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Background: Nearly one-half of patients admitted with acute decompensated heart failure (ADHF) are discharged with unresolved congestion, elevating rehospitalization risk. This may be due to suboptimal intravenous (IV) loop diuretic dosing, which may be influenced by home oral diuretic dose. Objectives: The objective of this study was to determine the association between: 1) home oral loop diuretic dose and optimal initial IV loop diuretic dosing in ADHF; and 2)receiving optimal initial IV loop diuretic dosing and length of stay and 30-day readmission. Methods: Retrospective analysis of adults admitted to a large U.S. hospital for ADHF on home oral loop diuretics from 1 January 2014 to 21 December 2021. Patients were categorized by home dose: low (≤40 mg furosemide equivalents), medium (>40-80 mg furosemide equivalents), and high (>80 mg furosemide equivalents). Optimal initial IV dosing was considered ≥2 times home oral dosing. Poisson regression models estimated prevalence ratios (CIs) for optimal initial IV loop diuretic dosing. Results: Among 3,269 adults admitted for ADHF (mean age 63 years, 62% male), optimal initial IV dosing occurred in 2,218 (67.9%). The prevalence of optimal initial IV dosing among low, medium, and high home dosing was 95.5%, 59.9%, and 4.0%, respectively. Adjusted prevalence ratios for optimal IV dosing with high and medium home dosing, compared to low, were 0.05 (95% CI: 0.03-0.07) and 0.66 (95% CI: 0.62-0.70), respectively. There was no difference in length of stay or 30-day readmission between optimal and suboptimal initial IV diuretic dosing. Conclusions: Among patients with ADHF, higher home loop diuretic dose was strongly associated with a substantially lower likelihood of optimal initial IV diuretic dosing.

Novel metal ceramic multilayer composites with the ability to phase transform into a single phase ultra-high temperature ceramic are described. These materials offer enhanced low-temperature fracture toughness and reliability without sacrificing high-temperature mechanical properties by eliminating the metal reinforcement layers upon reaching temperatures sufficient for the activation of carbon diffusion. At low temperatures, these materials are practically indefinitely stable because of the high activation energy for carbon diffusion in the carbide layers that control the phase transformation kinetics. Here, knowledge of the overall thermodynamics, i.e., carbon content, is combined with prediction of phase transformation kinetics and toughening in the limit of small-scale yielding to characterize the design space of these novel composites. It is proposed that the ability to control thermodynamic and mechanical properties of the post-transformation ceramic via selection of metal-to-ceramic layer ratios makes these novel composites an excellent alternative to current methods for reinforcement of ultra-high temperature ceramics.

Summary: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016–2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92–5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07–7.59), Group A streptococcus (OR 2.73, 95% CI 1.13–6.09) and E. coli (OR 2.7, 95% CI 1.02–6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11–0.46), influenza B (OR 0.12, 95% CI 0.02–0.37) and RSV (OR 0.16, 95% CI: 0.06–0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23–0.72) and EBV (OR 0.71, 95% CI 0.56–0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

Summary: Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection.

Introduction: Evidence-based smoking cessation interventions are underused settings where behavioral health treatment is provided, contributing to smoking-related health disparities in this patient group. This study assessed the relationship of provider’s beliefs about patients’ smoking, perceptions of treatment capability, and knowledge of referral options and their use of the 5A’s (Ask, Advise, Assess, Assist, and Arrange) intervention for smoking cessation. Methods: Surveys were collected from providers in healthcare settings in Texas where patients receive behavioral health care (N = 86; 9 federally qualified health centers, 16 Local Mental Health Authorities (LMHAs), 6 substance use treatment programs in LMHAs, and 55 stand-alone substance use treatment centers). Logistic regression analyses were used to assess the association between provider’s beliefs about patients’ concern and desire to quit smoking; perceptions of their confidence, skills, and effectiveness in treating smoking; their knowledge of referral options; and their use of the 5A’s with patients who smoked. Results: Providers who believed that patients were concerned about smoking and wanted to quit; who perceived themselves as confident in providing cessation care, having the required skills, and being effective in providing advice; and/or who had greater referral knowledge were more likely to use the 5A’s with patients who smoked than their (respective) provider counterparts (ps

