synthesis and theoretical analyses found that the response of a consumer-resource interaction (predatory sportfish and forage fish prey) to the addition of prey refuge habitat differed among systems with low and high rates of biomass transfer from resource to consumer (i.e., biomass potential); stabilization was not the rule. Greater prey refuge habitat availability tended to stabilize systems characterized by high biomass potential while simultaneously increasing consumer densities. In contrast, increasing prey refuge habitat availability in systems characterized by low biomass potential tended to mute energy transfer and moved consumer densities toward local extinction. Importantly, biomass potential and prey refuge can have antagonistic effects on stability and relative consumer densities, and it is therefore important to consider the local conditions of a system when using habitat manipulation as a management measure. Further development of our context-dependent perspective to whole food webs, and across different environments, may help to guide structural habitat management to better restore and protect aquatic ecosystems.

Delivery of seasonal malaria chemoprevention with enhanced infection prevention and control measures during the COVID-19 pandemic in Nigeria, Burkina Faso and Chad: a cross-sectional study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a WHO-recommended intervention for children aged 3-59 months living in areas of high malaria transmission to provide protection against malaria during the rainy season. Operational guidelines were developed, based on WHO guidance, to support countries to mitigate the risk of coronavirus disease 2019 (COVID-19) transmission within communities and among community distributors when delivering SMC. METHODS: A cross-sectional study to determine adherence to infection prevention and control (IPC) measures during two distribution cycles of SMC in Nigeria, Chad and Burkina Faso. Community distributors were observed receiving equipment and delivering SMC. Adherence across six domains was calculated as the proportion of indications in which the community distributor performed the correct action. Focus group discussions were conducted with community distributors to understand their perceptions of the IPC measures and barriers and facilitators to adherence. RESULTS: Data collectors observed community distributors in Nigeria (n = 259), Burkina Faso (n = 252) and Chad (n = 266) receiving IPC equipment and delivering SMC. Adherence to IPC indications varied. In all three countries, adherence to mask use was the highest (ranging from 73.3% in Nigeria to 86.9% in Burkina Faso). Adherence to hand hygiene for at least 30 s was low (ranging from 3.6% in Nigeria to 10.3% in Burkina Faso) but increased substantially when excluding the length of time spent hand washing (ranging from 36.7% in Nigeria to 61.4% in Burkina Faso). Adherence to safe distancing in the compound ranged from 5.4% in Chad to 16.4% in Nigeria. In Burkina Faso and Chad, where disinfection wipes widely available compliance with disinfection of blister packs for SMC was low (17.4% in Burkina Faso and 16.9% in Chad). Community distributors generally found the IPC measures acceptable, however there were barriers to optimal hand hygiene practices, cultural norms made social distancing difficult to adhere to and caregivers needed assistance to administer the first dose of SMC. CONCLUSION: Adherence to IPC measures for SMC delivery during the COVID-19 pandemic varied across domains of IPC, but was largely insufficient, particularly for hand hygiene and safe distancing. Improvements in provision of protective equipment, early community engagement and adaptations to make IPC measures more feasible to implement could increase adherence.

Sporadic vestibular schwannoma: a molecular testing summary.

OBJECTIVES: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis. METHODS: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups. RESULTS: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants. CONCLUSIONS: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

Extending seasonal malaria chemoprevention to five cycles: a pilot study of feasibility and acceptability in Mangodara district, Burkina Faso.

BACKGROUND: Seasonal malaria chemoprevention (SMC) involves administering antimalarial drugs at monthly intervals during the high malaria transmission period to children aged 3 to 59 months as recommended by the World Health Organization. Typically, a full SMC course is administered over four monthly cycles from July to October, coinciding with the rainy season. However, an analysis of rainfall patterns suggest that the malaria transmission season is longer and starting as early as June in the south of Burkina Faso, leading to a rise in cases prior to the first cycle. This study assessed the acceptability and feasibility of extending SMC from four to five cycles to coincide with the earlier rainy season in Mangodara health district. METHODS: The mixed-methods study was conducted between July and November 2019. Quantitative data were collected through end-of-cycle and end-of-round household surveys to determine the effect of the additional cycle on the coverage of SMC in Mangodara. The data were then compared with 22 other districts where SMC was implemented by Malaria Consortium. Eight focus group discussions were conducted with caregivers and community distributors and 11 key informant interviews with community, programme and national-level stakeholders. These aimed to determine perceptions of the acceptability and feasibility of extending SMC to five cycles. RESULTS: The extension was perceived as acceptable by caregivers, community distributors and stakeholders due to the positive impact on the health of children under five. However, many community distributors expressed concern over the feasibility, mainly due to the clash with farming activities in June. Stakeholders highlighted the need for more evidence on the impact of the additional cycle on parasite resistance prior to scale-up. End-of-cycle survey data showed no difference in coverage between five SMC cycles in Mangodara and four cycles in the 22 comparison districts. CONCLUSIONS: The additional cycle should begin early in the day in order to not coincide with the agricultural activities of community distributors. Continuous sensitisation at community level is critical for the sustainability of SMC and acceptance of an additional cycle, which should actively engage male caregivers. Providing additional support in proportion to the increased workload from a fifth cycle, including timely remuneration, is critical to avoid the demotivation of community distributors. Further studies are required to understand the effectiveness, including cost-effectiveness, of tailoring SMC according to the rainy season. Understanding the impact of an additional cycle on parasite resistance to SPAQ is critical to address key informants' concerns around the deviation from the current four-cycle policy recommendation.

