The Breadth, but Not the Magnitude, of Circulating Memory B Cell Responses to P. falciparum Increases with Age/Exposure in an Area of Low Transmission

BACKGROUND: Malaria caused by Plasmodium falciparum remains a major cause of death in sub-Saharan Africa. Immunity against symptoms of malaria requires repeated exposure, suggesting either that the parasite is poorly immunogenic or that the development of effective immune responses to malaria may be impaired. METHODS: We carried out two age-stratified cross-sectional surveys of anti-malarial humoral immune responses in a Gambian village where P. falciparum malaria transmission is low and sporadic. Circulating antibodies and memory B cells (MBC) to four malarial antigens were measured using ELISA and cultured B cell ELISpot. FINDINGS AND CONCLUSIONS: The proportion of individuals with malaria-specific MBC and antibodies, and the average number of antigens recognised by each individual, increased with age but the magnitude of these responses did not. Malaria-specific antibody levels did not correlate with either the prevalence or median number of MBC, indicating that these two assays are measuring different aspects of the humoral immune response. Among those with immunological evidence of malaria exposure (defined as a positive response to at least one malarial antigen either by ELISA or ELISPOT), the median number of malaria-specific MBC was similar to median numbers of diphtheria-specific MBC, suggesting that the circulating memory cell pool for malaria antigens is of similar size to that for other antigens

Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.</p

Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461

The deoxycytidine analog KP1212, and its prodrug KP1461, are prototypes of a new class of antiretroviral drugs designed to increase viral mutation rates, with the goal of eventually causing the collapse of the viral population. Here we present an extensive analysis of viral sequences from HIV-1 infected volunteers from the first “mechanism validation” phase II clinical trial of a mutagenic base analog in which individuals previously treated with antiviral drugs received 1600 mg of KP1461 twice per day for 124 days. Plasma viral loads were not reduced, and overall levels of viral mutation were not increased during this short-term study, however, the mutation spectrum of HIV was altered. A large number (N = 105 per sample) of sequences were analyzed, each derived from individual HIV-1 RNA templates, after 0, 56 and 124 days of therapy from 10 treated and 10 untreated control individuals (>7.1 million base pairs of unique viral templates were sequenced). We found that private mutations, those not found in more than one viral sequence and likely to have occurred in the most recent rounds of replication, increased in treated individuals relative to controls after 56 (p = 0.038) and 124 (p = 0.002) days of drug treatment. The spectrum of mutations observed in the treated group showed an excess of A to G and G to A mutations (p = 0.01), and to a lesser extent T to C and C to T mutations (p = 0.09), as predicted by the mechanism of action of the drug. These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach.Koronis Pharmaceutical

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Pervasive Service Platform (PSP): Facilitating Pervasive Services

Pervasive computing is a new and emerging technology. The concept of pervasiveness and its deployment into reality are still not well aligned. This is because the vision of pervasiveness is a highly complex area that encompasses a large number of issues. The real vision of pervasiveness will never become a reality if everyone involved needs to repeatedly address all the issues involved in the concept. This paper focuses on the DAIDALOS Pervasive Service Platform (PSP) as an enabler of pervasive services. DAIDALOS is an EU Framework Programme 6 Integrated Project with 46 multinational partners from both the industry and academia. The paper details the strategy employed in DAIDALOS to facilitate Service Providers to offer pervasive services on top of the PSP. It argues that pervasiveness should be provided to Service Providers as part of the platform, instead of requiring pervasiveness to be totally embedded in the services themselves. This approach consequently opens up the service provision market to more players, driving the idea of a truly pervasive world. The paper gives an overview of the DAIDALOS platform as a pervasive service enabler, detailing how it facilitates pervasiveness by removing most of the work from the Service Providers themselves

Onset detection in surface electromyographic signals across isometric explosive and ramped contractions: a comparison of computer-based methods

Objective. Accurate identification of surface electromyography (EMG) muscle onset is vital when examining short temporal parameters such as electromechanical delay. The visual method is considered the ‘gold standard’ in onset detection. Automatic detection methods are commonly employed to increase objectivity and reduce analysis time, but it is unclear if they are sensitive enough to accurately detect EMG onset when relating them to short-duration motor events. Approach. This study aimed to determine: (1)if automatic detection methods could be used interchangeably with visual methods in detecting EMG onsets(2)if the Teager–Kaiser energy operator(TKEO) as a conditioning step would improve the accuracy of popular EMG onset detection methods. The accuracy of three automatic onset detection methods: approximated generalized likelihood ratio (AGLR), TKEO, and threshold-based method were examined against the visual method. EMG signals from fast, explosive, and slow, ramped isometric plantarflexor contractions were evaluated using each technique. Main results. For fast, explosive contractions, the TKEO was the best-performing automatic detection method, with a low bias level(4.7 ± 5.6 ms) and excellent intraclass correlation coefficient (ICC) of 0.993, however with wide limits of agreement (LoA) (−6.2 to +15.7 ms). For slow, ramped contractions, the AGLR with TKEO conditioning was the best-performing automatic detection method with the smallest bias(11.3 ± 32.9 ms) and excellent ICC(0.983) but produced wide LoA (−53.2 to +75.8 ms). For visual detection, the inclusion of TKEO conditioning improved inter-rater and intra-rater reliability across contraction types compared with visual detection without TKEO conditioning. Significance. In conclusion, the examined automatic detection methods are not sensitive enough to be applied when relating EMG onset to a motor event of short duration. To attain the accuracy needed, visual detection is recommended. The inclusion of TKEO as a conditioning step before visual detection of EMG onsets is recommended to improve visual detection reliability

Plantarflexor electromechanical delay: influence of contraction type and muscle-tendon unit length

Electromechanical delay (EMD) is an important determinant of explosive neuromuscular performance. Factors such as muscle contraction type and initial muscle-tendon unit (MTU) length influence this delay period. The aim of this study is to compare differences in EMD from plantar flexors across different contraction modes and MTU lengths. EMD of physically-active individuals (n = 14) was assessed during a series of twitch and explosive isometric plantarflexions across different MTU lengths. For involuntary and voluntary explosive conditions, EMD tended to decrease while the MTU length increased from plantarflexion to neutral/dorsiflexion. No significant differences in EMD were observed between neutral and dorsiflexion MTU lengths. These results have implications for sporting performance where the ability to rapidly produce muscular force is crucial

Electronic cigarettes induce DNA strand breaks and cell death independently of nicotine in cell lines

ObjectivesEvaluate the cytotoxicity and genotoxicity of short- and long-term e-cigarette vapor exposure on a panel of normal epithelial and head and neck squamous cell carcinoma (HNSCC) cell lines.Materials and methodsHaCaT, UMSCC10B, and HN30 were treated with nicotine-containing and nicotine-free vapor extract from two popular e-cigarette brands for periods ranging from 48 h to 8 weeks. Cytotoxicity was assessed using Annexin V flow cytometric analysis, trypan blue exclusion, and clonogenic assays. Genotoxicity in the form of DNA strand breaks was quantified using the neutral comet assay and γ-H2AX immunostaining.ResultsE-cigarette-exposed cells showed significantly reduced cell viability and clonogenic survival, along with increased rates of apoptosis and necrosis, regardless of e-cigarette vapor nicotine content. They also exhibited significantly increased comet tail length and accumulation of γ-H2AX foci, demonstrating increased DNA strand breaks.ConclusionE-cigarette vapor, both with and without nicotine, is cytotoxic to epithelial cell lines and is a DNA strand break-inducing agent. Further assessment of the potential carcinogenic effects of e-cigarette vapor is urgently needed

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease