Respiratory carriage of hypervirulent Klebsiella pneumoniae by indigenous populations of Malaysia.

Klebsiella pneumoniae is a Gram-negative Enterobacteriaceae that is classified by the World Health Organisation (WHO) as a Priority One ESKAPE pathogen. South and Southeast Asian countries are regions where both healthcare associated infections (HAI) and community acquired infections (CAI) due to extended-spectrum ß-lactamase (ESBL)-producing and carbapenem-resistant K. pneumoniae (CRKp) are of concern. As K. pneumoniae can also exist as a harmless commensal, the spread of resistance genotypes requires epidemiological vigilance. However there has been no significant study of carriage isolates from healthy individuals, particularly in Southeast Asia, and specially Malaysia. Here we describe the genomic analysis of respiratory isolates of K. pneumoniae obtained from Orang Ulu and Orang Asli communities in Malaysian Borneo and Peninsular Malaysia respectively. The majority of isolates were K. pneumoniae species complex (KpSC) 1 K. pneumoniae (n = 53, 89.8%). Four Klebsiella variicola subsp. variicola (KpSC3) and two Klebsiella quasipneumoniae subsp. similipneumoniae (KpSC4) were also found. It was discovered that 30.2% (n = 16) of the KpSC1 isolates were ST23, 11.3% (n = 6) were of ST65, 7.5% (n = 4) were ST13, and 13.2% (n = 7) were ST86. Only eight of the KpSC1 isolates encoded ESBL, but importantly not carbapenemase. Thirteen of the KpSC1 isolates carried yersiniabactin, colibactin and aerobactin, all of which harboured the rmpADC locus and are therefore characterised as hypervirulent. Co-carriage of multiple strains was minimal. In conclusion, most isolates were KpSC1, ST23, one of the most common sequence types and previously found in cases of K. pneumoniae infection. A proportion were hypervirulent (hvKp) however antibiotic resistance was low.

A virtual library of small molecules mimicking dipeptides.

Virtual combinatorial libraries are prevalent in drug discovery due to improvements in the prediction of synthetic reactions that can be performed. This has gone hand in hand with the development of virtual screening capabilities to effectively screen the large chemical spaces spanned by exhaustive enumeration of reaction products. In this study, we generated a small-molecule dipeptide mimic library to target proteins binding small peptides. The library was created based on the general idea of peptide synthesis, that is, amino acid mimics were reacted in silico to form the dipeptide mimics, yielding 2,036,819 unique compounds. After docking calculations, two compounds from the library were synthesized and tested against WD repeat-containing protein 5 (WDR5) and histamine receptors H1-H4 to evaluate whether these molecules are viable in assays. The compounds showed the highest potency at the histamine H3 receptor, with Ki values in the two-digit micromolar range.

A multicentre study to determine the in vitro efficacy of flomoxef against extended-spectrum beta-lactamase producing Escherichia coli in Malaysia.

Background: The high burden of extended-spectrum beta-lactamase-producing (ESBL)-producing Enterobacterales worldwide, especially in the densely populated South East Asia poses a significant threat to the global transmission of antibiotic resistance. Molecular surveillance of ESBL-producing pathogens in this region is vital for understanding the local epidemiology, informing treatment choices, and addressing the regional and global implications of antibiotic resistance. Methods: Therefore, an inventory surveillance of the ESBL-Escherichia coli (ESBL-EC) isolates responsible for infections in Malaysian hospitals was conducted. Additionally, the in vitro efficacy of flomoxef and other established antibiotics against ESBL-EC was evaluated. Results: A total of 127 non-repetitive ESBL-EC strains isolated from clinical samples were collected during a multicentre study performed in five representative Malaysian hospitals. Of all the isolates, 33.9% were isolated from surgical site infections and 85.8% were hospital-acquired infections. High rates of resistance to cefotaxime (100%), cefepime (100%), aztreonam (100%) and trimethoprim-sulfamethoxazole (100%) were observed based on the broth microdilution test. Carbapenems remained the most effective antibiotics against the ESBL-EC, followed by flomoxef. Antibiotic resistance genes were identified by PCR. The blaCTX-M-1 was the most prevalent ESBL gene, with 28 isolates (22%) harbouring blaCTX-M-1 only, 27 isolates (21.3%) co-harbouring blaCTX-M-1 and blaTEM, and ten isolates (7.9%) co-harbouring blaCTX-M-1, blaTEM and blaSHV. A generalised linear model showed significant antibacterial activity of imipenem against different types of infection. Besides carbapenems, this study also demonstrated a satisfactory antibacterial activity of flomoxef (81.9%) on ESBL-EC, regardless of the types of ESBL genes.

