The evolution of drug resistance in clinical isolates of Candida albicans

Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation.National Science Foundation (U.S.). Graduate Research Fellowship ProgramHoward Hughes Medical InstituteHelen Hay Whitney Foundation (Postdoctoral Fellowship)Alfred P. Sloan FoundationNational Institutes of Health (U.S.) (Grant 8DP1CA174427)National Institutes of Health (U.S.) (Grant 2R01CA119176-01

Centralising Local Aboriginal Language and Culture in Healthy Skin Books on the See Treat Prevent (SToP) Trial in the Kimberley Region of Western Australia: A Process and Impact Inquiry

Language is significant for communicating knowledge across cultures and generations and has the power to attribute meanings and alter our worldviews. More than 250 Aboriginal and Torres Strait Islanders languages were spoken in 1788. This number has diminished to approximately 110 languages spoken in 2016, of which 90% were considered endangered in 2019. Language custodians and speakers across Australia are working to preserve and ensure languages are strongly spoken into the future. Language revitalisation initiatives can facilitate (re)connection to Country, cultures and communities and be recognised as acts of reconciliation for Aboriginal and Torres Strait Islander peoples. In a health context, recent evidence indicates that connection to language and culture is important in promoting overall health and wellbeing for Indigenous people. Embedding culture and language into health resources is now a key strategy for public health to reduce the existing health inequities experienced by Aboriginal and Torres Strait Islander people. With the increased demand for Indigenous language health promotion resources, practical policies and guidelines on development and distribution are required. Furthermore, investigation is warranted into the effectiveness and impact of local community context and how end users perceive and may apply these resources. MethodsThis study reports a qualitative research process and impact inquiry of Aboriginal community-led healthy skin resources to address the gaps in understanding the development and impact of Indigenous language health promotion resources. The development of these resources is described in detail, followed by an impact inquiry, including perspectives from six end users employed in health care, health ethics and governance. Data for this impact inquiry were collected via audio recorded semi-structured interviews, which were transcribed verbatim before an inductive thematic analysis was conducted. It is anticipated that these perspectives will help guide best practice in the development and use of future resources in language. FindingsOur study validates how strong Aboriginal leadership from Elders and community members guided the development of the books. Using local language custodians and speakers to translate healthy skin messages facilitated two-way learning opportunities and enabled self-determination in the communities. Healthcare practitioners articulated the benefit of using language and visuals to help explain skin infections and their sequelae. An Aboriginal health research ethics committee and research governance staff believed these books were best practice for guiding future health promotion resources in an Aboriginal context

Adaptive mistranslation accelerates the evolution of fluconazole resistance and induces major genomic and gene expression alterations in Candida albicans

Regulated erroneous protein translation (adaptive mistranslation) increases proteome diversity and produces advantageous phenotypic variability in the human pathogen Candida albicans. It also increases fitness in the presence of fluconazole, but the underlying molecular mechanism is not understood. To address this question, we evolved hypermistranslating and wild-type strains in the absence and presence of fluconazole and compared their fluconazole tolerance and resistance trajectories during evolution. The data show that mistranslation increases tolerance and accelerates the acquisition of resistance to fluconazole. Genome sequencing, array-based comparative genome analysis, and gene expression profiling revealed that during the course of evolution in fluconazole, the range of mutational and gene deregulation differences was distinctively different and broader in the hypermistranslating strain, including multiple chromosome duplications, partial chromosome deletions, and polyploidy. Especially, the increased accumulation of loss-of-heterozygosity events, aneuploidy, translational and cell surface modifications, and differences in drug efflux seem to mediate more rapid drug resistance acquisition under mistranslation. Our observations support a pivotal role for adaptive mistranslation in the evolution of drug resistance in C. albicans. IMPORTANCE Infectious diseases caused by drug-resistant fungi are an increasing threat to public health because of the high mortality rates and high costs associated with treatment. Thus, understanding of the molecular mechanisms of drug resistance is of crucial interest for the medical community. Here we investigated the role of regulated protein mistranslation, a characteristic mechanism used by C. albicans to diversify its proteome, in the evolution of fluconazole resistance. Such codon ambiguity is usually considered highly deleterious, yet recent studies found that mistranslation can boost adaptation in stressful environments. Our data reveal that CUG ambiguity diversifies the genome in multiple ways and that the full spectrum of drug resistance mechanisms in C. albicans goes beyond the traditional pathways that either regulate drug efflux or alter the interactions of drugs with their targets. The present work opens new avenues to understand the molecular and genetic basis of microbial drug resistance.publishe