The kinetics of the carbon-diffusion-controlled Me/MeC phase transformation in transition metal carbide metal ceramic multilayer composites were investigated using mesoscale and continuum level modeling. To track the metal-ceramic interface the phase transformation was modeled as a Stephan problem wherein the interface was treated as a moving boundary controlled by the bulk and interfacial diffusion of carbon. Simulations were allowed to continue until the disappearance of the metal layers whereupon an effective diffusivity relating the bilayer width, transformation time, and temperature was calculated. The effective diffusivity data was subsequently used to develop a coarse-grained model capable of predicting phase transformation characteristics and providing valuable insight into the parameters that control the phase transformation.

Summary: Low monocyte (m)HLA-DR expression is associated with mortality in sepsis. G-286A∗rs3087456 polymorphism in promoter III of HLA class II transactivator (CIITA), the master regulator of HLA, has been associated with autoimmune diseases but its role in sepsis has never been demonstrated. In 203 patients in septic shock, GG genotype was associated with 28-day mortality and mHLA-DR remained low whereas it increased in patients with AA or AG genotype. In ex vivo cells, mHLA-DR failed to augment in GG in comparison with AG or AA genotype on exposure to IFN-γ. Promoter III transcript levels were similar in control monocytes regardless of genotype and exposure to IFN-γ. Promoter III activity was decreased in GG genotype in monocyte cell line but restored after stimulation with IFN-γ. Hereby, we demonstrated that G-286A∗rs3087456 significantly impact mHLA-DR expression in patients with septic shock in part through CIITA promoter III activity, that can be rescued using IFN-γ.

Summary: Background: In Nepal, Streptococcus pneumoniae (pneumococcus) is a common cause of bacterial pneumonia in children, and is a major health concern. There are few data on the effect of vaccination on the disease or colonisation with pneumococci in the nasopharynx of children in this setting. The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine infant immunisation schedule in Nepal in 2015. We aimed to investigate the effect of the introduction of PCV10 on pneumococcal carriage and disease in children in Nepal. Methods: We did an observational cohort study in children in Nepal. The hospital surveillance study took place in Patan Hospital, Kathmandu, and community studies in healthy children took place in Kathmandu and Okhaldhunga district. For the surveillance study, all children admitted to Patan Hospital between March 20, 2014, and Dec 31, 2019, aged between 2 months and 14 years with clinician-suspected pneumonia, were eligible for enrolment. For the community study, healthy children aged 0–8 weeks, 6–23 months, and 24–59 months were recruited from Kathmandu, and healthy children aged 6–23 months were recruited from Okhaldhunga. We assessed the programmatic effect of PCV10 introduction using surveillance for nasopharyngeal colonisation, pneumonia, and invasive bacterial disease from 1·5 years before vaccine introduction and 4·5 years after vaccine introduction. For the surveillance study, nasopharyngeal swabs, blood cultures, and chest radiographs were obtained from children admitted to Patan Hospital with suspected pneumonia or invasive bacterial disease. For the community study, nasopharyngeal swabs were obtained from healthy children in the urban and rural settings. Pneumonia outcomes were analysed using log-binomial models and adjusted prevalence ratios (aPR) comparing each calendar year after the introduction of the vaccine into the national programme with the pre-vaccine period (2014–15), adjusted for calendar month, age, and sex. Findings: Between March 20, 2014, and Dec 31, 2019, we enrolled 2051 children with suspected pneumonia, and 11 354 healthy children (8483 children aged 6–23 months, 761 aged 24–59 months, and 2110 aged 0–8 weeks) to assess nasopharyngeal colonisation. Among clinical pneumonia cases younger than 2 years, vaccine serotype carriage declined 82% (aPR 0·18 [95% CI 0·07–0·50]) by 2019. There was no decrease in vaccine serotype carriage in cases among older unvaccinated age groups. Carriage of the additional serotypes in PCV13 was 2·2 times higher by 2019 (aPR 2·17 [95% CI 1·16–4·05]), due to increases in serotypes 19A and 3. Vaccine serotype carriage in healthy children declined by 75% in those aged 6–23 months (aPR 0·25 [95% CI 0·19–0·33]) but not in those aged 24–59 months (aPR 0·59 [0·29–1·19]). A decrease in overall vaccine serotype carriage of 61% by 2019 (aPR 0·39 [95% CI 0·18–0·85]) was also observed in children younger than 8 weeks who were not yet immunised. Carriage of the additional PCV13 serotypes in children aged 6–23 months increased after PCV10 introduction for serotype 3 and 19A, but not for serotype 6A. The proportion of clinical pneumonia cases with endpoint consolidation on chest radiographs declined from 41% in the pre-vaccine period to 25% by 2018, but rose again in 2019 to 36%. Interpretation: The introduction of the PCV10 vaccine into the routine immunisation programme in Nepal has reduced vaccine serotype carriage in both healthy children and children younger than 2 years with pneumonia. Increases in serotypes 19A and 3 highlight the importance of continued surveillance to monitor the effect of vaccine programmes. This analysis demonstrates a robust approach to assessing vaccine effect in situations in which pneumococcal disease endpoint effectiveness studies are not possible. Funding: Gavi, the Vaccine Alliance and the World Health Organization.

