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Endometriosis is described as the proliferation of endometrial tissue outside of the uterus. This most frequently occurs within the pelvis and is a common cause of chronic pelvic pain in women of reproductive age. Rarely, endometriosis can manifest outside of the pelvis and can uncommonly involve the musculoskeletal and peripheral nervous systems. Extrapelvic endometriosis is a difficult radiologic diagnosis due to its rarity and varied magnetic resonance imaging (MRI) appearance. Diagnosis of extrapelvic endometriosis is most frequently made with biopsy and most cases within the literature are treated with surgical resection. Of the cases that were treated medically, there is a paucity of available follow-up imaging to characterize the natural history and treatment response of this entity.We present a case of extrapelvic endometriosis involving the right sciatic notch, in a 26 year old female who presented with cyclic hip pain and lumbosacral plexopathy. Initial MRI findings were nonspecific, and diagnosis was made via image guided biopsy. The patient underwent medical treatment with a gonadotropin-release hormone agonist and oral contraceptives, with close imaging follow-up including a 6-month post-treatment MRI.

Background Telemonitoring-guided interventions can improve short-term positive airway pressure (PAP) therapy adherence, but long-term effects are unknown. This study investigated long-term PAP therapy termination in patients with sleep apnoea managed with standard care, telemonitoring-guided proactive care or telemonitoring-guided proactive care + patient engagement tool. Methods German healthcare provider data were analysed retrospectively. Individuals aged 18–100 years who started PAP from 2014 to 2019 and had device type/interface data were included. Time-to-termination periods were analysed using Kaplan–Meier plots and Cox proportional hazards regression, adjusted for age, sex, insurance type, and device and mask type. Results The per-protocol population (valid telemonitoring data) included 104 612 individuals (71% male; 95% aged >40 years). Mean follow-up was 3.3±2.0 years. The overall therapy termination rate was significantly lower in the telemonitoring-guided proactive care group versus standard care (20% versus 27%; p59 years and use of a nasal pillows or full-face mask were significant predictors of therapy termination; male sex, use of telemonitoring-guided proactive care (± patient engagement) and private insurance were significantly associated with lower therapy termination rates. Conclusions Use of telemonitoring-guided proactive care and a patient engagement tool was associated with lower rates of PAP therapy termination.

BackgroundSub-Saharan Africa region bears the highest chronic hepatitis B virus (HBV) infection burden worldwide. National estimates of HBV burden are necessary for a viral hepatitis program planning. This study estimated the national prevalence of HBV infection in Kenya among people aged 15-64 years.MethodsOf 27,745 participants age 15-64 years in the Kenya Population-based HIV Impact Assessment (KENPHIA) 2018 household survey, we analyzed data for all persons living with HIV (PLHIV; n = 1,521) and a random sample of HIV-negative persons (n = 1,551), totaling to 3,072 participants. We tested whole blood samples for hepatitis B surface antigen (HBsAg) using Determine™ HBsAg rapid test and used population projections to estimate national disease burden. Pearson chi square was performed and the weighted prevalence proportions presented.FindingsOf the 3,072 participants,124 tested HBsAg positive, resulting in a weighted national HBV prevalence of 3.0% (95% CI: 2.2-3.9%). This translated to an HBV infection burden of 810,600 (95% CI: 582,700-1,038,600) persons age 15-64 years in Kenya. Distribution of HBV prevalence varied widely (pInterpretationHBV prevalence among persons aged 15-64 years in Kenya was 3.0%. Higher prevalence was documented among persons without formal education, in the lowest wealth quintile, and those living in Kenya's North-Eastern, Rift Valley-North and Nyanza regions. Targeted programmatic measures to strengthen interventions against HBV infections including newborn vaccination and treatment of infected adults to limit mother-to-child transmission, would be helpful in reducing burden of HBV-associated viral hepatitis.

Abstract Background Quantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET. Here, we employ penalised reconstruction alongside iterative thresholding methods and simple partial volume correction methods to produce IDIFs from a single PET scan, and subsequently, compare these to blood-sampled input curves (BSIFs) as ground truth. Retrospectively we used data from sixteen subjects with two dynamic 15O-labelled water PET scans and continuous arterial blood sampling: one baseline scan and another post-administration of acetazolamide. Results IDIFs and BSIFs agreed well in terms of the area under the curve of input curves when comparing peaks, tails and peak-to-tail ratios with R2 values of 0.95, 0.70 and 0.76, respectively. Grey matter cerebral blood flow (CBF) values showed good agreement with an average difference between the BSIF and IDIF CBF values of 2% ± and a coefficient of variation (CoV) of 7.3%. Conclusion Our results show promising results that a robust IDIF can be produced for dynamic 15O–water PET scans using only the dynamic PET scan images with no need for a corresponding MRI or complex analytical techniques and thereby making routine clinical use of quantitative CBF measurements with 15O–water feasible.

Abstract Background For assessing the HIV epidemic in Kenya, a series of independent HIV indicator household-based surveys of similar design can be used to investigate the trends in key indicators relevant to HIV prevention and control and to describe geographic and sociodemographic disparities, assess the impact of interventions, and develop strategies. We developed methods and tools to facilitate a robust analysis of trends across three national household-based surveys conducted in Kenya in 2007, 2012, and 2018. Methods We used data from the 2007 and 2012 Kenya AIDS Indicator surveys (KAIS 2007 and KAIS 2012) and the 2018 Kenya Population-based HIV Impact Assessment (KENPHIA 2018). To assess the design and other variables of interest from each study, variables were recoded to ensure that they had equivalent meanings across the three surveys. After assessing weighting procedures for comparability, we used the KAIS 2012 nonresponse weighting procedure to revise normalized KENPHIA weights. Analyses were restricted to geographic areas covered by all three surveys. The revised analysis files were then merged into a single file for pooled analysis. We assessed distributions of age, sex, household wealth, and urban/rural status to identify unexpected changes between surveys. To demonstrate how a trend analysis can be carried out, we used continuous, binary, and time-to-event variables as examples. Specifically, temporal trends in age at first sex and having received an HIV test in the last 12 months were used to demonstrate the proposed analytical approach. These were assessed with respondent-specific variables (age, sex, level of education, and marital status) and household variables (place of residence and wealth index). All analyses were conducted in SAS 9.4, but analysis files were created in Stata and R format to support additional analyses. Results This study demonstrates trends in selected indicators to illustrate the approach that can be used in similar settings. The incidence of early sexual debut decreased from 11.63 (95% CI: 10.95–12.34) per 1,000 person-years at risk in 2007 to 10.45 (95% CI: 9.75–11.2) per 1,000 person-years at risk in 2012 and to 9.58 (95% CI: 9.08–10.1) per 1,000 person-years at risk in 2018. HIV-testing rates increased from 12.6% (95% CI: 11.6%–13.6%) in 2007 to 56.1% (95% CI: 54.6%–57.6%) in 2012 but decreased slightly to 55.6% [95% CI: 54.6%–56.6%) in 2018. The decrease in incidence of early sexual debut could be convincingly demonstrated between 2007 and 2012 but not between 2012 and 2018. Similarly, there was virtually no difference between HIV Testing rates in 2012 and 2018. Conclusions Our approach can be used to support trend comparisons for variables in HIV surveys in low-income settings. Independent national household surveys can be assessed for comparability, adjusted as appropriate, and used to estimate trends in key indicators. Analyzing trends over time can not only provide insights into Kenya’s progress toward HIV epidemic control but also identify gaps.

Splenic infarction in COVID-19 patients is a rare entity with few documented cases. We report a case of symptomatic complete splenic infarction and discuss COVID-19 related thrombosis, splenic infarction, diagnostic imaging for splenic infarction, and the management. Thrombotic events related to COVID-19 have been reported in unusual locations, and our case highlights an example of one such location, the splenic artery. Contrast enhanced Computed Tomography (CT) is the standard diagnostic modality and will typically reveal foci of hypo-enhancement, peripheral and wedge-shaped. CT angiography can be performed to evaluate the arteries and diagnose thrombosis. The primary treatment is aimed at addressing the underlying cause and includes supportive care. It is important that physicians consider splenic infarction as an explanation for abdominal pain in COVID-19 patients.

Background We examined the epidemiology and transmission potential of HIV population viral load (VL) in 12 sub-Saharan African countries. Methods We analyzed data from Population-based HIV Impact Assessments (PHIAs), large national household-based surveys conducted between 2015 and 2019 in Cameroon, Cote d’Ivoire, Eswatini, Kenya, Lesotho, Malawi, Namibia, Rwanda, Tanzania, Uganda, Zambia, and Zimbabwe. Blood-based biomarkers included HIV serology, recency of HIV infection, and VL. We estimated the number of people living with HIV (PLHIV) with suppressed viral load (Results The proportion of female PLHIV with viral suppression was higher than that among males in all countries, however, the number of unsuppressed females outnumbered that of unsuppressed males in all countries due to higher overall female HIV prevalence, with ratios ranging from 1.08 to 2.10 (median: 1.43). The spatial distribution of HIV seroprevalence, viremia prevalence, and number of unsuppressed adults often differed substantially within the same countries. The 1% and 5% of PLHIV with the highest VL on average accounted for 34% and 66%, respectively, of countries’ total VL. HIV transmission ratios varied widely across countries and were higher for male-to-female (range: 2.3–28.3/100 PY) than for female-to-male transmission (range: 1.5–10.6/100 PY). In all countries mean log10 VL among unsuppressed males was higher than that among females. Correlations between VL measures and incident HIV varied, were weaker for VL metrics among females compared to males and were strongest for the number of unsuppressed PLHIV per 100 HIV-negative adults (R2 = 0.92). Conclusions Despite higher proportions of viral suppression, female unsuppressed PLHIV outnumbered males in all countries examined. Unsuppressed male PLHIV have consistently higher VL and a higher risk of transmitting HIV than females. Just 5% of PLHIV account for almost two-thirds of countries’ total VL. Population-level VL metrics help monitor the epidemic and highlight key programmatic gaps in these African countries.

Abstract Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.

IntroductionTo date, a few studies have used somatosensory evoked potentials (SEP) to demonstrate cortical sensory changes among healthy subjects or to estimate cortical plasticity and rehabilitation prognosis in stroke patients after peripheral electrical stimulation (PES) intervention. The primary aim was to systematically review whether PES has a role in changing latencies and amplitudes of SEPs in healthy subjects and stroke patients. Moreover, we searched for a correlation between sensory and motor function assessments and changes in SEP components of included studies.MethodsThe following databases were searched: Pubmed/MEDLINE, Scopus/ScienceDirect, Web of Science/Clarivate, Cochrane Library, The Physiotherapy Evidence Database (PEDro), and ClinicalTrials.gov. Titles and abstracts, as well as full-text reports, were screened for eligibility by two independent reviewers according to a priori defined eligibility criteria. There were no study limitations concerning the treatment of the upper limb, lower limb, or torso with PES.ResultsThe final systematic search resulted in 11,344 records, however only 10 were evaluated. We could not find enough evidence to confirm use of SEP as a predictor to estimate the rehabilitation prognosis after stroke. However, we found a correlation between different sensory and motor function assessments and changes in SEP components. The stroke studies involving PES that initiate a voluntary contraction used for a specific movement or task indicate a positive relationship and correlation to assessments of motor function. It could be indicated that PES have a predictive impact of sensory reorganization, as mirrored by the change in SEP amplitude and latency. However, it is not possible to verify the degree of connectivity between SEP and cortical plasticity. To confirm this hypothesis, we propose the conduction of randomized controlled trials in healthy volunteers and stroke patients.Systematic review registrationhttps://doi.org/10.17605/OSF.IO/U7PSY.