Differential interaction patterns of opioid analgesics with µ opioid receptors correlate with ligand-specific voltage sensitivity.

The µ opioid receptor (MOR) is the key target for analgesia, but the application of opioids is accompanied by several issues. There is a wide range of opioid analgesics, differing in their chemical structure and their properties of receptor activation and subsequent effects. A better understanding of ligand-receptor interactions and the resulting effects is important. Here, we calculated the respective binding poses for several opioids and analyzed interaction fingerprints between ligand and receptor. We further corroborated the interactions experimentally by cellular assays. As MOR was observed to display ligand-induced modulation of activity due to changes in membrane potential, we further analyzed the effects of voltage sensitivity on this receptor. Combining in silico and in vitro approaches, we defined discriminating interaction patterns responsible for ligand-specific voltage sensitivity and present new insights into their specific effects on activation of the MOR.

The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human ß1-Adrenoceptor.

Known off-target interactions frequently cause predictable drug side-effects (e.g., ß1-antagonists used for heart disease, risk ß2-mediated bronchospasm). Computer-aided drug design would improve if the structural basis of existing drug selectivity was understood. A mutagenesis approach determined the ligand-amino acid interactions required for ß1-selective affinity of xamoterol and nebivolol, followed by computer-based modeling to provide possible structural explanations. 3H-CGP12177 whole cell binding was conducted in Chinese hamster ovary cells stably expressing human ß1, ß2, and chimeric ß1/ß2-adrenoceptors (ARs). Single point mutations were investigated in transiently transfected cells. Modeling studies involved docking ligands into three-dimensional receptor structures and performing molecular dynamics simulations, comparing interaction frequencies between apo and holo structures of ß1 and ß2-ARs. From these observations, an ICI89406 derivative was investigated that gave further insights into selectivity. Stable cell line studies determined that transmembrane 2 was crucial for the ß1-selective affinity of xamoterol and nebivolol. Single point mutations determined that the ß1-AR isoleucine (I118) rather than the ß2 histidine (H93) explained selectivity. Studies of other ß1-ligands found I118 was important for ICI89406 selective affinity but not that for betaxolol, bisoprolol, or esmolol. Modeling studies suggested that the interaction energies and solvation of ß1-I118 and ß2-H93 are factors determining selectivity of xamoterol and ICI89406. ICI89406 without its phenyl group loses its high ß1-AR affinity, resulting in the same affinity as for the ß2-AR. The human ß1-AR residue I118 is crucial for the ß1-selective affinity of xamoterol, nebivolol, and ICI89406 but not all ß1-selective compounds. SIGNIFICANCE STATEMENT: Some ligands have selective binding affinity for the human ß1 versus the ß2-adrenoceptor; however, the molecular/structural reason for this is not known. The transmembrane 2 residue isoleucine I118 is responsible for the selective ß1-binding of xamoterol, nebivolol, and ICI89406 but does not explain the selective ß1-binding of betaxolol, bisoprolol, or esmolol. Understanding the structural basis of selectivity is important to improve computer-aided ligand design, and targeting I118 in ß1-adrenoceptors is likely to increase ß1-selectivity of drugs.

Does Older Age Affect the Likelihood to Achieve Normal Quality of Life After Traumatic Spinal Cord Injury? A Prospective Observational Cohort Study.

Previous studies suggest that health-related quality of life (HRQoL) is impaired after a traumatic spinal cord injury (TSCI) and may be worse with older age. This study determines whether the expectations to achieve normal HRQoL in Canadians after a TSCI is indeed influenced by older age. A prospective observational study was conducted on adult patients admitted acutely at a single level-1 trauma center after a TSCI. We assessed HRQoL using the SF-36 physical and mental component summary (PCS and MCS) scores obtained one year post injury. Using Canadian normative HRQoL data matched for age and sex, we defined normal PCS and MCS as a score within 2 standard deviations with respect to the normative Canadian mean. We then conducted logistic regression models to determine the relationship between age at the time of injury and the likelihood of achieving normal PCS and MCS, while controlling for confounding variables. Overall, 39.3% of individuals displayed normal PCS, whereas 80.4% displayed normal MCS. When adjusted for confounders, older age remained significantly associated with increased likelihood of achieving normal PCS (Odds Ratio: 1.03; 95% Confidence Interval: 1.01-1.06; P = 0.002). We observed no association between age and achieving normal MCS. A significant proportion of individuals can achieve a normal HRQoL similar to their healthy peers following a TSCI, particularly for the mental component. When compared to younger individuals, older individuals are more likely to achieve normal PCS and present a similar likelihood for achieving normal MCS.

How Carvedilol activates ß2-adrenoceptors.

Carvedilol is among the most effective ß-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of ß1-adrenoceptors, arrestin-biased signalling via ß2-adrenoceptors is a molecular mechanism proposed to explain the survival benefits. Here, we offer an alternative mechanism to rationalize carvedilol's cellular signalling. Using primary and immortalized cells genome-edited by CRISPR/Cas9 to lack either G proteins or arrestins; and combining biological, biochemical, and signalling assays with molecular dynamics simulations, we demonstrate that G proteins drive all detectable carvedilol signalling through ß2ARs. Because a clear understanding of how drugs act is imperative to data interpretation in basic and clinical research, to the stratification of clinical trials or to the monitoring of drug effects on the target pathway, the mechanistic insight gained here provides a foundation for the rational development of signalling prototypes that target the ß-adrenoceptor system.

The Development of a Parental Questionnaire (QQ-MediaSEED) on Bilingual Children's Quantity and Quality of Digital Media Use at Home.

The quantity and quality of children's digital screen media exposure is an emerging area of early childhood studies because of its strong social relevance, and this has been particularly true since the COVID-19 pandemic. The few existing parental questionnaires on children's digital screen media exposure mainly focus on monolingual children's media habits and address either the quantity or quality of children's media exposure. Inspired by the existing instruments, the current study introduces a new parental questionnaire to comprehensively assess the duration, frequency, content, design, and use of bilingual children's digital screen media exposure at home, before and since the COVID-19 pandemic. Focus group discussions and the first wave of our data collection on 141 3-6 years old Singaporean bilingual children indicate good face validity and internal consistency of the parental questionnaire. Our results reveal substantial differences in children's quantity and quality of daily digital screen media exposure, as well as the discrepancies in their digital media habits between English and their mother tongue languages, before and since the COVID-19 pandemic.

Who Recovers Independent Bowel Management During the First Year After a Traumatic Spinal Cord Injury?: A Case-Control Study.

OBJECTIVES: The aims of the study were (1) to document the characteristics of patients with impaired bowel functioning during the subacute and chronic phases and (2) to identify factors associated with recovery of independent bowel functioning during the first year after traumatic spinal cord injury in patients who present impaired bowel functioning during the subacute phase, when bowel rehabilitation is completed. DESIGN: This is a case-control study on 123 adult traumatic spinal cord injury patients. Bowel function assessments using item 7 of the Spinal Cord Independence Measure III were obtained 3 mos after traumatic spinal cord injury and during the early chronic phase. Univariate and multivariate analyses were conducted to identify predictors associated with recovery of independent bowel functioning between the initial assessment and follow-up. RESULTS: Of the 110 patients available for analysis, 54 (49%) displayed impaired bowel functioning 3 mos after traumatic spinal cord injury. Of these, 19 (35%) recovered independent bowel functioning over the following 9 mos. The total motor score was the only significant predictor of this outcome. A total motor score lower than 42 was 100% predictive of absence of recovery. CONCLUSIONS: Recovering independent bowel management 1 yr after traumatic spinal cord injury was possible in 35% of patients despite impaired bowel functioning during the subacute phase. The total motor score measured 3 mos after injury could be useful for prognosticating potential for bowel functioning recovery because patients with total motor score lower than 42 are unlikely to recover. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME. CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Demonstrate a comprehensive understanding of the course of recovery of independent bowel function after traumatic spinal cord injury; (2) Describe the vulnerable subset of patients who present impaired bowel function at 3 mos after injury despite having received specialized bowel rehabilitation; and (3) Predict with improved accuracy the level of bowel function reached in the chronic phase for patients who present with impaired bowel function at 3 mos after injury. LEVEL: Advanced. ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Carriage of upper respiratory tract pathogens in rural communities of Sarawak, Malaysian Borneo.

INTRODUCTION: Pneumonia is a leading cause of death in Malaysia. Whilst many studies have reported the aetiology of pneumonia in Western countries, the epidemiology of pneumonia in Malaysia remains poorly understood. As carriage is a prerequisite for disease, we sought to improve our understanding of the carriage and antimicrobial resistance (AMR) of respiratory tract pathogens in Malaysia. The rural communities of Sarawak are an understudied part of the Malaysian population and were the focus of this study, allowing us to gain a better understanding of bacterial epidemiology in this population. METHODS: A population-based survey of bacterial carriage was undertaken in participants of all ages from rural communities in Sarawak, Malaysia. Nasopharyngeal, nasal, mouth and oropharyngeal swabs were taken. Bacteria were isolated from each swab and identified by culture-based methods and antimicrobial susceptibility testing conducted by disk diffusion or E test. RESULTS: 140 participants were recruited from five rural communities. Klebsiella pneumoniae was most commonly isolated from participants (30.0%), followed by Staphylococcus aureus (20.7%), Streptococcus pneumoniae (10.7%), Haemophilus influenzae (9.3%), Moraxella catarrhalis (6.4%), Pseudomonas aeruginosa (6.4%) and Neisseria meningitidis (5.0%). Of the 21 S. pneumoniae isolated, 33.3 and 14.3% were serotypes included in the 13 valent PCV (PCV13) and 10 valent PCV (PCV10) respectively. 33.8% of all species were resistant to at least one antibiotic, however all bacterial species except S. pneumoniae were susceptible to at least one type of antibiotic. CONCLUSION: To our knowledge, this is the first bacterial carriage study undertaken in East Malaysia. We provide valuable and timely data regarding the epidemiology and AMR of respiratory pathogens commonly associated with pneumonia. Further surveillance in Malaysia is necessary to monitor changes in the carriage prevalence of upper respiratory tract pathogens and the emergence of AMR, particularly as PCV is added to the National Immunisation Programme (NIP).

Factors associated with discharge destination following inpatient functional rehabilitation in patients with traumatic spinal cord injury.

STUDY DESIGN: Retrospective review of data from a prospective database of a Level 1 trauma center. OBJECTIVES: This project aims to identify factors collected during the acute and rehabilitative care following a traumatic spinal cord injury (TSCI) associated with success and failure to return home after inpatient intensive functional rehabilitation (IFR). SETTING: Level 1 trauma center specialized in TSCI care in Montreal, Canada. METHODS: All eligible patients from our prospective database were separated into two groups according to discharge destination following IFR. Clinical variables collected during the acute and rehabilitative care as well as demographic variables were compared between patients who managed to return home (Group 1) and those who were discharged elsewhere (Group 2). Multivariable regression analyses were conducted with variables that were significant at the univariate level. RESULTS: Out of the 193 patients included, 22 (11%) failed to return home following IFR. Six variables were associated with failure to return home at the univariate level: longer acute length of stay (LOS), longer rehabilitation LOS, living alone, higher neurological level of injury, having comorbidities, and having a pressure injury (PI) during acute care. Three variables remained significant at the multivariate level: living alone, increasing acute LOS and presenting a high cervical (C1-C4) neurological level of injury. CONCLUSIONS: It is important that acute care clinicians recognize the aforementioned factors early after TSCI in order to optimize patients for community reintegration.