Dietary Almonds Increase Serum HDL Cholesterol in Coronary Artery Disease Patients in a Randomized Controlled Trial.

Background: More than one-half of coronary artery disease (CAD) patients have low HDL cholesterol despite having well-managed LDL cholesterol. Almond supplementation has not been shown to elevate circulating HDL cholesterol concentrations in clinical trials, perhaps because the baseline HDL cholesterol of trial subjects was not low. Objective: This clinical trial was designed to test the effect of almond supplementation on low HDL cholesterol in CAD patients. Methods: A total of 150 CAD patients (50 per group), with serum LDL cholesterol ≤100 mg/dL and HDL cholesterol ≤40 mg/dL in men and ≤50 mg/dL in women, were recruited from the Aga Khan University Hospital. After recording vital signs and completing a dietary and physical activity questionnaire, patients were randomly assigned to 1 of the following 3 groups: the no-intervention group (NI), the Pakistani almonds group (PA), and the American almonds group (AA). The respective almond varieties (10 g/d) were given to patients with instructions to soak them overnight, remove the skin, and eat them before breakfast. Blood samples for lipid profiling, body weight, and blood pressure were collected, and assessment of dietary patterns was done at baseline, week 6, and week 12. Results: Almonds significantly increased HDL cholesterol. At weeks 6 and 12, HDL cholesterol was 12-14% and 14-16% higher, respectively, in the PA and AA than their respective baselines. In line with previous reports, serum concentrations of total cholesterol, triglycerides, LDL cholesterol, and VLDL cholesterol; total-to-HDL and LDL-to-HDL cholesterol ratios, and the atherogenic index were reduced in both the PA and AA at weeks 6 and 12 compared with baseline (P \u3c 0.05). Effects on serum lipids did not differ between the 2 almond groups. Dietary patterns, body weight, and blood pressure did not change in any of the 3 groups during the trial. Conclusion: A low dose of almonds (10 g/d) consumed before breakfast can increase HDL cholesterol, in addition to improving other markers of abnormal lipid metabolism in CAD patients with low initial HDL cholesterol. This trial was registered at the Australian New Zealand Clinical Trial Registry as ACTRN12614000036617

Intimate Partner Violence and Health Care-Seeking Patterns Among Female Users of Urban Adolescent Clinics

To assess the prevalence of intimate partner violence (IPV) and associations with health care-seeking patterns among female patients of adolescent clinics, and to examine screening for IPV and IPV disclosure patterns within these clinics. A self-administered, anonymous, computerized survey was administered to female clients ages 14–20 years (N = 448) seeking care in five urban adolescent clinics, inquiring about IPV history, reasons for seeking care, and IPV screening by and IPV disclosure to providers. Two in five (40%) female urban adolescent clinic patients had experienced IPV, with 32% reporting physical and 21% reporting sexual victimization. Among IPV survivors, 45% reported abuse in their current or most recent relationship. IPV prevalence was equally high among those visiting clinics for reproductive health concerns as among those seeking care for other reasons. IPV victimization was associated with both poor current health status (AOR 1.57, 95% CI 1.03–2.40) and having foregone care in the past year (AOR 2.59, 95% CI 1.20–5.58). Recent IPV victimization was associated only with past 12 month foregone care (AOR 2.02, 95% CI 1.18–3.46). A minority (30%) reported ever being screened for IPV in a clinical setting. IPV victimization is pervasive among female adolescent clinic attendees regardless of visit type, yet IPV screening by providers appears low. Patients reporting poor health status and foregone care are more likely to have experienced IPV. IPV screening and interventions tailored for female patients of adolescent clinics are needed

Ploidy variation in fungi: Polyploidy, aneuploidy, and genome evolution

The ability of an organism to replicate and segregate its genome with high fidelity is vital to its survival and for the production of future generations. Errors in either of these steps (replication or segregation) can lead to a change in ploidy or chromosome number. While these drastic genome changes can be detrimental to the organism, resulting in decreased fitness, they can also provide increased fitness during periods of stress. A change in ploidy or chromosome number can fundamentally change how a cell senses and responds to its environment. Here, we discuss current ideas in fungal biology that illuminate how eukaryotic genome size variation can impact the organism at a cellular and evolutionary level. One of the most fascinating observations from the past 2 decades of research is that some fungi have evolved the ability to tolerate large genome size changes and generate vast genomic heterogeneity without undergoing canonical meiosis

Altered trunk and lower extremity movement coordination after neuromuscular training with and without external focus instruction: a randomized controlled trial

Abstract Background This study sought to determine the effects of a 6-week neuromuscular training (NMT) and NMT plus external focus (NMT plus EF) programs on trunk and lower extremity inter-segmental movement coordination in active individuals at risk of injury. Methods Forty-six active male athletes (controls = 15, NMT = 16, NMT plus EF = 15) participated (age = 23.26 ± 2.31 years) in this controlled, laboratory study. Three-dimensional kinematics were collected during a drop vertical jump (DVJ). A continuous relative phase (CRP) analysis quantified inter-segmental coordination of the: (1) thigh (flexion/extension)—shank (flexion/extension), (2) thigh (abduction/adduction)—shank (flexion/extension), (3) thigh (abduction/adduction)—trunk (flexion/extension), and (4) trunk (flexion/extension)—pelvis (posterior tilt/anterior tilt). Analysis of covariance compared biomechanical data between groups. Results After 6 weeks, inter-segmental coordination patterns were significantly different between the NMT and NMT plus EF groups (p &lt; 0.05). No significant differences were observed in CRP for trunk-pelvis coupling comparing between NMT and NMT plus EF groups (p = 0.134), while significant differences were observed CRP angle of the thigh-shank, thigh-trunk couplings (p &lt; 0.05). Conclusions Trunk and lower extremity movement coordination were more in-phase during DVJ in the NMT plus EF compared to NMT in active individuals at risk of anterior cruciate ligament injury. Trial registration: The protocol was prospectively registered at UMIN_RCT website with ID number: UMIN000035050, Date of provisional registration 2018/11/27. </jats:sec

Emergency medical equipment storage: benefits of visual cues tested in field and simulated settings

Objective: We tested the effectiveness of an illustrated divider ("the divider") for bedside emergency equipment drawers in an intensive care unit (ICU). In Study 1, we assessed whether the divider increases completeness and standardizes the locations of emergency equipment within the drawer. In Study 2, we investigated whether the divider decreases nurses' restocking and retrieval times and decreases their workload. Background: Easy access to fully stocked emergency equipment is important during emergencies. However, inefficient equipment storage and cognitively demanding work settings might mean that drawers are incompletely stocked and access to items is slow. Method: A pre-post-post study investigated drawer completeness and item locations before and after the introduction of the divider to 30 ICU drawers. A subsequent experiment measured item restocking time, item retrieval time, and subjective workload for nurses. Results: At 2 weeks and 10 weeks after the divider was introduced, the completeness of the drawer increased significantly compared with before the divider was introduced. The divider decreased the variability of the locations of the 17 items in the drawer to 16% of its original value. Study 2 showed that restocking times but not retrieval times were significantly faster with the divider present. For both tasks, nurses rated their workload lower with the divider. Conclusions: The divider improved the standardization and completeness of emergency equipment. In addition, restocking times and workload were decreased with the divider. Application: Redesigning storage for certain equipment using human factors design principles can help to speed and standardize restocking and ease access to equipment

Additional file 1 of Altered trunk and lower extremity movement coordination after neuromuscular training with and without external focus instruction: a randomized controlled trial

Additional file 1. Appendix 1. The neuromuscular training protocols