The fine structure of the IsoVector Giant Dipole Resonance (IVGDR) in the doubly-magic nuclei 40,48Ca observed in inelastic proton scattering experiments under 0∘ is used to investigate the role of different mechanisms contributing to the IVGDR decay width. Characteristic energy scales are extracted from the fine structure by means of wavelet analysis. The experimental scales are compared to different theoretical approaches allowing for the inclusion of complex configurations beyond the mean-field level. Calculations are performed in the framework of RPA and beyond-RPA in a relativistic approach based on an effective meson-exchange interaction, with the UCOM effective interaction and, for the first time, with realistic two- plus three-nucleon interactions from chiral effective field theory employing the in-medium similarity renormalization group. All models highlight the role of Landau fragmentation for the damping of the IVGDR, while the differences in the coupling strength between one particle-one hole (1p-1h) and two particle-two hole (2p-2h) correlated (relativistic) and non-correlated (non-relativistic) configurations lead to very different pictures of the importance of the spreading width resulting in wavelet scales being a sensitive measure of their interplay. The relativistic approach with particle-vibration coupling, in particular, shows impressive agreement with the number and absolute values of the scales extracted from the experimental data.

Abstract Background Branch pulmonary artery (PA) stenosis (PAS) commonly occurs in patients with congenital heart disease (CHD). Prior studies have documented technical success and clinical outcomes of PA stent interventions for PAS but the impact of PA stent interventions on ventricular function is unknown. The objective of this study was to utilize 4D flow cardiovascular magnetic resonance (CMR) to better understand the impact of PAS and PA stenting on ventricular contraction and ventricular flow in a swine model of unilateral branch PA stenosis. Methods 18 swine (4 sham, 4 untreated left PAS, 10 PAS stent intervention) underwent right heart catheterization and CMR at 20 weeks age (55 kg). CMR included ventricular strain analysis and 4D flow CMR. Results 4D flow CMR measured inefficient right ventricular (RV) and left ventricular (LV) flow patterns in the PAS group (RV non-dimensional (n.d.) vorticity: sham 82 ± 47, PAS 120 ± 47; LV n.d. vorticity: sham 57 ± 5, PAS 78 ± 15 p

