Divergent Plasmodium actin residues are essential for filament localization, mosquito salivary gland invasion and malaria transmission.

Actin is one of the most conserved and ubiquitous proteins in eukaryotes. Its sequence has been highly conserved for its monomers to self-assemble into filaments that mediate essential cell functions such as trafficking, cell shape and motility. The malaria-causing parasite, Plasmodium, expresses a highly sequence divergent actin that is critical for its rapid motility at different stages within its mammalian and mosquito hosts. Each of Plasmodium actin's four subdomains have divergent regions compared to canonical vertebrate actins. We previously identified subdomains 2 and 3 as providing critical contributions for parasite actin function as these regions could not be replaced by subdomains of vertebrate actins. Here we probed the contributions of individual divergent amino acid residues in these subdomains on parasite motility and progression. Non-lethal changes in these subdomains did not affect parasite development in the mammalian host but strongly affected progression through the mosquito with striking differences in transmission to and through the insect. Live visualization of actin filaments showed that divergent amino acid residues in subdomains 2 and 4 enhanced localization associated with filaments, while those in subdomain 3 negatively affected actin filaments. This suggests that finely tuned actin dynamics are essential for efficient organ entry in the mosquito vector affecting malaria transmission. This work provides residue level insight on the fundamental requirements of actin in highly motile cells.

Pustular psoriasis in Malaysia: A review of the Malaysian Psoriasis Registry 2007-2018.

Pustular psoriasis (PP) is an uncommon subtype of psoriasis with distinct genetic features and clinical phenotypes. Patients with PP tend to experience frequent flares and significant morbidity. This study aims to determine the clinical characteristics, co-morbidities and treatment of PP patients in Malaysia. This was a cross-sectional study of patients with PP notified to the Malaysian Psoriasis Registry (MPR) between January 2007 and December 2018. Of 21 735 psoriasis patients, 148 (0.7%) had pustular psoriasis. Of these, 93 (62.8%) were diagnosed with generalized pustular psoriasis (GPP) and 55 (37.2%) with localized PP (LPP). The mean age for pustular psoriasis onset was 31.71 ± 18.33 years with a male to female ratio of 1:2.1. Patients with PP were more likely to have dyslipidaemia (23.6% vs. 16.5%, p = 0.022), severe disease (Body surface area >10 and/or Dermatology Life Quality Index [DLQI] >10) (64.8% vs. 50%, p = 0.003) and require systemic therapy (51.4% vs. 13.9%, p < 0.001) compared to non-PP patients. Patients with PP also suffered greater impairment to their quality of life (DLQI >10, 48.9% vs. 40.3%, p = 0.046), had more days off school/work (2.06 ± 6.09 vs. 0.5 ± 4.91, p = 0.004) and a higher mean number of hospitalizations (0.31 ± 0.95 vs. 0.05 ± 1.22, p = 0.001) in 6 months compared to non-PP patients. Overall, 0.7% of psoriasis patients in the MPR had pustular psoriasis. Patients with PP had a higher rate of dyslipidaemia, severe disease, greater impairment of quality of life and systemic therapy usage compared to other psoriasis subtypes.

Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance.

The length and complexity of tuberculosis (TB) therapy, as well as the propensity of Mycobacterium tuberculosis to develop drug resistance, are major barriers to global TB control efforts. M. tuberculosis is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in M. tuberculosis caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the glpK gene. Inactivating frameshift mutations associated with the 7C HT in glpK produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same glpK HT region. These reversible frameshift mutations in the 7C HT of M. tuberculosis glpK occur in clinical isolates, accumulate in M. tuberculosis-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of dosR and sigH and repression of kstR regulons, similar to that observed in other in vitro models of M. tuberculosis tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant M. tuberculosis may hasten TB treatment and improve cure rates.

Vitamin A and Bone Health: A Review on Current Evidence.

Vitamin A is a fat-soluble micronutrient essential for growth, immunity, and good vision. The preformed retinol is commonly found in food of animal origin whereas provitamin A is derived from food of plant origin. This review summarises the current evidence from animal, human and cell-culture studies on the effects of vitamin A towards bone health. Animal studies showed that the negative effects of retinol on the skeleton were observed at higher concentrations, especially on the cortical bone. In humans, the direct relationship between vitamin A and poor bone health was more pronounced in individuals with obesity or vitamin D deficiency. Mechanistically, vitamin A differentially influenced the stages of osteogenesis by enhancing early osteoblastic differentiation and inhibiting bone mineralisation via retinoic acid receptor (RAR) signalling and modulation of osteocyte/osteoblast-related bone peptides. However, adequate vitamin A intake through food or supplements was shown to maintain healthy bones. Meanwhile, provitamin A (carotene and ß-cryptoxanthin) may also protect bone. In vitro evidence showed that carotene and ß-cryptoxanthin may serve as precursors for retinoids, specifically all-trans-retinoic acid, which serve as ligand for RARs to promote osteogenesis and suppressed nuclear factor-kappa B activation to inhibit the differentiation and maturation of osteoclasts. In conclusion, we suggest that both vitamin A and provitamin A may be potential bone-protecting agents, and more studies are warranted to support this hypothesis.

Missense Mutations in the Unfoldase ClpC1 of the Caseinolytic Protease Complex Are Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis.

Previously, we showed that mutations in Mycobacterium tuberculosis panD, involved in coenzyme A biosynthesis, cause resistance against pyrazinoic acid, the bioactive component of the prodrug pyrazinamide. To identify additional resistance mechanisms, we isolated mutants resistant against pyrazinoic acid and subjected panD wild-type strains to whole-genome sequencing. Eight of the nine resistant strains harbored missense mutations in the unfoldase ClpC1 associated with the caseinolytic protease complex.

Ambient fine particulate matter, nitrogen dioxide, and term birth weight in New York, New York.

Building on a unique exposure assessment project in New York, New York, we examined the relationship of particulate matter with aerodynamic diameter less than 2.5 µm and nitrogen dioxide with birth weight, restricting the population to term births to nonsmokers, along with other restrictions, to isolate the potential impact of air pollution on growth. We included 252,967 births in 2008-2010 identified in vital records, and we assigned exposure at the residential location by using validated models that accounted for spatial and temporal factors. Estimates of association were adjusted for individual and contextual sociodemographic characteristics and season, using linear mixed models to quantify the predicted change in birth weight in grams related to increasing pollution levels. Adjusted estimates for particulate matter with aerodynamic diameter less than 2.5 µm indicated that for each 10-µg/m(3) increase in exposure, birth weights declined by 18.4, 10.5, 29.7, and 48.4 g for exposures in the first, second, and third trimesters and for the total pregnancy, respectively. Adjusted estimates for nitrogen dioxide indicated that for each 10-ppb increase in exposure, birth weights declined by 14.2, 15.9, 18.0, and 18.0 g for exposures in the first, second, and third trimesters and for the total pregnancy, respectively. These results strongly support the association of urban air pollution exposure with reduced fetal growth.

Medical Students' Perspectives on Family Planning and Impact on Specialty Choice.

Importance: Physicians are known to delay childbearing compared with nonphysicians and to experience higher rates of age-related pregnancy complications. Delay of childbearing is more pronounced in surgical specialties, and family planning and building goals may influence specialty choice. Objective: To assess medical students' perspectives on the development of family planning goals and the timing of family building within a medical career to elucidate how these perceptions impact their choice of specialty. Design, Setting, and Participants: This qualitative study included fourth-year medical students at the University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada, and was conducted between May and August 2021. Participants were purposively sampled to maximize diversity of gender and specialty choice. Interviews were conducted via videoconferencing software that were recorded, transcribed verbatim, and verified for accuracy. Thematic analysis was completed independently by 2 researchers and consensus on final themes was reached through discussion among study investigators. Data were analyzed between September and December 2021. Main Outcomes and Measures: Participants were asked to share their perceptions of personal family planning goals, support currently in place, family planning education in medicine and factors contributing to their choice of specialty and program. Thematic analysis was completed. Results: A total of 34 fourth-year medical students (median [range] age, 26 [24-33] years; 23 females [67.6%]) were interviewed. Four main themes were identified: (1) there is no ideal time to family build in a medical career, (2) family planning is a taboo topic, (3) surgical specialties offer less support for family building, and (4) residents who have children are perceived to place a burden on their colleagues. Medical students considered their family planning while deliberating among specialty choices and their experiences were highly influential in shaping their specialty selection. Conclusions and Relevance: Results of this qualitative study suggest that medical students perceive that family building during training may have unfavorable implications for team dynamics and relationships with colleagues, and these perceptions may affect specialty choice and family planning goals. Integration of family planning discussions and support for family building into medical curricula is needed along with efforts to improve culture by supporting team dynamics and workload when students take parental leave.

Spatial and temporal estimation of air pollutants in New York City: exposure assignment for use in a birth outcomes study.

BACKGROUND: Recent epidemiological studies have examined the associations between air pollution and birth outcomes. Regulatory air quality monitors often used in these studies, however, were spatially sparse and unable to capture relevant within-city variation in exposure during pregnancy. METHODS: This study developed two-week average exposure estimates for fine particles (PM2.5) and nitrogen dioxide (NO2) during pregnancy for 274,996 New York City births in 2008-2010. The two-week average exposures were constructed by first developing land use regression (LUR) models of spatial variation in annual average PM2.5 and NO2 data from 150 locations in the New York City Community Air Survey and emissions source data near monitors. The annual average concentrations from the spatial models were adjusted to account for city-wide temporal trends using time series derived from regulatory monitors. Models were developed using Year 1 data and validated using Year 2 data. Two-week average exposures were then estimated for three buffers of maternal address and were averaged into the last six weeks, the trimesters, and the entire period of gestation. We characterized temporal variation of exposure estimates, correlation between PM2.5 and NO2, and correlation of exposures across trimesters. RESULTS: The LUR models of average annual concentrations explained a substantial amount of the spatial variation (R2 = 0.79 for PM2.5 and 0.80 for NO2). In the validation, predictions of Year 2 two-week average concentrations showed strong agreement with measured concentrations (R2 = 0.83 for PM2.5 and 0.79 for NO2). PM2.5 exhibited greater temporal variation than NO2. The relative contribution of temporal vs. spatial variation in the estimated exposures varied by time window. The differing seasonal cycle of these pollutants (bi-annual for PM2.5 and annual for NO2) resulted in different patterns of correlations in the estimated exposures across trimesters. The three levels of spatial buffer did not make a substantive difference in estimated exposures. CONCLUSIONS: The combination of spatially resolved monitoring data, LUR models and temporal adjustment using regulatory monitoring data yielded exposure estimates for PM2.5 and NO2 that performed well in validation tests. The interaction between seasonality of air pollution and exposure intervals during pregnancy needs to be considered in future studies.

The NYU Data Catalog: a modular, flexible infrastructure for data discovery.

OBJECTIVE: Researchers at New York University (NYU) Grossman School of Medicine contacted the Health Sciences Library for help with locating large datasets for reuse. In response, the library developed and maintained the NYU Data Catalog, a public-facing data catalog that has supported not only faculty acquisition of data but also the dissemination of the products of their research in various ways. MATERIALS AND METHODS: The current NYU Data Catalog is built upon the Symfony framework with a tailored metadata schema reflecting the scope of faculty research areas. The project team curates new resources, including datasets and supporting software code, and conducts quarterly and annual evaluations to assess user interactions with the NYU Data Catalog and opportunities for growth. RESULTS: Since its launch in 2015, the NYU Data Catalog underwent a number of changes prompted by an increase in the disciplines represented by faculty contributors. The catalog has also utilized faculty feedback to enhance support of data reuse and researcher collaboration through alterations to its schema, layout, and visibility of records. DISCUSSION: These findings demonstrate the flexibility of data catalogs as a platform for enabling the discovery of disparate sources of data. While not a repository, the NYU Data Catalog is well-positioned to support mandates for data sharing from study sponsors and publishers. CONCLUSION: The NYU Data Catalog makes the most of the data that researchers share and can be harnessed as a modular and adaptable platform to promote data sharing as a cultural practice.

A Review of the Application of Natural and Synthetic Scaffolds in Bone Regeneration.

The management of bone defects is complicated by the presence of clinical conditions, such as critical-sized defects created by high-energy trauma, tumour resection, infection, and skeletal abnormalities, whereby the bone regeneration capacity is compromised. A bone scaffold is a three-dimensional structure matrix serving as a template to be implanted into the defects to promote vascularisation, growth factor recruitment, osteogenesis, osteoconduction, and mechanical support. This review aims to summarise the types and applications of natural and synthetic scaffolds currently adopted in bone tissue engineering. The merits and caveats of natural and synthetic scaffolds will be discussed. A naturally derived bone scaffold offers a microenvironment closer to in vivo conditions after decellularisation and demineralisation, exhibiting excellent bioactivity, biocompatibility, and osteogenic properties. Meanwhile, an artificially produced bone scaffold allows for scalability and consistency with minimal risk of disease transmission. The combination of different materials to form scaffolds, along with bone cell seeding, biochemical cue incorporation, and bioactive molecule functionalisation, can provide additional or improved scaffold properties, allowing for a faster bone repair rate in bone injuries. This is the direction for future research in the field of bone growth and repair.

Percutaneous Ultrasound-Guided Tenotomy of the Iliotibial Band for Trochanteric Pain Syndrome: A Longitudinal Observational Study With One-Year Durability Results.

BACKGROUND: Upper lateral hip pain is a common complaint in adults and is referred to as greater trochanteric pain syndrome (GTPS) and is more prevalent among older women. This is a debilitating condition that could result in lower physical activity and quality of life, and higher unemployment rate. GTPS is a clinical diagnosis, and many cases improve with conservative medical management (CMM). However, there is still a gap between patients not responding to CMM and those who are not good surgical candidates. Thus, percutaneous ultrasound tenotomy (PUT) may be a valuable treatment option to limit this gap. OBJECTIVES: Demonstration of the one-year pain and functional outcomes, including sit to stand. SETTING: Academic tertiary care medical center. METHODS: Forty-eight consecutive patients with refractory trochanteric pain due to iliotibial band (ITB) tendinopathy. Fifty-six hips were treated; 8 patients underwent bilateral procedures. Electronic medical record review of consecutive patients who underwent ITB TENEX® was performed at Montefiore Medical Center from December 2019 to December 2021. Institutional guidelines recommended TENEX® for greater trochanteric pain refractory to conservative treatment and ultrasound (US) confirmed ITB tendinopathy (hypoechogenicity or thickened tendon > 6 mm). Pain level, as well as sit-to-stand, side-lying, and walking tolerance levels were evaluated at baseline preprocedure visit and one-year visit. Follow-up was performed by independent practitioners and corroborated by chart review. RESULTS: Numeric Rating Scale (NRS-11) improved by 4 points across all patients. Seventy percent of patients endorsed pain relief at one-year visit. Median preprocedure NRS-11 was 9. The reported median NRS-11at one year was 5 (Wilcoxon signed rank NRS-11 demonstrated a Z score of -6.042 with P < 0.001). One-year analysis among all patients revealed 57%, 78%, and 66% improvement in side-lying, sit-to-stand, and walking tolerance levels, respectively. LIMITATIONS: We believe that our results must be confirmed with a randomized control trial with a control arm and more patients included. CONCLUSIONS: PUT of the ITB using the TENEX® tissue remodeling device could be a safe and effective treatment for ITB tendinopathy-associated GTPS.

Clinical characteristics, management, and quality of life of psoriasis patients with coexistent lupus erythematosus: Data from the Malaysian Psoriasis Registry.