Abstract Insomnia is defined as difficulties of initiating and maintaining sleep, early awakening and poor subjective sleep quality despite adequate opportunity and circumstances for sleep with impairment of daytime performance. These components of insomnia – namely persistent sleep difficulties despite of adequate sleep opportunity resulting in daytime dysfunction - appear secondary or co-morbid to neurological diseases. Comorbid insomnia originates from neurodegenerative, inflammatory, traumatic or ischemic changes in sleep regulating brainstem and hypothalamic nuclei with consecutive changes of neurotransmitters. Symptoms of neurological disorders (i.e motor deficits), co-morbidities (i.e. pain, depression, anxiety) and some disease-specific pharmaceuticals may cause insomnia and/or other sleep problems. This guideline focuses on insomnias in headaches, neurodegenerative movement disorders, multiple sclerosis, traumatic brain injury, epilepsies, stroke, neuromuscular disease and dementia. The most important new recommendations are: Cognitive behavioral therapy (CBTi) is recommended to treat acute and chronic insomnia in headache patients. Insomnia is one of the most frequent sleep complaints in neurodegenerative movement disorders. Patients may benefit from CBTi, antidepressants (trazodone, doxepin), melatonin and gaba-agonists. Insomnia is a frequent precursor of MS symptoms by up to 10 years. CBTi is recommended in patients with MS, traumatic brain injury and. Melatonin may improve insomnia symptoms in children with epilepsies. Patients with insomnia after stroke can be treated with benzodiazepine receptor agonists and sedating antidepressants. For patients with dementia suffering from insomnia trazodone, light therapy and physical exercise are recommended.

Abstract High quality, representative data from HIV surveillance systems that have country ownership and commitment are critical for guiding national HIV responses, especially among key and priority populations given their disproportionate role in the transmission of the virus. Between 2011 to 2013, the Mozambique Ministry of Health has conducted five Biobehavioral Surveillance Surveys among key populations (female sex workers, men who has sex with men and people who inject drugs) and priority populations (long distance truck drives and miners) as part of the national HIV surveillance system. We describe the experience of strengthening the HIV surveillance system among those populations through the implementation of these surveys in Mozambique. We document the lessons learned through the impact on coordination and collaboration; workforce development and institutional capacity building; data use and dissemination; advocacy and policy impact; financial sustainability and community impact. Key lessons learned include the importance of multisectoral collaboration, vital role of data to support key populations visibility and advocacy efforts, and institutional capacity building of government agencies and key populations organizations. Given that traditional surveillance methodologies from routine data often do not capture these hidden populations, it will be important to ensure that Biobehavioral Surveillance Surveys are an integral part of ongoing HIV surveillance activities in Mozambique.

Summary: Background: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. Methods: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. Findings: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. Interpretation: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. Funding: UK National Institute for Health Research and UK Medical Research Council.

The Gemini High-resolution Optical SpecTrograph (GHOST) is the newest high-resolution spectrograph to be developed for a large-aperture telescope, recently deployed and commissioned at the Gemini-South telescope. In this paper, we present the first science results from the GHOST spectrograph taking during its commissioning runs. We have observed the bright metal-poor benchmark star HD 122563, along with two stars in the ultrafaint dwarf galaxy Reticulum II (Ret ii ), one of which was previously identified as a candidate member, but did not have a previous detailed chemical abundance analysis. We find that this candidate (GDR3 0928) to be a bona fide member of Ret ii , and from a spectral synthesis analysis it is also revealed to be a CEMP- r star, with significant enhancements in several light elements (C, N, O, Na, Mg, and Si), in addition to featuring an r -process enhancement like many other Ret ii stars. The light-element enhancements in this star resemble the abundance patterns seen in the CEMP-no stars of other ultrafaint dwarf galaxies, and are thought to have been produced by an independent source from the r -process. These unusual abundance patterns are thought to be produced by faint supernovae, which may be produced by some of the earliest generations of stars.

Summary: We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

Temperate phages play important roles in bacterial communities but have been largely overlooked, particularly in non-pathogenic bacteria. In rhizobia the presence of temperate phages has the potential to have significant ecological impacts but few examples have been described. Here we characterize a novel group of 5 Rhizobium leguminosarum prophages, capable of sustaining infections across a broad host range within their host genus. Genome comparisons identified further putative prophages infecting multiple Rhizobium species isolated globally, revealing a wider family of 10 temperate phages including one previously described lytic phage, RHEph01, which appears to have lost the ability to form lysogens. Phylogenetic discordance between prophage and host phylogenies suggests a history of active mobilization between Rhizobium lineages. Genome comparisons revealed conservation of gene content and order, with the notable exception of an approximately 5 kb region of hypervariability, containing almost exclusively hypothetical genes. Additionally, several horizontally acquired genes are present across the group, including a putative antirepressor present only in the RHEph01 genome, which may explain its apparent inability to form lysogens. In summary, both phenotypic and genomic comparisons between members of this group of phages reveals a clade of viruses with a long history of mobilization within and between Rhizobium species.

Introduction: In slowly progressive myopathies, diaphragm weakness early manifests through sleep-related hypoventilation as reflected by nocturnal hypercapnia. This study investigated whether daytime tests of respiratory muscle function and diaphragm ultrasound predict hypercapnia during sleep.Methods: Twenty-seven patients with genetic myopathies (myotonic dystrophy type 1 and 2, late-onset Pompe disease, facioscapulohumeral dystrophy; 48 ± 11 years) underwent overnight transcutaneous capnometry, spirometry, measurement of mouth occlusion pressures, and diaphragm ultrasound.Results: Sixteen out of 27 patients showed nocturnal hypercapnia (peak ptcCO2 ≥ 50 mmHg for ≥ 30 min or increase in ptcCO2 by 10 mmHg or more from the baseline value). In these patients, forced vital capacity (FVC; % predicted) and maximum inspiratory pressure (MIP; % of lower limit or normal or LLN) were significantly reduced compared to normocapnic individuals. Nocturnal hypercapnia was predicted by reduction in FVC of 8.0 cm/s on diaphragm ultrasound.

Objectives The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors.Design Cross-sectional study.Setting and participants Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009–2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples.Outcome measures Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality.Results Vitamin D insufficiency (total 25(OH)D 25–50 nmol/L) and deficiency (

Legumes of the Fabeae tribe form nitrogen-fixing root nodules resulting from symbiotic interaction with the soil bacteria Rhizobium leguminosarum symbiovar viciae (Rlv). These bacteria are all potential symbionts of the Fabeae hosts but display variable partner choice when co-inoculated in mixture. Because partner choice and symbiotic nitrogen fixation mostly behave as genetically independent traits, the efficiency of symbiosis is often suboptimal when Fabeae legumes are exposed to natural Rlv populations present in soil. A core collection of 32 Rlv bacteria was constituted based on the genomic comparison of a collection of 121 genome sequences, representative of known worldwide diversity of Rlv. A variable part of the nodD gene sequence was used as a DNA barcode to discriminate and quantify each of the 32 bacteria in mixture. This core collection was co-inoculated on a panel of nine genetically diverse Pisum sativum, Vicia faba, and Lens culinaris genotypes. We estimated the relative Early Partner Choice (EPC) of the bacteria with the Fabeae hosts by DNA metabarcoding on the nodulated root systems. Comparative genomic analyses within the bacterial core collection identified molecular markers associated with host-dependent symbiotic partner choice. The results revealed emergent properties of rhizobial populations. They pave the way to identify genes related to important symbiotic traits operating at this level.

Abstract Background Few countries in sub-Saharan Africa know the magnitude of their HIV epidemic among people who inject drugs (PWID). This was the first study in Mozambique to measure prevalence of HIV, HBV, and HCV, and to assess demographic characteristics and risk behaviors in this key population. Methods We used respondent-driven sampling (RDS) to conduct a cross-sectional behavioral surveillance survey of PWID in two cities of Mozambique lasting six months. Participants were persons who had ever injected drugs without a prescription. Participants completed a behavioral questionnaire and provided blood specimens for HIV, hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) testing. We performed RDS-adjusted analysis in R 3.2 using RDSAT 7.1 weights. Results We enrolled 353 PWID in Maputo and 139 in Nampula/Nacala; approximately 95% of participants were men. Disease prevalence in Maputo and Nampula/Nacala, respectively, was 50.1 and 19.9% for HIV, 32.1 and 36.4% for HBsAg positivity, and 44.6 and 7.0% for anti-HCV positivity. Additionally, 8% (Maputo) and 28.6% (Nampula/Nacala) of PWID reported having a genital sore or ulcer in the 12 months preceding the survey. Among PWID who injected drugs in the last month, 50.3% (Maputo) and 49.6% (Nampula/Nacala) shared a needle at least once that month. Condomless sex in the last 12 months was reported by 52.4% of PWID in Maputo and 29.1% in Nampula/Nacala. Among PWID, 31.6% (Maputo) and 41.0% (Nampula/Nacala) had never tested for HIV. In multivariable analysis, PWID who used heroin had 4.3 (Maputo; 95% confidence interval [CI]: 1.2, 18.2) and 2.3 (Nampula/Nacala; 95% CI: 1.2, 4.9) greater odds of having HIV. Conclusion Unsafe sexual behaviors and injection practices are frequent among PWID in Mozambique, and likely contribute to the disproportionate burden of disease we found. Intensified efforts in prevention, care, and treatment specific for PWID have the potential to limit disease transmission.

Abdominal aortic aneurysm (AAA) is an important cause of death in older adults, which has no current drug therapy. Inflammation and abnormal redox status are believed to be key pathogenic mechanisms for AAA. In light of evidence correlating inflammation with aberrant fatty acid profiles, this study compared erythrocyte fatty acid content in 43 AAA patients (diameter 3.0–4.5 cm) and 52 healthy controls. In addition, the effect of omega-3 PUFA (n-3 PUFA) supplementation on erythrocyte fatty acid content was examined in a cohort of 30 AAA patients as part of a 12 week randomized placebo-controlled clinical trial. Blood analyses identified associations between AAA and decreased linoleic acid (LA), and AAA and increased Δ6-desaturase activity and biosynthesis of arachidonic acid (AA) from LA. Omega-3 PUFA supplementation (1.5 g DHA + 0.3 g EPA/day) decreased red blood cell distribution width (14.8 ± 0.4% to 13.8 ± 0.2%; P = 0.003) and levels of pro-inflammatory n-6 PUFAs (AA, 12.46 ± 0.23% to 10.14 ± 0.3%, P < 0.001; adrenic acid, 2.12 ± 0.13% to 1.23 ± 0.09%; P < 0.001). In addition, Δ-4 desaturase activity increased (DHA/docosapentaenoic acid ratio, 1.85 ± 0.14 to 3.93 ± 0.17; P < 0.001) and elongase 2/5 activity decreased (adrenic acid/AA ratio, 0.17 ± 0.01 to 0.12 ± 0.01; P < 0.01) following supplementation. The findings suggest that n-3 PUFAs improve fatty acid profiles and ameliorate factors associated with inflammation in AAA patients.

The hippocampus plays a key role for episodic memory. In addition, a small but growing number of studies has shown that it also contributes to the resolution of response conflicts. It is less clear how these two functions are related, and how they are affected by hippocampal lesions in patients with mesial temporal lobe epilepsy (MTLE). Previous studies suggested that conflict stimuli might be better remembered, but whether the hippocampus is critical for supporting this interaction between conflict processing and memory formation is unknown. Here, we tested 19 patients with MTLE due to hippocampal sclerosis and 19 matched healthy controls. Participants performed a face-word Stroop task during functional magnetic resonance imaging (fMRI) followed by a recognition task for the faces. We tested whether memory performance and activity in brain regions implicated in long-term memory were modulated by conflict during encoding, and whether this differed between MTLE patients and controls. In controls, we largely replicated previous findings of improved memory for conflict stimuli. While MTLE patients showed response time slowing during conflict trials as well, they did not exhibit a memory benefit. In controls, neural activity of conflict resolution and memory encoding interacted within a hippocampal region of interest. Here, left hippocampal recruitment was less efficient for memory performance in incongruent trials than in congruent trials, suggesting an intrahippocampal competition for limited resources. They also showed an involvement of precuneus and posterior cingulate cortex during conflict resolution. Both effects were not observed in MTLE patients, where activation of the precuneus and posterior cingulate cortex instead predicted later memory. Further research is needed to find out whether our findings reflect widespread functional reorganization of the episodic memory network due to hippocampal dysfunction.

Sleep-disordered breathing (SDB) is frequent in patients with acute stroke. Little is known, however about the evolution of SDB after stroke. Most of our knowledge stems from smaller cohort studies applying limited cardiopulmonary sleep recordings or from cross-sectional data collected in different populations. This study aims to determine prevalence, type and intra-individual evolution of SDB based on full-night polysomnography (PSG) in acute stroke and 3 months thereafter. Furthermore, we aimed to identify predictors of SDB in the acute and chronic phase and to evaluate associations between SDB and functional outcome at 3 months (M3). A total of 166 patients with acute cerebrovascular events were evaluated by full PSG at baseline and 105 again at M3. The baseline prevalence of SDB (apnoea–hypopnoea index (AHI)>5·h−1) was 80.5% and 25.4% of the patients had severe SDB (AHI>30·h−1). Obstructive sleep apnoea was more prevalent than central sleep apnoea (83.8% versus 13%). Mean±SD AHI was 21.4±17.6·h−1and decreased significantly at M3 (18±16.4·h−1; p=0.018). At M3, 91% of all patients with baseline SDB still had an AHI>5·h−1 and in 68.1% the predominant type of SDB remained unchanged (78.9% in obstructive sleep apnoea and 44.4% in central sleep apnoea). The only predictors of SDB at baseline were higher age and body mass index and in the chronic phase additionally baseline AHI. Baseline AHI was associated with functional outcome (modified Rankin score >3) at M3. The high prevalence of SDB in acute stroke, its persistence after 3 months, and the association with functional outcome supports the recommendation for a rapid SDB screening in stroke patients.

Recent evidence suggests that the human hippocampus (HC) is not only involved in the processing of motivationally relevant approach-avoidance conflicts but is also engaged in the resolution of more general response conflicts as measured in the Stroop paradigm. Here we investigated whether neural activity in the HC is necessary for successful response conflict resolution. We compared hippocampal recruitment during an auditory Stroop paradigm in 20 patients with mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis and 20 age-matched healthy controls using functional magnetic resonance imaging (fMRI). We analyzed hippocampal activation and behavioral performance in conflict trials relative to non-conflict trials. Moreover, functional connectivity (FC) analyses with left and right HCs as seeds were performed. Subjects’ regional gray matter volumes were analyzed based on high-resolution T2-weighted MRI scans. The current study replicated previous results showing increased activation in left HC during the processing of conflict trials in healthy subjects. By contrast, MTLE patients showed higher behavioral costs of response conflict resolution and reduced conflict-related HC activation. In patients with left MTLE, left HC activation was predictive of faster conflict-related response times (RTs). By contrast, right HC activation was related to RT slowing, suggestive of a maladaptive compensation attempt in MTLE patients. Our results provide evidence that left hippocampal activation is required for the successful resolution of response conflicts.

Rationale: Treatment of aphasia is still challenging for clinicians and patients. So far, there is proven evidence for “face-to-face” speech therapy. However, the digital age potentially offers new and complementary strategies that may add to treatment outcome in a cost-effective way. Neolexon® is a commercial tablet-based software for treatment of aphasia, which can be applied with the help of a therapist or as self-training by the patient.Aims and hypothesis: In the Lexi study, we aim to determine whether treatment with Neolexon® is superior to standard therapy in acute post-stroke aphasia.Sample size estimates: A sample size of 180 patients, 90 for each group, will be included with an assumed dropout rate of ~20%.Methods and design: Prospective, randomized, parallel group, open-label, blinded-endpoint clinical, and experimental controlled non-invasive trial (PROBE). Adult German native speakers with acute aphasia after stroke are included. Computer-generated, blocked, and stratified randomization by aphasia severity will assign patients to one of two groups: 4 weeks of either standard logopedic speech therapy or logopedic speech therapy with the app version of Neolexon®. Both groups will be instructed in self-training: the frequency and duration of self-training will be documented. Screening for aphasia will be performed using the Language Screening Test (LAST). The severity of aphasia in general and in subitems will be assessed using the Bielefelder Aphasie Screening (BIAS) and the Aphasia Check List (ACL). Follow-up will be assessed after 3 months.Study outcomes: Based on the consensus in our study team, we considered a 10% mean difference in the change of percentile rank (PR) of BIAS to be a minimal and clinically important difference. The primary endpoint is defined as a significant difference in BIAS comparing the two groups. Differences in quality of life, Beck Depression Inventory (BDI), and modified Ranking Scale (mRS) will be evaluated as secondary outcome parameters.Discussion: This trial will determine whether speech therapy with the use of Neolexon® is superior to standard logopedic therapy. Subgroups with the greatest response to Neolexon® will be described. The trial was prospectively registered on the “EU Clinical Trials Register” (NCT04080817)1.

Abstract Background There is a lack of robust data about factors predicting continuation (or termination) of positive airway pressure therapy (PAP) for sleep apnea. This analysis of big data from a German homecare provider describes patients treated with PAP, analyzes the therapy termination rate over the first year, and investigates predictive factors for therapy termination. Methods Data from a German homecare service provider were analyzed retrospectively. Patients who had started their first PAP therapy between September 2009 and April 2014 were eligible. Patient demographics, therapy start date, and the date of and reason for therapy termination were obtained. At 1 year, patients were classified as having compliance-related therapy termination or remaining on therapy. These groups were compared, and significant predictors of therapy termination determined. Results Of 98,329 patients included in the analysis, 11,702 (12%) terminated PAP therapy within the first year (after mean 171 ± 91 days). There was a U-shaped relationship between therapy termination and age; therapy termination was higher in the youngest (

Background/Aims: Migration of Schwann cells (SCs) progenitors and neurite outgrowth from embryonic dorsal root ganglions (DRGs) are two central events during the development of the peripheral nervous system (PNS). How these two enthralling events preceding myelination are promoted is of great relevance from basic research and clinical aspects alike. Recent evidence demonstrates that biophysical cues (extracellular matrix stiffness) and biochemical signaling act in concert to regulate PNS myelination. Microenvironment stiffness of SCs progenitors and embryonic neurites dynamically changes during development. Methods: DRG explants were isolated from day 12.5 to 13.5 mice embryos and plated on laminin-coated substrates with varied stiffness values. After 4 days in culture and immunostaining with specific markers, neurite outgrowth pattern, SCs progenitors migration, and growth cone shape and advance were analyzed with confocal fluorescence microscopy. Results: We found out that growing substrate stiffness promotes directional neurite outgrowth, SCs progenitors migration, growth cone advance and presumably axons fasciculation. Conclusions: DRG explants are in vitro models for the research of PNS development, myelination and regeneration. Consequently, we conclude the following: Our observations point out the importance of mechanosensitivity for the PNS. At the same time, they prompt the investigation of the important yet unclear links between PNS biomechanics and inherited neuropathies with myelination disorders such as Charcot-Marie-Tooth 1A and hereditary neuropathy with liability to pressure palsies. Finally, they encourage the consideration of mechanosensitivity in bioengineering of scaffolds to aid nerve regeneration after injury.

Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3′-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.

INTRODUCTION:Reproducible research is increasingly gaining interest in the research community. Automating the production of research manuscript tables from statistical software can help increase the reproducibility of findings. Logistic regression is used in studying disease prevalence and associated factors in epidemiological studies and can be easily performed using widely available software including SAS, SUDAAN, Stata or R. However, output from these software must be processed further to make it readily presentable. There exists a number of procedures developed to organize regression output, though many of them suffer limitations of flexibility, complexity, lack of validation checks for input parameters, as well as inability to incorporate survey design. METHODS:We developed a SAS macro, %svy_logistic_regression, for fitting simple and multiple logistic regression models. The macro also creates quality publication-ready tables using survey or non-survey data which aims to increase transparency of data analyses. It further significantly reduces turn-around time for conducting analysis and preparing output tables while also addressing the limitations of existing procedures. In addition, the macro allows for user-specific actions to handle missing data as well as use of replication-based variance estimation methods. RESULTS:We demonstrate the use of the macro in the analysis of the 2013-2014 National Health and Nutrition Examination Survey (NHANES), a complex survey designed to assess the health and nutritional status of adults and children in the United States. The output presented here is directly from the macro and is consistent with how regression results are often presented in the epidemiological and biomedical literature, with unadjusted and adjusted model results presented side by side. CONCLUSIONS:The SAS code presented in this macro is comprehensive, easy to follow, manipulate and to extend to other areas of interest. It can also be incorporated quickly by the statistician for immediate use. It is an especially valuable tool for generating quality, easy to review tables which can be incorporated directly in a publication.

Category: Basic Sciences/Biologics Introduction/Purpose: In biomaterial engineering, the surface of an implant can influence cell differentiation, adhesion and affinity towards the implant. On contact with an implant, bone marrow-derived mesenchymal stromal cells (BMSCs) demonstrate differentiation towards bone forming osteoblasts, which can improve osteointegration. The process of micropatterning has been shown to improve osteointegration in polymers, but there are few reports surrounding ceramics. Several implants in forefoot surgery like the Moje metatarsal phalangeal joint replacement were made from smoother ceramic zirconia toughened alumina (ZTA). The aim was to establish whether the pits were specifically bioactive towards osteogenesis or were generally bioactive and would also stimulate osteoclastogenesis that could potentially lead to osteolysis. Methods: We established a co-culture of bone marrow-derived mesenchymal stromal cells (BMSCs) with osteoclast progenitor cells and to observe the response to micropatterned ZTA ceramics with 30 µm diameter pits compared to smooth controls. Micropatterned masks were fabricated using a standard photolithography and electroplating technique. Micropatterned ceramic substrates were produced by embossing of visco-plastic green ceramic tapes at room temperature followed by sintering. After informed consent was obtained from healthy patients undergoing routine total hip arthroplasty, bone marrow was aspirated from the femoral medullary canal. At day 3, non-adherent cells were removed within the supernatant and cultured separately until a confluent BMSC layer was identified. The co-culture was maintained up to specific time points (days 3, 7, 14, 21 and 28) with thrice weekly media exchange. At each time point, duplicate samples were fixed and prepared for analysis by scanning electron microscopy (SEM) with immuofluorescence and histochemical staining, Results: SEM analysis of the patterned materials demonstrated successful micropatterning of the ZTA ceramic with approximately 30 µm diameter, 1.7 µm depth pits due to sintering shrinkage. At the longest time-point (day 28), osteoclast-like cells were visible across the planar surfaces and had strong interactions with the ceramic grains. Podosomes were notable on some of the osteoclast membranes. On the pitted surfaces, we observed significantly less osteoclast-like cells. Also, pit bridging by macrophage-like cells was regularly noted. Nodular clusters of osteoblast-like cells were noted statistically more often on the micropatterned ceramics. Conclusion: These results demonstrated specific bioactivity of micropatterned ZTA ceramics towards osteogenesis, with more bone nodule formation and less osteoclastogenesis compared to planar controls. In addition, we found that that macrophage and osteoclast-like cells did not interact with the pits and formed fewer full-size osteoclast-like cells on the pitted surfaces. This may have a role when designing ceramic orthopaedic foot implants. We are now using this co-culture for research on other micropatterned biomaterials used in foot and ankle surgery.

The vast majority of living organisms have evolved a circadian rhythm of roughly 24 h in adaptation to ever-changing environmental conditions, such as the cycle of light and darkness. In some sleep disorders like idiopathic hypersomnia (IH) this adaptation is defective. As the etiology of this disease is largely unknown, we examined the in vitro circadian period length of patients suffering from IH. The patients were diagnosed according to the ICSD3-criteria by clinical history, polysomnography (PSG), and multiple sleep latency testing (MSLT). In order to gain insight into the molecular mechanism of this sleep disorder we collected fibroblasts from skin biopsies of IH patients and healthy subjects. We determined the circadian period length of the primary fibroblast cells by lentiviral infection with a construct expressing a luciferase gene under the control of a BMAL1 promoter. The group of IH patients revealed on average a prolonged circadian period length. In comparison to the group of healthy controls (HC) the mean period length was estimated to be 0.82 h (95%-CI 0.44–1.20 h) longer in the patient group. This finding further stresses a disturbed regulation of the circadian rhythm in IH patients as part of the pathophysiology of this complex and poorly understood primary sleep disorder.

BACKGROUND:Kenya is 1 of 14 priority countries in Africa scaling up voluntary medical male circumcision (VMMC) for HIV prevention following the recommendations of the World Health Organization and the Joint United Nations Programme on HIV/AIDS. To inform VMMC target setting, we modeled the impact of circumcising specific client age groups across several Kenyan geographic areas. METHODS:The Decision Makers' Program Planning Tool, Version 2 (DMPPT 2) was applied in Kisumu, Siaya, Homa Bay, and Migori counties. Initial modeling done in mid-2016 showed coverage estimates above 100% in age groups and geographic areas where demand for VMMC continued to be high. On the basis of information obtained from country policy makers and VMMC program implementers, we adjusted circumcision coverage for duplicate reporting, county-level population estimates, migration across county boundaries for VMMC services, and replacement of traditional circumcision with circumcisions in the VMMC program. To address residual inflated coverage following these adjustments we applied county-specific correction factors computed by triangulating model results with coverage estimates from population surveys. RESULTS:A program record review identified duplicate reporting in Homa Bay, Kisumu, and Siaya. Using county population estimates from the Kenya National Bureau of Statistics, we found that adjusting for migration and correcting for replacement of traditional circumcision with VMMC led to lower estimates of 2016 male circumcision coverage especially for Kisumu, Migori, and Siaya. Even after addressing these issues, overestimation of 2016 male circumcision coverage persisted, especially in Homa Bay. We estimated male circumcision coverage in 2016 by applying correction factors. Modeled estimates for 2016 circumcision coverage for the 10- to 14-year age group ranged from 50% in Homa Bay to approximately 90% in Kisumu. Results for the 15- to 19-year age group suggest almost complete coverage in Kisumu, Migori, and Siaya. Coverage for the 20- to 24-year age group ranged from about 80% in Siaya to about 90% in Homa Bay, coverage for those aged 25-29 years ranged from about 60% in Siaya to 80% in Migori, and coverage in those aged 30-34 years ranged from about 50% in Siaya to about 70% in Migori. CONCLUSIONS:Our analysis points to solutions for some of the data issues encountered in Kenya. Kenya is the first country in which these data issues have been encountered because baseline circumcision rates were high. We anticipate that some of the modeling methods we developed for Kenya will be applicable in other countries.

The presence of bones around the central nervous system (CNS) provides it with highly effective physiologically crucial mechanical protection. The peripheral nervous system (PNS), in contrast, lacks this barrier. Consequently, the long held belief is that the PNS is mechanically vulnerable. On the other hand, the PNS is exposed to a variety of physiological mechanical stresses during regular daily activities. This fact prompts us to question the dogma of PNS mechanical vulnerability. As a matter of fact, impaired mechanics of PNS nerves is associated with neuropathies with the liability to mechanical stresses paralleled by significant impairment of PNS physiological functions. Our recent biomechanical integrity investigations on nerve fibers from wild-type and neuropathic mice lend strong support in favor of natural mechanical protection of the PNS and demonstrate a key role of Schwann cells (SCs) therein. Moreover, recent works point out that SCs can sense mechanical properties of their microenvironment and the evidence is growing that SCs mechanosensitivity is important for PNS development and myelination. Hence, SCs exhibit mechanical strength necessary for PNS mechanoprotection as well as mechanosensitivity necessary for PNS development and myelination. This mini review reflects on the intriguing dual ability of SCs and implications for PNS physiology and pathophysiology.

The links between neuropathies of the peripheral nervous system (PNS), including Charcot-Marie-Tooth1A and hereditary neuropathy with liability to pressure palsies, and impaired biomechanical and structural integrity of PNS nerves remain poorly understood despite the medical urgency. Here, we present a protocol describing simultaneous structural and biomechanical integrity investigations on isolated nerve fibers, the building blocks of nerves. Nerve fibers are prepared from nerves harvested from wild-type and exemplary PNS neuropathy mouse models. The basic principle of the designed experimental approach is based on the simultaneous combination of atomic force microscopy (AFM) and confocal microscopy. AFM is used to visualize the surface structure of nerve fibers at nano-scale resolution. The simultaneous combination of AFM and confocal microscopy is used to perform biomechanical, structural, and functional integrity measurements at nano- to micro-scale. Isolation of sciatic nerves and subsequent teasing of nerve fibers take ~45 min. Teased fibers can be maintained at 37°C in a culture medium and kept viable for up to 6 h allowing considerable time for all measurements which require 3–4 h. The approach is designed to be widely applicable for nerve fibers from mice of any PNS neuropathy. It can be extended to human nerve biopsies.

Chromatin regulation is driven by multicomponent protein complexes, which form functional modules. Deciphering the components of these modules and their interactions is central to understanding the molecular pathways these proteins are regulating, their functions, and their relation to both normal development and disease. We describe the use of affinity purifications of tagged human proteins coupled with mass spectrometry to generate a protein-protein interaction map encompassing known and predicted chromatin-related proteins. On the basis of 1,394 successful purifications of 293 proteins, we report a high-confidence (85% precision) network involving 11,464 protein-protein interactions among 1,738 different human proteins, grouped into 164 often overlapping protein complexes with a particular focus on the family of JmjC-containing lysine demethylases, their partners, and their roles in chromatin remodeling. We show that RCCD1 is a partner of histone H3K36 demethylase KDM8 and demonstrate that both are important for cell-cycle-regulated transcriptional repression in centromeric regions and accurate mitotic division.

Sleep related breathing disorders (SRBD) are common in patients with ischemic stroke and are associated with poor outcome. SRBD after stroke were assumed to be a direct consequence of injury of specific central nervous system structures. However, whether specific locations of ischemic infarcts cause SRBD is yet unknown. We therefore investigated the association of ischemic lesion location with SRBD.Patients with acute ischemic stroke treated on our stroke unit were included in a prospective observational study. All patients underwent magnetic resonance imaging (MRI) and polygraphy in the acute phase after stroke. SRBD was defined by an apnea-hypopnea index (AHI) ≥10. MRI were evaluated using standardized maps to depict voxel-wise probability distribution of infarction for patients with and without SRBD. Groups were compared using logistic regression analysis.Of 142 patients included, 86 (59%) had a SRBD. Age, body mass index and prevalence of arterial hypertension were significantly higher in patients with SRBD. There was no statistically significant association between any lesion location and SRBD.We found no association of lesion location and SRBD in stroke patients, whereas established risk factors for SRBD, known from general population, were significantly associated with SRBD. Given the high prevalence of SRBD in stroke patients, these findings suggest that cerebral ischemia facilitates the occurrence of SRBD in patients with pre-existing risk factors rather than causing it by damaging specific central nervous system structures. Our findings can be used to identify stroke patients who might benefit from polygraphy screening.