Neurological symptoms following cerebellar stroke can range from motor to cognitive-affective impairments. Topographic imaging studies from patients with lesions confined to the cerebellum have shown evidence linking anterior cerebellar lobules with motor function and posterior lobules with cognitive function. Damage to the cerebellum can disrupt functional connectivity in cerebellar stroke patients, as it is highly interconnected with forebrain motor and cognitive areas. The hippocampus plays a key role in memory acquisition, a cognitive domain that is negatively impacted by posterior cerebellar stroke, and there is increasing evidence that the cerebellum can affect hippocampal function in health and disease. To study these topographical dissociations, we developed a mouse photo-thrombosis model to produce unilateral strokes in anterior (lobules III-V) or posterior (lobules VI-VIII) cerebellar cortex to examine hippocampal plasticity and behavior. Histological and MRI data demonstrate reproducible injury that is confined to the targeted lobules. We then measured hippocampal long-term potentiation (LTP) ex-vivo with extracellular field recording experiments in acute brain slices obtained from mice 7 days post-cerebellar stroke. Interestingly, we found that a unilateral posterior stroke resulted in a contralateral hippocampal impairment, matching the cerebellothalamic pathway trajectory, while LTP was intact in both hippocampi of mice with anterior strokes. We also assessed motor coordination and memory function at 7 days post-stroke using a balance beam, contextual and delay fear conditioning (CFC and DFC), and novel object recognition (NOR) tasks. Mice with anterior strokes showed lack of coordination evaluated as an increased number of missteps, while mice with posterior strokes did not. Mice with anterior or posterior cerebellar strokes demonstrated similar freezing behavior to shams in CFC and DFC, while only posterior stroke mice displayed a reduced discrimination index in the NOR task. These data suggest that a unilateral LTP impairment observed in mice with posterior strokes produces a mild memory impairment. Our results demonstrate that our model recapitulates aspects of clinical lesion-symptom mapping, with anterior cerebellar strokes producing impaired motor coordination and posterior cerebellar strokes producing an object-recognition memory impairment. Further studies are warranted to interrogate other motor and cognitive-affective behaviors and brain region specific alterations following focal cerebellar stroke. The novel model presented herein will allow for future preclinical translational studies to improve neurological deficits after cerebellar stroke.

Summary: X chromosome inactivation (XCI) is mediated by the non-coding RNA Xist, which directs chromatin modification and gene silencing in cis. The RNA binding protein SPEN and associated corepressors have a central role in Xist-mediated gene silencing. Other silencing factors, notably the Polycomb system, have been reported to function downstream of SPEN. In recent work, we found that SPEN has an additional role in correct localization of Xist RNA in cis, indicating that its contribution to chromatin-mediated gene silencing needs to be reappraised. Making use of a SPEN separation-of-function mutation, we show that SPEN and Polycomb pathways, in fact, function in parallel to establish gene silencing. We also find that differentiation-dependent recruitment of the chromosomal protein SmcHD1 is required for silencing many X-linked genes. Our results provide important insights into the mechanism of X inactivation and the coordination of chromatin-based gene regulation with cellular differentiation and development.

Purpose: Alloplastic joint replacement is the mainstay treatment for end-stage temporomandibular joint (TMJ) disease. The aim of this study is to evaluate the 2 year quality of life (QoL) outcomes for patients who have undergone alloplastic TMJ total joint replacement with either custom or stock devices. Methods: This was a retrospective cohort study of patients who had TMJ replacement with either Biomet stock or OMX custom prostheses. All patients were recruited from the patient database of a single surgeon, at a single location. QoL was assessed using a patient completed TMJ Surgery specific QoL (TMJ-S-QoL) questionnaire. Patients answered questions pertaining to pain, diet, speech and aspects related to social and mental health. Results: A 2 year follow up was completed by 26 Biomet and 40 OMX patients. Survey results demonstrated that 84.6% (N = 22) of Biomet stock and 92.5% (N = 37) of OMX custom prosthesis patients derived significant QoL benefits from their surgery. There was no difference in QoL between the two groups (p > 0.4). Conclusion: This study shows that TMJ total joint replacements provide an improved quality of life for patients with end-stage TMJ disease regardless of whether the prosthesis is stock or individually custom made.

