Sulfa or Sulfone Prophylaxis and Geographic Region Predict Mutations in the Pneumocystis carinii Dihydropteroate Synthase Gene

To determine factors associated with mutations in the Pneumocystis carinii dihydropteroate synthase (DHPS) gene, a prospective study of human immunodeficiency virus (HIV)-infected patients with confirmed P. carinii pneumonia was conducted in Atlanta, Seattle, and San Francisco. Clinical information was obtained from patient interview and chart abstraction. DHPS genotype was determined from DNA sequencing. Overall, 76 (68.5%) of 111 patients had a mutant DHPS genotype, including 22 (81.5%) of 27 patients from San Francisco. In multivariate analysis, sulfa or sulfone prophylaxis and study site were independent predictors of a mutant genotype. Fourteen (53.8%) of 26 patients who were newly diagnosed with HIV infection and had never taken prophylaxis had a mutant genotype. The significance of geographic location as a risk factor for mutant genotype and the high proportion of mutant genotypes among persons never prescribed prophylaxis, including those newly diagnosed with HIV infection, provide indirect evidence that these mutations are transmitted from person to person either directly or through a common environmental source

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers.

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 10(6)-fold improvement over comparable liposomes

Exploring the impact of selection bias in observational studies of COVID-19: a simulation study

BACKGROUND: Non-random selection of analytic subsamples could introduce selection bias in observational studies. We explored the potential presence and impact of selection in studies of SARS-CoV-2 infection and COVID-19 prognosis. METHODS: We tested the association of a broad range of characteristics with selection into COVID-19 analytic subsamples in the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank (UKB). We then conducted empirical analyses and simulations to explore the potential presence, direction and magnitude of bias due to this selection (relative to our defined UK-based adult target populations) when estimating the association of body mass index (BMI) with SARS-CoV-2 infection and death-with-COVID-19. RESULTS: In both cohorts, a broad range of characteristics was related to selection, sometimes in opposite directions (e.g. more-educated people were more likely to have data on SARS-CoV-2 infection in ALSPAC, but less likely in UKB). Higher BMI was associated with higher odds of SARS-CoV-2 infection and death-with-COVID-19. We found non-negligible bias in many simulated scenarios. CONCLUSIONS: Analyses using COVID-19 self-reported or national registry data may be biased due to selection. The magnitude and direction of this bias depend on the outcome definition, the true effect of the risk factor and the assumed selection mechanism; these are likely to differ between studies with different target populations. Bias due to sample selection is a key concern in COVID-19 research based on national registry data, especially as countries end free mass testing. The framework we have used can be applied by other researchers assessing the extent to which their results may be biased for their research question of interest

Defining Ecological Drought for the Twenty-First Century

THE RISING RISK OF DROUGHT. Droughts of the twenty-first century are characterized by hotter temperatures, longer duration, and greater spatial extent, and are increasingly exacerbated by human demands for water. This situation increases the vulnerability of ecosystems to drought, including a rise in drought-driven tree mortality globally (Allen et al. 2015) and anticipated ecosystem transformations from one state to another—for example, forest to a shrubland (Jiang et al. 2013). When a drought drives changes within ecosystems, there can be a ripple effect through human communities that depend on those ecosystems for critical goods and services (Millar and Stephenson 2015). For example, the “Millennium Drought” (2002–10) in Australia caused unanticipated losses to key services provided by hydrological ecosystems in the Murray–Darling basin—including air quality regulation, waste treatment, erosion prevention, and recreation. The costs of these losses exceeded AUD $800 million, as resources were spent to replace these services and adapt to new drought-impacted ecosystems (Banerjee et al. 2013). Despite the high costs to both nature and people, current drought research, management, and policy perspectives often fail to evaluate how drought affects ecosystems and the “natural capital” they provide to human communities. Integrating these human and natural dimensions of drought is an essential step toward addressing the rising risk of drought in the twenty-first century

Co-circulation of Multidrug-resistant Shigella Among Men Who Have Sex With Men in Australia.

BACKGROUND: In urban Australia, the burden of shigellosis is either in returning travelers from shigellosis-endemic regions or in men who have sex with men (MSM). Here, we combine genomic data with comprehensive epidemiological data on sexual exposure and travel to describe the spread of multidrug-resistant Shigella lineages. METHODS: A population-level study of all cultured Shigella isolates in the state of Victoria, Australia, was undertaken from 1 January 2016 through 31 March 2018. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatic analyses of 545 Shigella isolates were performed at the Microbiological Diagnostic Unit Public Health Laboratory. Risk factor data on travel and sexual exposure were collected through enhanced surveillance forms or by interviews. RESULTS: Rates of antimicrobial resistance were high, with 17.6% (95/541) and 50.6% (274/541) resistance to ciprofloxacin and azithromycin, respectively. There were strong associations between antimicrobial resistance, phylogeny, and epidemiology. Specifically, 2 major MSM-associated lineages were identified: a Shigellasonnei lineage (n = 159) and a Shigella flexneri 2a lineage (n = 105). Of concern, 147/159 (92.4%) of isolates within the S. sonnei MSM-associated lineage harbored mutations associated with reduced susceptibility to recommended oral antimicrobials: namely, azithromycin, trimethoprim-sulfamethoxazole, and ciprofloxacin. Long-read sequencing demonstrated global dissemination of multidrug-resistant plasmids across Shigella species and lineages, but predominantly associated with MSM isolates. CONCLUSIONS: Our contemporary data highlight the ongoing public health threat posed by resistant Shigella, both in Australia and globally. Urgent multidisciplinary public health measures are required to interrupt transmission and prevent infection

Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer\u27s Disease-Relevant Phenotypes in Mice.

Obesity is recognized as a significant risk factor for Alzheimer\u27s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model wit

Dental profile of patients with Gaucher disease

BACKGROUND: This study was conducted to determine whether patients with Gaucher disease had significant dental pathology because of abnormal bone structure, pancytopenia, and coagulation abnormalities. METHODS: Each patient received a complete oral and periodontal examination in addition to a routine hematological evaluation. RESULTS: Gaucher patients had significantly fewer carious lesions than otherwise healthy carriers. Despite prevalence of anemia, there was no increase in gingival disease; despite the high incidence of thrombocytopenia, gingival bleeding was not noted; and despite radiological evidence of bone involvement, there was no greater incidence loss of teeth or clinical tooth mobility. CONCLUSIONS: These data represent the first survey of the oral health of a large cohort of patients with Gaucher disease. It is a pilot study of a unique population and the results of the investigation are indications for further research. Based on our findings, we recommend regular oral examinations with appropriate dental treatment for patients with Gaucher disease as for other individuals. Consultation between the dentist and physician, preferably one with experience with Gaucher disease, should be considered when surgical procedures are planned

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes