Search

Abstract Mathematical models of complex systems rely on parameter values to produce a desired behavior. As mathematical and computational models increase in complexity, it becomes correspondingly difficult to find parameter values that satisfy system constraints. We propose a Markov Chain Monte Carlo (MCMC) approach for the problem of constrained model parameter generation by designing a Markov chain that efficiently explores a model’s parameter space. We demonstrate the use of our proposed methodology to analyze responses of a newly constructed bistability-constrained model of protein phosphorylation to perturbations in the underlying protein network. Our results suggest that parameter generation for constrained models using MCMC provides powerful tools for modeling-aided analysis of complex natural processes.

Introduction: Despite the wide availability of clinical decision rules for imaging of the cervical spine after a traumatic injury (eg, NEXUS C-spine rule and Canadian C-spine rule), there is significant overutilization of computed tomography (CT) imaging in patients who are deemed to be at low risk for a clinically significant cervical spine injury by these clinical decision rules. The purpose of this study was to identify the major factors associated with the overuse of CT cervical spine imaging using a logistic regression model. Methods: This was a retrospective review of all adult patients who underwent CT cervical spine imaging for evaluation of a traumatic injury at a tertiary academic emergency department (ED) and three affiliate community EDs in January and February 2019. We performed multivariable logistic regression to identify factors associated with obtaining CT cervical spine imaging despite low-risk classification by the NEXUS C-spine Rule. Results: A total of 1,051 patients underwent CT cervical spine imaging for traumatic indications during the study period, and 889 patients were included in the analysis. Of these patients, 376 (42.3%) were negative by the NEXUS C-spine rule. Variables that were associated with increased likelihood of unnecessary imaging included age over 65, Emergency Severity Index (ESI) score 2 and 3, arrival as a walk-in, and anticoagulation status. Patients who presented to the tertiary academic ED had a significantly lower likelihood of unnecessary imaging. Twenty-one patients (2.4%) were found to have cervical spine fractures on imaging, two of whom were negative by the NEXUS C-spine rule, but neither had a clinically significant fracture. Conclusion: Cervical spine imaging is vastly overused in patients presenting to the ED with traumatic injuries, as adjudicated using the NEXUS C-spine rule as a reference standard. Older age, ESI level, arrival as a walk-in, and taking anticoagulation drugs were associated with overutilization of CT imaging. Conversely, presenting to the tertiary academic ED was associated with a lower likelihood of undergoing unnecessary imaging. This model can guide future interventions to optimize ED CT utilization and minimize unnecessary testing.

Abstract Many members of the scorpaenid subfamily: Sebastinae (rockfishes and their relatives) exhibit slow growth and extreme longevity (> 100 y), thus are estimated to be vulnerable to overfishing. Blackbelly rosefish (Helicolenus dactylopterus) is a deepwater sebastine whose longevity estimates range widely, possibly owing to different regional levels of fisheries exploitation across its Atlantic Ocean range. However, age estimation has not been validated for this species and ageing for sebastines in general is uncertain. We performed age validation of northern Gulf of Mexico blackbelly rosefish via an application of the bomb radiocarbon chronometer which utilized eye lens cores instead of more traditional otolith cores as the source of birth year Δ14C signatures. The correspondence of eye lens core Δ14C with a regional reference series was tested with a novel Bayesian spline analysis, which revealed otolith opaque zone counts provide accurate age estimates. Maximum observed longevity was 90 y, with 17.5% of individuals aged to be > 50 y. Bayesian growth analysis, with estimated length-at-birth included as a prior, revealed blackbelly rosefish exhibit extremely slow growth (k = 0.08 y−1). Study results have important implications for the management of blackbelly rosefish stocks, as extreme longevity and slow growth imply low resilience to fishing pressure.