Clinical Protocol for Identifying and Managing Bladder Dysfunction during Acute Care after Traumatic Spinal Cord Injury.

Bladder dysfunction is widespread following traumatic spinal cord injury (TSCI). Early diagnosis of bladder dysfunction is crucial in preventing complications, determining prognosis, and planning rehabilitation. We aim to suggest the first clinical protocol specifically designed to evaluate and manage bladder dysfunction in TSCI patients during acute care. A retrospective cohort study was conducted on 101 patients admitted for an acute TSCI between C1 and T12. Following spinal surgery, presence of voluntary anal contraction (VAC) was used as a criterion for removal of indwelling catheter and initiating trial of void (TOV). Absence of bladder dysfunction was determined from three consecutive post-void bladder scan residuals ≤200 mL without incontinence. All patients were reassessed 3 months post-injury using the Spinal Cord Independence Measure (SCIM). A total of 74.3% were diagnosed with bladder dysfunction during acute care, while 57.4% had a motor-complete TSCI. Three months later, 94.7% of them reported impaired bladder function. None of the patients discharged from acute care after a functional bladder was diagnosed reported impaired bladder function at the 3-month follow-up. A total of 95.7% patients without VAC had persisting impaired bladder function at follow-up. The proposed protocol is specifically adapted to the dynamic nature of neurogenic bladder function following TSCI. The assessment of VAC into the protocol provides major insight on the potential for reaching adequate bladder function during the subacute phase. Conducting TOV using bladder scan residuals in patients with VAC is a non-invasive and easy method to discriminate between a functional and an impaired bladder following acute TSCI.

COVID-19 in adult patients with pre-existing chronic cardiac, respiratory and metabolic disease: a critical literature review with clinical recommendations.

BACKGROUND: A high burden of severe disease and death from the coronavirus disease 2019 (COVID-19) has been consistently observed in older patients, especially those with pre-existing medical co-morbidities. The global pandemic lockdown has isolated many patients with chronic illnesses from their routine medical care. This narrative review article analyses the multitude of issues faced by individuals with underlying medical conditions during the COVID-19 pandemic. METHODS: Sources for this publication were identified through searches of PubMed for articles published between 31st December 2019 and 4th June 2020, using combinations of search terms. Guidelines and updates from reputable agencies were also consulted. Only articles published in the English language were included. RESULTS: The volume of literature on COVID-19 continues to expand, with 17,845 articles indexed on PubMed by 4th June 2020, 130 of which were deemed particularly relevant to the subject matter of this review. Older patients are more likely to progress to severe COVID-19 disease requiring intensive care unit (ICU) admission. Patients with pre-existing cardiovascular disease, especially hypertension and coronary heart disease, are at greatly increased risk of developing severe and fatal COVID-19 disease. A controversial aspect of the management of COVID-19 disease has been the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Obese COVID-19 patients are more likely to require complex ICU management. Putative mechanisms of increased COVID-19 disease severity in diabetes include hyperglycaemia, altered immune function, sub-optimal glycaemic control during hospitalisation, a pro-thrombotic and pro-inflammatory state. Patients with mental health disorders are particularly vulnerable to social isolation, and this has been compounded by the suspension of non-emergency care in hospitals around the world, making it difficult for patients with chronic mental illness to attend outpatient appointments. CONCLUSIONS: The global pandemic of COVID-19 disease has had a disproportionately negative impact on patients living with chronic medical illness. Future research should be directed at efforts to protect vulnerable patients from possible further waves of COVID-19 and minimising the negative impact of pandemic mitigation strategies on these individuals.

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia.

CONTEXT: Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. OBJECTIVE: To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. DESIGN AND PARTICIPANTS: We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. RESULTS: Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ±â€…0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. CONCLUSION: We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

Association of G6PD variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals.

OBJECTIVE: Hemoglobin A1c (HbA1c) accuracy is important for diabetes diagnosis and estimation of overall glycemia. The G6PD-Asahi variant which causes glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to lower HbA1c independently of glycemia in African ancestry populations. As different G6PD variants occur in Asian ancestry, we sought to identify Asian-specific G6PD variants associated with HbA1c. RESEARCH DESIGN AND METHODS: In eight Asian population-based cohorts, we performed imputation on the X chromosome using the 1000 Genomes reference panel and tested for association with HbA1c (10 005 East Asians and 2051 South Asians). Results were meta-analyzed across studies. We compared the proportion of individuals classified as having diabetes/pre-diabetes by fasting glucose ≥100 mg/dL or HbA1c ≥5.7% units among carriers and non-carriers of HbA1c-associated variants. RESULTS: The strongest association was a missense variant (G6PD-Canton, rs72554665, minor allele frequency=2.2%, effect in men=-0.76% unit, 95% CI -0.88 to -0.64, p=1.25×10-27, n=2844). Conditional analyses identified a secondary distinct signal, missense variant (G6PD-Kaiping, rs72554664, minor allele frequency=1.6%, effect in men=-1.12 % unit, 95% CI -1.32 to -0.92, p=3.12×10-15, pconditional_Canton=7.57×10-11). Adjusting for glucose did not attenuate their effects. The proportion of individuals with fasting glucose ≥100 mg/dL did not differ by carrier status of G6PD-Canton (p=0.21). Whereas the proportion of individuals with HbA1c ≥5.7% units was lower in carriers (5%) compared with non-carriers of G6PD-Canton (30%, p=0.03). CONCLUSIONS: We identified two G6PD variants in East Asian men associated with non-glycemic lowering of HbA1c. Carriers of these variants are more likely to be underdiagnosed for diabetes or pre-diabetes than non-carriers if screened by HbA1c without confirmation by direct glucose measurements.

A benchmarking study on virtual ligand screening against homology models of human GPCRs.

G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10 GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening. For a small subset of GPCRs, we also explored how certain methods like consensus enrichment and sidechain perturbation affect the utility of homology models in virtual screening, as well as the selectivity between agonists and antagonists. Most notably, consensus enrichment across multiple homology models often yields results comparable to the best performing model, suggesting that ligand candidates predicted with consensus scores from multiple models can be the optimal option in practical applications where the performance of each model cannot be estimated.

Pneumococcal conjugate vaccine implementation in middle-income countries.

BACKGROUND: Since 2000, the widespread adoption of pneumococcal conjugate vaccines (PCVs) has had a major impact in the prevention of pneumonia. Limited access to international financial support means some middle-income countries (MICs) are trailing in the widespread use of PCVs. We review the status of PCV implementation, and discuss any needs and gaps related to low levels of PCV implementation in MICs, with analysis of possible solutions to strengthen the PCV implementation process in MICs. MAIN BODY: We searched PubMed, PubMed Central, Ovid MEDLINE, and SCOPUS databases using search terms related to pneumococcal immunization, governmental health policy or programmes, and MICs. Two authors independently reviewed the full text of the references, which were assessed for eligibility using pre-defined inclusion and exclusion criteria. The search terms identified 1,165 articles and the full texts of 21 were assessed for suitability, with eight articles included in the systematic review. MICs are implementing PCVs at a slower rate than donor-funded low-income countries and wealthier developed countries. A significant difference in the uptake of PCV in lower middle-income countries (LMICs) (71%) and upper middle-income countries (UMICs) (48%) is largely due to an unsuccessful process of "graduation" of MICs from GAVI assistance, an issue that arises as countries cross the income eligibility threshold and are no longer eligible to receive the same levels of financial assistance. A lack of country-specific data on disease burden, a lack of local expertise in economic evaluation, and the cost of PCV were identified as the leading causes of the slow uptake of PCVs in MICs. Potential solutions mentioned in the reviewed papers include the use of vaccine cost-effectiveness analysis and the provision of economic evidence to strengthen decision-making, the evaluation of the burden of disease, and post-introduction surveillance to monitor vaccine impact. CONCLUSION: The global community needs to recognise the impediments to vaccine introduction into MICs. Improving PCV access could help decrease the incidence of pneumonia and reduce the selection pressure for pneumococcal antimicrobial resistance.