Infection with Legionella spp. (legionellosis) causes two distinct clinical presentations: Legionnaires’ Disease and Pontiac Fever. Legionnaire’s Disease primarily involves the lungs, often with accompanying gastrointestinal symptoms, and can also affect the liver, central nervous system, and kidneys, and cause metabolic derangements. Manifestations in the integumentary system are rare; to date, there have been eleven cases reported in the literature of Legionellosis with associated rash, with varied presentation. The relationship between Legionella pneumophila and the skin has not yet been clearly defined; immunological and/or toxic pathogenesis are possible. We report a case of Legionnaires’ Disease in a young immunocompromised man with a largely benign clinical course consisting of predominantly gastrointestinal symptoms and an extensive maculopapular rash. Chest radiography showed lobar infiltrate in the absence of clinical symptoms of pneumonia. The importance of this case is for clinicians to maintain high clinical suspicion for Legionella when extra-pulmonary symptoms predominate, specifically in immunocompromised hosts who may have atypical presentations and have higher mortality rates when treatment is delayed.

Background: Postmenopausal women exhibit higher rates of disability and cardiovascular disease (CVD) with aging compared to men. Whereas habitual exercise training is a known strategy to enhance physiologic function in men and premenopausal women, exercise-related adaptations are often modest in postmenopausal women. We propose dietary nitrate (beetroot juice) administered prior to exercise training may be a feasible approach to improve mobility and cardio-metabolic health outcomes in postmenopausal women. Methods: Our randomized, placebo-controlled study aims to determine preliminary effects sizes for changes in functional mobility and endothelium-dependent vasodilation across three study arms: exercise only (EX), exercise + placebo (EX + PL), and exercise + beetroot (EX + BR). Thirty-six postmenopausal women are recruited in small cohorts wherein group exercise is implemented to facilitate social support and adherence to an 8-week training progression. Participants are randomized to one of three study arms (n = 12 per group) following baseline assessments. Post-intervention assessments are used to determine pre-post changes in outcome measures including distance covered during a 6 min walk test, walking economy, muscle speed and power, and endothelial-dependent vasodilation as determined by flow-mediated dilation. Measures of feasibility include recruitment, retention, adherence to exercise prescription, perceived exercise session difficulty, and adverse event rates. Discussion: Evidence-based, translational strategies are needed to optimize exercise training-related adaptations in postmenopausal women. Findings will inform larger randomized clinical trials to determine if pre-exercise consumption of beetroot juice is an efficacious strategy to promote mobility and attenuate CVD disease risk.

The data supplied in this work are related to the research article entitled “Characterization of Bispecific and Mispaired IgGs by Native Charge-Variant Mass Spectrometry” (Phung et al., 2019). This data article describes a powerful analytical platform using native weak cation exchange chromatography coupled to a high-resolution mass spectrometer, charge variant mass spectrometry (CV-MS), to characterize bispecific and mispaired antibody species. Elution order is investigated through analytical methods and molecular modeling in an effort to understand the intrinsic charge, size and shape differences of these molecules.

Summary: A novel myosin heavy chain 7 mutation (E848G) identified in a familial cardiomyopathy was studied in patient-specific induced pluripotent stem cell–derived cardiomyocytes. The cardiomyopathic human induced pluripotent stem cell–derived cardiomyocytes exhibited reduced contractile function as single cells and engineered heart tissues, and genome-edited isogenic cells confirmed the pathogenic nature of the E848G mutation. Reduced contractility may result from impaired interaction between myosin heavy chain 7 and cardiac myosin binding protein C. Key Words: disease-modeling, engineered heart tissue, genetic cardiomyopathy, induced pluripotent stem cells

The phenomenon of fine structure of the Isoscalar Giant Quadrupole Resonance (ISGQR) has been studied with high energy-resolution proton inelastic scattering at iThemba LABS in the chain of stable even-mass Nd isotopes covering the transition from spherical to deformed ground states. A wavelet analysis of the background-subtracted spectra in the deformed 146, 148, 150Nd isotopes reveals characteristic scales in correspondence with scales obtained from a Skyrme RPA calculation using the SVmas10 parameterization. A semblance analysis shows that these scales arise from the energy shift between the main fragments of the K=0,1 and K=2 components. Keywords: 146, 148, 150Nd(p,p′), ISGQR K-splitting, Wavelet analysis, Characteristic energy scales, Semblance analysis

Proton inelastic scattering experiments at energy Ep=200 MeV and a spectrometer scattering angle of 0° were performed on 144,146,148,150Nd and 152Sm exciting the IsoVector Giant Dipole Resonance (IVGDR). Comparison with results from photo-absorption experiments reveals a shift of resonance maxima towards higher energies for vibrational and transitional nuclei. The extracted photo-absorption cross sections in the most deformed nuclei, 150Nd and 152Sm, exhibit a pronounced asymmetry rather than a distinct double-hump structure expected as a signature of K-splitting. This behaviour may be related to the proximity of these nuclei to the critical point of the phase shape transition from vibrators to rotors with a soft quadrupole deformation potential. Self-consistent random-phase approximation (RPA) calculations using the SLy6 Skyrme force provide a relevant description of the IVGDR shapes deduced from the present data.

There has been a substantial research focus on the presence of pesticides in flowers and the subsequent exposure to honeybees. Here we demonstrate for the first time that honeybees can also be exposed to pharmaceuticals, commonly present in wastewater. Residues of carbamazepine (an anti-epileptic drug) up to 371 ng/mL and 30 µg/g were detected in nectar and pollen sampled from zucchini flowers (Cucurbita pepo) grown in carbamazepine spiked soil (0.5–20 µg/g). Under realistic exposure conditions from the use of recycled wastewater, carbamazepine concentrations were estimated to be 0.37 ng/L and 30 ng/kg in nectar and pollen, respectively. Incorporation of environmentally relevant carbamazepine residues in nectar and pollen into a modelling framework able to simulate beehive dynamics including the honeybee foraging activity at the landscape scale (BEEHAVE and BEESCOUT) enabled the simulation of carbamazepine translocation from zucchini fields into honeybee hives. Carbamazepine accumulation was modelled in 11 beehives across a 25 km2 landscape over three years chosen to represent distinct climatic conditions. During a single flowering period, carbamazepine concentrations were simulated to range between 0 and 2478 ng per beehive. The amount of carbamazepine gathered not only varied across the simulated years but there were also differences in accumulation of carbamazepine between beehives within the same year. This work illustrates a fundamental first step in assessing the risk of pharmaceuticals to bees through realistic scenarios by demonstrating a method to quantify potential exposure of honeybees at the landscape scale. Pharmaceuticals are being inadvertently but increasingly applied to agricultural lands globally via the use of wastewater for agricultural irrigation in response to water scarcity problems. We have demonstrated a route of pharmaceutical exposure to honeybees via contaminated nectar and pollen. Given the biological potency of pharmaceuticals, accumulation of these chemicals in nectar and pollen suggest potential implications for honeybee health, with unknown ecosystem consequences. Keywords: Nectar, Pollen, Plant accumulation, Emerging contaminants, Carbamazepine, Honeybee

We present data concerning the distribution of scientific publications for human protein-coding genes together with their protein products and genetic relevance. We annotated the gene2pubmed dataset Maglott et al., 2007 provided by the NCBI (National Center for Biotechnology Information) with publication years, genetic metadata corresponding to Online Mendelian Inheritance in Man (OMIM) Hamosh et al., 2005 entries and the frequency of their appearance in Genome-Wide Association Studies (GWAS) Buniello et al., 2019 provided by the European Bioinformatics Institute (EBI) using the KNIME® Analytics Platform Berthold et al., 2008. The results of this data integration process comprise two datasets: 1) A dataset containing information on all human protein-coding genes that can be used to analyse the number of scientific publications in context of the potential disease relevance of the individual genes. 2) A table with the annual and cumulated number of PubMed entries. For further interpretation of the data presented in this article, please see the research article ‘Target 2035 - probing the human proteome’ by Carter et al. https://doi.org/10.1016/j.drudis.2019.06.020 Carter et al., 2019. Keywords: Human proteome, Human genome, Scientific publications, Data integration, Genome-Wide Association Studies (GWAS), Online Mendelian Inheritance in Man (OMIM)

Although licensed human papillomavirus (HPV) vaccines are most efficacious in persons never infected with HPV, they also reduce infection and disease in previously infected subjects, indicating natural immunity is not entirely protective against HPV re-infection. The aim of this exploratory study was to examine the B cell memory elicited by HPV infection and evaluate whether vaccination merely boosts antibody (Ab) levels in previously infected subjects or also improves the quality of B cell memory. Toward this end, the memory B cells (Bmem) of five unvaccinated, HPV-seropositive subjects were isolated and characterized, and subject recall responses to a single HPV vaccine dose were analyzed. Vaccination boosted Ab levels 24- to 930-fold (median 77-fold) and Bmem numbers 3- to 27-fold (median 6-fold). In addition, Abs cloned from naturally elicited Bmem were generally non-neutralizing, whereas all those isolated following vaccination were neutralizing. Moreover, Ab and plasmablast responses indicative of memory recall responses were only observed in two subjects. These results suggest HPV vaccination augments both the magnitude and quality of natural immunity and demonstrate that sexually active persons could also benefit from HPV vaccination. This study may have important public policy implications, especially for the older ‘catch-up’ group within the vaccine's target population.

Summary: Background: The End TB Strategy and the Sustainable Development Goals (SDGs) are intimately linked by their common targets and approaches. SDG 1 aims to end extreme poverty and expand social protection coverage by 2030. Achievement of SDG 1 is likely to affect the tuberculosis epidemic through a range of pathways. We estimate the reduction in global tuberculosis incidence that could be obtained by reaching SDG 1. Methods: We developed a conceptual framework linking key indicators of SDG 1 progress to tuberculosis incidence via well described risk factor pathways and populated it with data from the SDG data repository and the WHO tuberculosis database for 192 countries. Correlations and mediation analyses informed the strength of the association between the SDG 1 subtargets and tuberculosis incidence, resulting in a simplified framework for modelling. The simplified framework linked key indicators for SDG 1 directly to tuberculosis incidence. We applied an exponential decay model based on linear associations between SDG 1 indicators and tuberculosis incidence to estimate tuberculosis incidence in 2035. Findings: Ending extreme poverty resulted in a reduction in global incidence of tuberculosis of 33·4% (95% credible interval 15·5–44·5) by 2035 and expanding social protection coverage resulted in a reduction in incidence of 76·1% (45·2–89·9) by 2035; both pathways together resulted in a reduction in incidence of 84·3% (54·7–94·9). Interpretation: Full achievement of SDG 1 could have a substantial effect on the global burden of tuberculosis. Cross-sectoral approaches that promote poverty reduction and social protection expansion will be crucial complements to health interventions, accelerating progress towards the End TB targets. Funding: World Health Organization.

The targeted disruption of the low density lipoprotein (LDL) receptor gene in mice results in accumulation of plasma LDL cholesterol and in predisposition to diet-induced aortic atherosclerosis. Although the liver is the central organ for receptor mediated clearance of LDL, the in vivo role of other organs and tissues in LDL catabolism has not been directly studied. Since bone marrow-derived cells such as blood leukocytes and tissue macrophages express LDL receptors and contribute a large mass to the body, we designed bone marrow transplantation (BMT) experiments to reconstitute LDL receptor null mice [LDL-R(-/-)] with marrow obtained from LDL-R wild-type mice [LDL-R(+/+)] and evaluate the effects on parameters of plasma lipid metabolism. Although reconstitution of the transplanted mice with donor bone marrow cells was complete, no differences in plasma lipid levels and lipoprotein distribution were found between groups, irrespective of the diet used, and turnover studies using 125I-labeled LDL showed that LDL receptor expression by leukocytes and macrophages does not significantly contribute to plasma LDL clearance. The complementary experiment of transplanting LDL-R(-/-) marrow into C57BL/6 recipients [LDL-R(-/-)–>LDL(+/+)], performed to evaluate the role of leukocyte LDL-R in normocholesterolemic condition, also produced no effects on plasma lipid parameters. LDL binding studies using macrophages isolated from transplanted mice showed a lack of LDL-R expression. Thus, despite their large number and wide distribution, bone marrow-derived cells do not significantly influence receptor-mediated clearance of plasma LDL.