The emergency department patient population is disproportionately under-screened for cancer, making it an optimal environment to promote cancer screening among hard-to-reach populations and those without routine access to primary care. The first step in a cancer screening process is identifying screening eligibility (e.g. age, sex) and need (i.e. due or past due). In an effort to support the scalability of an emergency department (ED)-based cervical cancer screening intervention, we examined the performance of a low-resource approach of determining cervical cancer screening needs among ED patients. A convenience sample of ED patients (N = 2807) was randomized to (a) an in-person interview with human subjects research staff or, (b) a self-administered, tablet computer-based survey for determining cervical cancer eligibility and need. Patients were recruited from a high-volume urban ED in Rochester, NY and a low-volume rural ED in Dansville, NY between December 2020 and December 2022. Results of these approaches were compared for equivalence of method for determining adherence status with screening guidelines and under/over-reporting of screening activity. Nearly identical reported rates of non-adherence with screening were identified across conditions (1.7% absolute difference; Χ2 1 = 0.96, p = 0.33). Our results demonstrate that a low-resource approach of using a tablet-based self-administered survey to determine cervical cancer screening needs is equivalent to a labor intensive in-person interview approach conducted by trained research staff among ED patients.

Acid soils are a major constraint to agricultural productivity in many parts of sub-Saharan Africa, including Ethiopia. Restoring soil pH to optimal ranges for agriculture can have a significant impact on yields, particularly for acid intolerant crops like wheat and barley. The application of agricultural lime is the standard corrective, although the large application requirements, lack of farmer awareness, and weak or non-existent lime supply chains make this a complex problem to address at scale. To date, no large-scale farmer trials of lime application have been undertaken in Ethiopia. This leaves open the question to local policy makers as to the economic benefits given the enormous capital and logistics investments required. To help address this we leverage existing spatial edaphic data and longitudinal crop surveys to simulate the productivity impact of varying lime and fertilizer applications. Our estimates find the impact of moving pH from 5.5 to 6.5, modeled as a lime soil remediation strategy, increases yields by 22% and 19% for wheat and barley, respectively. In addition, at lower pH levels our models indicate that commonly used nitrogen-based fertilizers are less cost-effective. For wheat in highly acidic soils, we find that fertilizers cost over two times as much as a single application of lime over a five-year period. The cost savings of the use of lime reaches as high as 121% of average one-year agricultural household income for wheat; with barley these savings are lower but still substantial at 24%. In general, we advocate for an integrated soil fertility management strategy that applies appropriate levels of fertilizer on pH balanced soil. If successful, Ethiopia's acid soil reclamation could become a modest version of Brazil's successful "cerrado miracle" and serve as an example for Africa.

Acid soils are a major constraint to agricultural productivity in many parts of sub-Saharan Africa, including Ethiopia. Restoring soil pH to optimal ranges for agriculture can have a significant impact on yields, particularly for acid intolerant crops like wheat and barley. The application of agricultural lime is the standard corrective, although the large application requirements, lack of farmer awareness, and weak or non-existent lime supply chains make this a complex problem to address at scale. To date, no large-scale farmer trials of lime application have been undertaken in Ethiopia. This leaves open the question to local policy makers as to the economic benefits given the enormous capital and logistics investments required. To help address this we leverage existing spatial edaphic data and longitudinal crop surveys to simulate the productivity impact of varying lime and fertilizer applications. Our estimates find the impact of moving pH from 5.5 to 6.5, modeled as a lime soil remediation strategy, increases yields by 22% and 19% for wheat and barley, respectively. In addition, at lower pH levels our models indicate that commonly used nitrogen-based fertilizers are less cost-effective. For wheat in highly acidic soils, we find that fertilizers cost over two times as much as a single application of lime over a five-year period. The cost savings of the use of lime reaches as high as 121% of average one-year agricultural household income for wheat; with barley these savings are lower but still substantial at 24%. In general, we advocate for an integrated soil fertility management strategy that applies appropriate levels of fertilizer on pH balanced soil. If successful, Ethiopia’s acid soil reclamation could become a modest version of Brazil’s successful “cerrado miracle” and serve as an example for Africa.