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O2 desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common symptoms of FD (angiokeratomas 61%; acroparaesthesia 51%; renal involvement 29%; cardiac involvement 27%), and the prevalence of chronic fatigue (48%). EDS was independently associated with the physical component summary of the SF-36 data (corrected R2 =–0.323, p 2 = –0.253, p < 0.001). We conclude that EDS is a common and underdiagnosed symptom in FD patients, accompanied by a significant impact on quality of life. EDS might be caused by central breathing disorders due to an affection of brain regions associated with respiratory control in FD.

From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN) controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH) in comparison to those of healthy controls (HC). Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG) and Multiple Sleep Latency Test (MSLT). Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH.

BACKGROUND: Experimental stress has been shown to have analgesic as well as allodynic effect in animals. Despite the obvious negative influence of stress in clinical pain conditions, stress-induced alteration of pain sensitivity has not been tested in humans so far. Therefore, we tested changes of pain sensitivity using an experimental stressor in ten female healthy subjects and 13 female patients with fibromyalgia. METHODS: Multiple sensory aspects of pain were evaluated in all participants with the help of the quantitative sensory testing protocol before (60 min) and after (10 and 90 min) inducing psychological stress with a standardized psychosocial stress test ("Trier Social Stress Test"). RESULTS: Both healthy subjects and patients with fibromyalgia showed stress-induced enhancement of pain sensitivity in response to thermal stimuli. However, only patients showed increased sensitivity in response to pressure pain. CONCLUSIONS: Our results provide evidence for stress-induced allodynia/hyperalgesia in humans for the first time and suggest differential underlying mechanisms determining response to stressors in healthy subjects and patients suffering from chronic pain. Possible mechanisms of the interplay of stress and mediating factors (e.g. cytokines, cortisol) on pain sensitivity are mentioned. Future studies should help understand better how stress impacts on chronic pain conditions.

BACKGROUND: The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea. PATIENTS AND METHODS: Genetically proven FD patients (n = 23) and age-matched healthy controls (n = 44) underwent a cardio-respiratory polysomnography and brain MRI at 3.0 Tesla. We applied different MR-imaging techniques, ranging from semiquantitative measurement of white matter lesion (WML) volumes and automated calculation of brain tissue volumes to VBM of gray matter and voxel-based diffusion tensor imaging (DTI) analysis. RESULTS: In 5 of 23 Fabry patients (22%) CSA-CSR was detected. Voxel-based DTI analysis revealed widespread structural changes in FD patients when compared to the healthy controls. When calculated as a separate group, DTI changes of CSA-CSR patients were most prominent in the brainstem. Voxel-based regression analysis revealed a significant association between CSR severity and microstructural DTI changes within the brainstem. CONCLUSION: Subtle microstructural changes in the brainstem might be a neuroanatomical correlate of CSA-CSR in patients at risk of WML. DTI is more sensitive and specific than conventional structural MRI and other advanced MR analyses tools in demonstrating these abnormalities.

There is increasing evidence that many solid tumors are hierarchically organized with the bulk tumor cells having limited replication potential, but are sustained by a stem-like cell that perpetuates the tumor. These cancer stem cells have been hypothesized to originate from transformation of adult tissue stem cells, or through re-acquisition of stem-like properties by progenitor cells. Adenosquamous carcinoma (ASC) is an aggressive type of lung cancer that contains a mixture of cells with squamous (cytokeratin 5+) and adenocarcinoma (cytokeratin 7+) phenotypes. The origin of these mixtures is unclear as squamous carcinomas are thought to arise from basal cells in the upper respiratory tract while adenocarcinomas are believed to form from stem cells in the bronchial alveolar junction. We have isolated and characterized cancer stem-like populations from ASC through application of selective defined culture medium initially used to grow human lung stem cells. Homogeneous cells selected from ASC tumor specimens were stably expanded in vitro. Primary xenografts and metastatic lesions derived from these cells in NSG mice fully recapitulate both the adenocarcinoma and squamous features of the patient tumor. Interestingly, while the CSLC all co-expressed cytokeratins 5 and 7, most xenograft cells expressed either one, or neither, with

In Mozambique, highly active antiretroviral treatment (HAART) was introduced in 2004 followed by decentralization and expansion, resulting in a more than 20-fold increase in coverage by 2009. Implementation of HIV drug resistance threshold surveys (HIVDR-TS) is crucial in order to monitor the emergence of transmitted viral resistance, and to produce evidence-based recommendations to support antiretroviral (ARV) policy in Mozambique.World Health Organization (WHO) methodology was used to evaluate transmitted drug resistance (TDR) in newly diagnosed HIV-1 infected pregnant women attending ante-natal clinics in Maputo and Beira to non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI). Subtypes were assigned using REGA HIV-1 subtyping tool and phylogenetic trees constructed using MEGA version 5.Although mutations associated with resistance to all three drug were detected in these surveys, transmitted resistance was analyzed and classified as

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of -27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P < 5 × 10(-8)) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3 × 10(-8)). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies.

Expression and transport activity of Sodium-dependent Vitamin C Transporter 2 (SVCT2) was shown in various tissues and organs. Vitamin C was shown to be cerebroprotective in several animal models of stroke. Data on expression, localization and transport activity of SVCT2 after cerebral ischemia, however, has been scarce so far. Thus, we studied the expression of SVCT2 after middle cerebral artery occlusion (MCAO) in mice by immunohistochemistry. We found an upregulation of SVCT2 after stroke. Co-stainings with Occludin, Von-Willebrand Factor and CD34 demonstrated localization of SVCT2 in brain capillary endothelial cells in the ischemic area after stroke. Time-course analyses of SVCT2 expression by immunohistochemistry and western blots showed upregulation in the subacute phase of 2-5 days. Radioactive uptake assays using (14)C-labelled ascorbic acid showed a significant increase of ascorbic acid uptake into the brain after stroke. Taken together, these results provide evidence for the expression and transport activity of SVCT2 in brain capillary endothelial cells after transient ischemia in mice. These results may lead to the development of novel neuroprotective strategies in stroke therapy.