OBJECTIVE: To describe the clinical characteristics, management and quality of life of psoriasis patients with and without coexistent lupus erythematosus (LE). METHODS: This retrospective cross-sectional study uses data from the Malaysian Psoriasis Registry (MPR) from January 2007 to December 2018. RESULTS: Of 21 735 psoriasis patients, 34 (0.16%) had coexistent LE. The male to female ratio among psoriasis patients with coexistent LE was 1:5.8 versus 1.3:1 in patients with psoriasis but without LE. Nearly 70% presented with LE preceding psoriasis. Psoriasis patients with LE had an earlier age of psoriasis onset (27.56 ± 11.51 versus 33.31 ± 16.94 years, P = 0.006), a higher rate of psoriatic arthropathy (26.5% versus 13.0%, P = 0.02), and a significantly greater impairment of quality of life (Dermatology Quality of Life Index >10; 57.6% versus 40.3%, P = 0.04) compared with psoriasis patients without LE. The majority (87.5%) had systemic LE. The incidences of lupus nephritis (72.7% versus 40%) and hematological abnormalities (50% versus 20%) were higher among patients with LE preceding psoriasis compared with those with psoriasis preceding LE. Antinuclear antibody and double-stranded DNA were positive in 59.4% and 28.1% of psoriasis patients with LE, respectively. Hydroxychloroquine triggered the onset of psoriasis in 7 (24.1%) patients. Patients with LE were more likely to receive systemic treatment for psoriasis compared with those without LE (30.3% versus 14.2%, P = 0.008). CONCLUSIONS: Psoriasis patients with coexistent LE were uncommon, displayed a female preponderance, were more likely to have joint involvement, and had greater quality of life impairment than those without LE. LE preceded psoriasis in most of these patients, and systemic LE was the most common subtype.

Co-designing a web-based education platform for patients with early pregnancy loss.

Canadian emergency departments (EDs) frequently provide care to patients undergoing early pregnancy loss. Unfortunately, in this setting, patients commonly have negative experiences, in part due to lack of appropriate follow-up and education on symptoms that may arise after discharge. In response to this gap, our team created a free, web-based, patient-informed educational platform for women to access accurate information on early pregnancy loss. This free and publicly accessible resource was launched in May 2022 at Mount Sinai Hospital in Toronto and was shared with EDs across Canada.

RéSUMé: Les services d'urgence (SU) canadiens fournissent fréquemment des soins aux patientes qui subissent une perte de grossesse précoce. Malheureusement, dans ce contexte, les patientes ont souvent des expériences négatives, en partie à cause du manque de suivi approprié et d'éducation sur les symptômes qui peuvent apparaître après la sortie de l'hôpital. Pour combler cette lacune, notre équipe a créé une plate-forme éducative gratuite, basée sur le Web et informée par les patientes, permettant aux femmes d'accéder à des informations précises sur la perte de grossesse précoce. Cette ressource gratuite et accessible au public a été lancée en mai 2022 à l'hôpital Mount Sinai de Toronto et a été partagée avec les services d'urgence de tout le Canada.

Pyrazinamide triggers degradation of its target aspartate decarboxylase.

Pyrazinamide is a sterilizing first-line tuberculosis drug. Genetic, metabolomic and biophysical analyses previously demonstrated that pyrazinoic acid, the bioactive form of the prodrug pyrazinamide (PZA), interrupts biosynthesis of coenzyme A in Mycobacterium tuberculosis by binding to aspartate decarboxylase PanD. While most drugs act by inhibiting protein function upon target binding, we find here that pyrazinoic acid is only a weak enzyme inhibitor. We show that binding of pyrazinoic acid to PanD triggers degradation of the protein by the caseinolytic protease ClpC1-ClpP. Thus, the old tuberculosis drug pyrazinamide exerts antibacterial activity by acting as a target degrader, a mechanism of action that has recently emerged as a successful strategy in drug discovery across disease indications. Our findings provide the basis for the rational discovery of next generation PZA.

Draft Genome Sequence of Mycobacterium abscessus Bamboo.

Mycobacterium abscessus, an intrinsically multidrug-resistant pathogen, causes chronic incurable lung disease. New drugs for this emerging pathogen represent an urgent unmet medical need. Here, we report a draft genome sequence of M. abscessus Bamboo, a clinical isolate used as a screening strain for drug discovery.

Draft Genome Sequence of Mycobacterium avium 11.

Mycobacterium avium accounts for most lung disease caused by nontuberculous mycobacteria (NTM). The lack of effective chemotherapy calls for the discovery of new drugs. Here, we report the draft genome sequence of M. avium 11, a clinical isolate used as a screening strain for NTM-focused drug discovery.