Co-implementing vitamin A supplementation with seasonal malaria chemoprevention in Sokoto State, Nigeria: a feasibility and acceptability study.

BACKGROUND: Bi-annual high dose vitamin A supplements administered to children aged 6-59 months can significantly reduce child mortality, but vitamin A supplementation (VAS) coverage is low in Nigeria. The World Health Organization recommends that VAS be integrated into other public health programmes which are aimed at improving child survival. Seasonal malaria chemoprevention (SMC) provides a ready platform for VAS integration to improve health outcomes. This study explored the feasibility and acceptability of integrating VAS with SMC in one local government area in Sokoto State. METHODS: A concurrent QUAN-QUAL mixed methods study was used to assess the feasibility and acceptability of co-implementing VAS with SMC in one LGA of Sokoto state. Existing SMC implementation tools and job aids were revised and SMC and VAS were delivered using a door-to-door approach. VAS and SMC coverage were subsequently assessed using questionnaires administered to 188 and 197 households at baseline and endline respectively. The qualitative component involved key informant interviews and focus group discussions with policymakers, programme officials and technical partners to explore feasibility and acceptability. Thematic analysis was carried out on the qualitative data. RESULTS: At endline, the proportion of children who received at least one dose of VAS in the last six months increased significantly from 2 to 59% (p < 0.001). There were no adverse effects on the coverage of SMC delivery with 70% eligible children reached at baseline, increasing to 76% (p = 0.412) at endline. There was no significant change (p = 0.264) in the quality of SMC, measured by proportion of children receiving their first dose as directly observed treatment (DOT), at baseline (54%) compared to endline (68%). The qualitative findings are presented as two overarching themes relating to feasibility and acceptability of the integrated VAS-SMC strategy, and within each, a series of sub-themes describe study participants' views of important considerations in implementing the strategy. CONCLUSION: This study showed that it is feasible and acceptable to integrate VAS with SMC delivery in areas of high seasonal malaria transmission such as northern Nigeria, where SMC campaigns are implemented. SMC-VAS integrated campaigns can significantly increase vitamin A coverage but more research is required to demonstrate the feasibility of this integration in different settings and on a larger scale.

The importance of genetic counseling and screening for people with pathogenic SMARCE1 variants: A family study.

Clear cell meningioma (CCM) is a rare variant of meningioma. In recent years, an association between cranial and spinal CCMs and germline loss of function mutations in the SMARCE1 gene (SWI/SNF chromatin remodeling complex subunit gene) has been discovered. We report a family with an incidental large spinal clear cell meningioma in a young adult following reflex screening for a germline loss of function pathogenic variant (PV) in the SMARCE1 gene. The index patient's mother and maternal grandfather were both also tested positive presymptomatically for SMARCE1. His mother developed intracranial and spinal meningiomas and his maternal grandfather developed a spinal CCM 4 years following a clear spinal MRI scan which required surgical excision. In this report we particularly emphasize the importance of genetic counseling and screening in siblings, parents and offspring of patients who are diagnosed with intracranial or spinal CCM in the context of SMARCE1 PVs. We recommend brain and spine Imaging screening of asymptomatic SMARCE1 PV carriers at least every 3 years, even if the baseline scan did not show any tumors.

Usability and acceptability of a multimodal respiratory rate and pulse oximeter device in case management of children with symptoms of pneumonia: A cross-sectional study in Ethiopia.

AIM: Pneumonia is the leading infectious cause of death among children under five globally. Many pneumonia deaths result from inappropriate treatment due to misdiagnosis of signs and symptoms. This study aims to identify whether health extension workers (HEWs) in Ethiopia, using an automated multimodal device (Masimo Rad-G), adhere to required guidelines while assessing and classifying under five children with cough or difficulty breathing and to understand device acceptability. METHODS: A cross-sectional study was conducted in three districts of Southern Nations, Nationalities, and Peoples' Region, Ethiopia. Between September and December 2018, 133 HEWs were directly observed using Rad-G while conducting 599 sick child consultations. Usability was measured as adherence to the World Health Organization requirements to assess fast breathing and device manufacturer instructions for use. Acceptability was assessed using semi-structured interviews with HEWs, first-level health facility workers and caregivers. RESULTS: Adherence using the Rad-G routinely for 2 months was 85.3% (95% CI 80.2, 89.3). Health workers and caregivers stated a preference for Rad-G. Users highlighted a number of device design issues. CONCLUSION: While demonstrating high levels of acceptability and usability, the device modifications to consider include better probe fit, improved user interface with exclusive age categories and simplified classification outcomes.

Health management information system (HMIS) data quality and associated factors in Massaguet district, Chad.

BACKGROUND: Quality data from Health Management Information Systems (HMIS) are important for tracking the effectiveness of malaria control interventions. However, HMIS data in many resource-limited settings do not currently meet standards set by the World Health Organization (WHO). We aimed to assess HMIS data quality and associated factors in Chad. METHODS: A cross-sectional study was conducted in 14 health facilities in Massaguet district. Data on children under 15 years were obtained from the HMIS and from the external patient register covering the period January-December 2018. An additional questionnaire was administered to 16 health centre managers to collect data on contextual variables. Patient registry data were aggregated and compared with the HMIS database at district and health centre level. Completeness and accuracy indicators were calculated as per WHO guidelines. Multivariate logistic regressions were performed on the Verification Factor for attendance, suspected and confirmed malaria cases for three age groups (1 to < 12 months, 1 to < 5 years and 5 to < 15 years) to identify associations between health centre characteristics and data accuracy. RESULTS: Health centres achieved a high level of data completeness in HMIS. Malaria data were over-reported in HMIS for children aged under 15 years. There was an association between workload and higher odds of inaccuracy in reporting of attendance among children aged 1 to < 5 years (Odds ratio [OR]: 10.57, 95% CI 2.32-48.19) and 5- < 15 years (OR: 6.64, 95% CI 1.38-32.04). Similar association was found between workload and stock-outs in register books, and inaccuracy in reporting of malaria confirmed cases. Meanwhile, we found that presence of a health technician, and of dedicated staff for data management, were associated with lower inaccuracy in reporting of clinic attendance in children aged under five years. CONCLUSION: Data completeness was high while the accuracy was low. Factors associated with data inaccuracy included high workload and the unavailability of required data collection tools. The results suggest that improvement in working conditions for clinic personnel may improve HMIS data quality. Upgrading from paper-based forms to a web-based HMIS may provide a solution for improving data accuracy and its utility for future evaluations of health interventions. Results from this study can inform the Ministry of Health and it partners on the precautions to be taken in the use of HMIS data and inform initiatives for improving its quality.

Evaluating the Interrater Agreement and Acceptability of a New Reference Tool for Assessing Respiratory Rate in Children under Five with Cough and/or Difficulty Breathing.

BACKGROUND: Manual assessment of respiratory rate (RR) in children is unreliable, but remains the main method to diagnose pneumonia in low-resource settings. While automated RR counters offer a potential solution, there is currently no gold standard to validate these diagnostic aids. A video-based reference tool is proposed that allows users to annotate breaths and distortions including movement periods, allowing the exclusion of distortions from the computation of RR measures similar to how new diagnostic aids account for distortions automatically. This study evaluated the interrater agreement and acceptability of the new reference tool. METHODS: Annotations were based on previously recorded reference videos of children under five years old with cough and/or difficulty breathing (n = 50). Five randomly selected medical experts from a panel of ten annotated each video. RR measures (breaths per minute, bpm) were computed as the number of annotated certain breaths divided by the length of calm periods after removing annotated distorted periods. RESULTS: Reviewers showed good interrater agreement on continuous RR {standard error of measurement (SEM) [4.8 (95%CI 4.4-5.3)]} and substantial agreement on classification of fast breathing (Fleiss kappa, κ 0.71). Agreement was lowest in the youngest age group [< 2 months: SEM 6.2 (5.4-7.4) bpm, κ 0.48; 2-11 months: 4.7 (4.0-5.8) bpm, κ 0.84; 12-59 months: 2.6 (2.2-3.1) bpm, κ 0.8]. Reviewers found the functionalities of the tool helpful in annotating breaths, but remained uncertain about the validity of their annotations. CONCLUSIONS: Before the new tool can be considered a reference standard for RR assessments, interrater agreement in children younger than 2 months must be improved.

Incidence of mosaicism in 1055 de novo NF2 cases: much higher than previous estimates with high utility of next-generation sequencing.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2). METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing. RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant. CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Usability and acceptability of an automated respiratory rate counter to assess children for symptoms of pneumonia: A cross-sectional study in Ethiopia.

AIM: Manually counting respiratory rate (RR) is commonly practiced by community health workers to detect fast breathing, an important sign of childhood pneumonia. Correctly counting and classifying breaths manually is challenging, often leading to inappropriate treatment. This study aimed to determine the usability of a new automated RR counter (ChARM) by health extension workers (HEWs), and its acceptability to HEWs, first-level health facility workers (FLHFWs) and caregivers in Ethiopia. METHODS: A cross-sectional study was conducted in one region of Ethiopia between May and August 2018. A total of 131 HEWs were directly observed conducting 262 sick child consultations after training and 337 after 2 months. Usability was measured as adherence to the WHO requirements to assess fast breathing and device manufacturer instructions for use (IFU). Acceptability was measured through semi-structured interviews. RESULTS: After 2 months, HEWs were shown to adhere to the requirements in 74.6% consultations; an increase of 18.6% after training (P < .001). ChARM is acceptable to users and caregivers, with HEWs suggesting that ChARM increased client flow and stating a willingness to use ChARM in future. CONCLUSION: Further research on the performance, cost-effectiveness and implementation of this device is warranted to inform policy decisions in countries with a high childhood pneumonia burden.

Usability and acceptability of an automated respiratory rate counter to assess childhood pneumonia in Nepal.

AIM: Pneumonia is the leading cause of child death after the neonatal period, resulting from late care seeking and inappropriate treatment. Diagnosis involves counting respiratory rate (RR); however, RR counting remains challenging for health workers and miscounting, and misclassification of RR is common. We evaluated the usability of a new automated RR counter, the Philips Children's Respiratory Monitor (ChARM), to Female Community Health Volunteers (FCHVs), and its acceptability to FCHVs and caregivers in Nepal. METHODS: A cross-sectional study was conducted in Jumla district, Nepal. About 133 FCHVs were observed between September and December 2018 when using ChARM during 517 sick child consultations, 264 after training and 253 after 2 months of routine use of ChARM. Acceptability of the ChARM was explored using semi-structured interviews. RESULTS: FCHV adherence to guidelines after 2 months of using ChARM routinely was 52.8% (95% CI 46.6-58.9). The qualitative findings suggest that ChARM is acceptable to FCHVs and caregivers; however, capacity constraints such as older age and low literacy and impacted device usability were mentioned. CONCLUSION: Further research on the performance, cost-effectiveness and implementation feasibility of this device is recommended, especially among low-literate CHWs.

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing.

PURPOSE: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). METHODS: Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. RESULTS: There was no evidence for usefulness of old criteria "glioma" or "neurofibroma." "Ependymoma" had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 nondermal schwannomas reduced PPV to 67%. CONCLUSIONS: The present study confirms important deficiencies in NF2 diagnostic criteria. The term "glioma" should be dropped and replaced by "ependymoma." Similarly "neurofibroma" should be removed. Dropping "sibling" from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

Schwannomatosis: a genetic and epidemiological study.

OBJECTIVES: Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. METHODS: Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. RESULTS: Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%-2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). CONCLUSIONS: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study.

BACKGROUND: In September, 2015, the UK became the first country to introduce the multicomponent group B meningococcal (MenB) vaccine (4CMenB, Bexsero) into a publicly funded national immunisation programme. A reduced two-dose priming schedule was offered to infants at 2 months and 4 months, alongside an opportunistic catch-up for 3 month and 4 month olds. 4CMenB was predicted to protect against 73-88% of MenB strains. We aimed to assess the effectiveness and impact of 4CMenB in vaccine-eligible infants in England. METHODS: Public Health England (PHE) undertakes enhanced surveillance of meningococcal disease through a combination of clinical, public health, and laboratory reporting. Laboratory-confirmed cases of meningococcal disease are followed up with PHE local health protection teams, general practitioners, and hospital clinicians to collect demographic data, vaccination history, clinical presentation, and outcome. For cases diagnosed between Sept 1, 2015, and June 30, 2016, vaccine effectiveness was assessed using the screening method. Impact was assessed by comparing numbers of cases of MenB in vaccine-eligible children to equivalent cohorts in the previous 4 years and to cases in vaccine-ineligible children. FINDINGS: Coverage of 4CMenB in infants eligible for routine vaccination was high, achieving 95·5% for one dose and 88·6% for two doses by 6 months of age. Two-dose vaccine effectiveness was 82·9% (95% CI 24·1-95·2) against all MenB cases, equivalent to a vaccine effectiveness of 94·2% against the highest predicted MenB strain coverage of 88%. Compared with the prevaccine period, there was a 50% incidence rate ratio (IRR) reduction in MenB cases in the vaccine-eligible cohort (37 cases vs average 74 cases; IRR 0·50 [95% CI 0·36-0·71]; p=0·0001), irrespective of the infants' vaccination status or predicted MenB strain coverage. Similar reductions were observed even after adjustment for disease trends in vaccine-eligible and vaccine-ineligible children. INTERPRETATION: The two-dose 4CMenB priming schedule was highly effective in preventing MenB disease in infants. Cases in vaccine-eligible infants halved in the first 10 months of the programme. While ongoing national surveillance will continue to monitor the longer-term impact of the programme, these findings represent a step forward in the battle against meningococcal disease and will help reassure that the vaccine protects against this deadly infection. FUNDING: Public Health England.

Urinary incontinence, but not fecal incontinence, is a risk factor for admission to aged residential care of older persons in New Zealand.

AIMS: To determine if urinary incontinence (UI) and fecal incontinence (FI) were independent risk factors for aged resident care (ARC) admissions for older people, after controlling for confounders and applying apposite statistical methods. METHODS: Since 2012, all community care recipients in New Zealand have undergone a standardized needs assessment using the Home Care International Residential Assessment Instrument (interRAI-HC). The interRAI-HC instrument elicits information on 236 questions over 20 domains, including UI and FI frequency within the last 3 days. Those aged 65+ years with an interRAI-HC assessment between July 1, 2012 and May 31, 2014 were matched to national mortality and ARC databases, and competing-risk regression models applied to those without collection devices or indwelling catheters who were admitted to ARC or alive 30+ days after their interRAI-HC assessment. RESULTS: Overall, 32 285 people were eligible, with average age of 82.1 years (range 65, 105 years) of whom 20 627 (63.9%) were female. UI and FI was reported by 36.4% and 12.9% of people, respectively. By June 30, 2014, 5993 (18.6%) had an ARC admission and 5443 (16.9%) had died before any such admission. In the multivariable analysis, the subhazard ratio (SHR) for ARC admission was significant for UI (SHR = 1.11, 95%CI: 1.05, 1.18) but not for FI (SHR = 1.07, 95%CI: 0.99, 1.16). CONCLUSIONS: UI is a common, independent risk factor for ARC admissions. Identifying the extent of incontinence and its impact on ARC admissions is the first vital step in addressing the burgeoning need for better community continence services.

Prostate cancer screening practices and diagnoses in patients age 50 and older, Southeastern Michigan, pre/post 2012.

INTRODUCTION: Studies investigating the regional impact of the 2012 U.S. Preventive Services Task Force (USPSTF) recommendation against the use of prostate specific antigen (PSA) screening for prostate cancer have been limited. METHODS: A retrospective cohort study was conducted on men age 50years and older in Southeastern Michigan pre (n=3647) and post (n=3618) USPSTF recommendation. PSA screening, transrectal ultrasound, and prostate biopsy rates were evaluated pre/post using a generalized piecewise linear model with a Poisson distribution, and log link. A knot was placed at year 2011 to estimate pre/post slope coefficients. Generalized estimating equations were used to estimate the marginal probability of a prostate diagnosis as a logistic function of pre and post-period, and comorbidities. RESULTS: PSA utilization significantly increased (ß=0.28; 95% CI: 0.25, 0.31) during the pre-period, but significantly decreased in the post-period (ß=-0.29; 95% CI: -0.34, -0.25). Prostate biopsies decreased pre (ß=-0.16; 95% CI: -0.25, -0.08) and did not change post (ß=0.01; 95% CI: -0.09, 0.12). Transrectal ultrasounds were stable pre (ß=0.16; 95% CI: -0.03, 0.35) and significantly decreased post (ß=-0.27; 95% CI: -0.50, -0.04). Patients in the post-period had a decreased probability of having a diagnosis of prostate cancer (OR: 0.81; 95% CI: 0.74-0.89) compared to the pre-period. CONCLUSION: Our study demonstrates how PSA tests are still being frequently used in Southeastern Michigan. Further research is needed to better understand regional variation in prostate cancer screening practices in the U.S.