Protective immunity against SARS-CoV-2 infection after COVID-19 vaccination may differ by variant. We enrolled vaccinated (n = 39) and unvaccinated (n = 11) individuals with acute, symptomatic SARS-CoV-2 Delta or Omicron infection and performed SARS-CoV-2 viral load quantification, whole-genome sequencing, and variant-specific antibody characterization at the time of acute illness and convalescence. Viral load at the time of infection was inversely correlated with antibody binding and neutralizing antibody responses. Across all variants tested, convalescent neutralization titers in unvaccinated individuals were markedly lower than in vaccinated individuals. Increases in antibody titers and neutralizing activity occurred at convalescence in a variant-specific manner. For example, among individuals infected with the Delta variant, neutralizing antibody responses were weakest against BA.2, whereas infection with Omicron BA.1 variant generated a broader response against all tested variants, including BA.2.

Abstract Background Artificial intelligence (AI) in diagnostic radiology is undergoing rapid development. Its potential utility to improve diagnostic performance for cardiopulmonary events is widely recognized, but the accuracy and precision have yet to be demonstrated in the context of current screening modalities. Here, we present findings on the performance of an AI convolutional neural network (CNN) prototype (AI-RAD Companion, Siemens Healthineers) that automatically detects pulmonary nodules and quantifies coronary artery calcium volume (CACV) on low-dose chest CT (LDCT), and compare results to expert radiologists. We also correlate AI findings with adverse cardiopulmonary outcomes in a retrospective cohort of 117 patients who underwent LDCT. Methods A total of 117 patients were enrolled in this study. Two CNNs were used to identify lung nodules and CACV on LDCT scans. All subjects were used for lung nodule analysis, and 96 subjects met the criteria for coronary artery calcium volume analysis. Interobserver concordance was measured using ICC and Cohen’s kappa. Multivariate logistic regression and partial least squares regression were used for outcomes analysis. Results Agreement of the AI findings with experts was excellent (CACV ICC = 0.904, lung nodules Cohen’s kappa = 0.846) with high sensitivity and specificity (CACV: sensitivity = .929, specificity = .960; lung nodules: sensitivity = 1, specificity = 0.708). The AI findings improved the prediction of major cardiopulmonary outcomes at 1-year follow-up including major adverse cardiac events and lung cancer (AUCMACE = 0.911, AUCLung Cancer = 0.942). Conclusion We conclude the AI prototype rapidly and accurately identifies significant risk factors for cardiopulmonary disease on standard screening low-dose chest CT. This information can be used to improve diagnostic ability, facilitate intervention, improve morbidity and mortality, and decrease healthcare costs. There is also potential application in countries with limited numbers of cardiothoracic radiologists.

Abstract Soil property and class maps for the continent of Africa were so far only available at very generalised scales, with many countries not mapped at all. Thanks to an increasing quantity and availability of soil samples collected at field point locations by various government and/or NGO funded projects, it is now possible to produce detailed pan-African maps of soil nutrients, including micro-nutrients at fine spatial resolutions. In this paper we describe production of a 30 m resolution Soil Information System of the African continent using, to date, the most comprehensive compilation of soil samples ( $$N \approx 150,000$$ N ≈ 150 , 000 ) and Earth Observation data. We produced predictions for soil pH, organic carbon (C) and total nitrogen (N), total carbon, effective Cation Exchange Capacity (eCEC), extractable—phosphorus (P), potassium (K), calcium (Ca), magnesium (Mg), sulfur (S), sodium (Na), iron (Fe), zinc (Zn)—silt, clay and sand, stone content, bulk density and depth to bedrock, at three depths (0, 20 and 50 cm) and using 2-scale 3D Ensemble Machine Learning framework implemented in the mlr (Machine Learning in R) package. As covariate layers we used 250 m resolution (MODIS, PROBA-V and SM2RAIN products), and 30 m resolution (Sentinel-2, Landsat and DTM derivatives) images. Our fivefold spatial Cross-Validation results showed varying accuracy levels ranging from the best performing soil pH (CCC = 0.900) to more poorly predictable extractable phosphorus (CCC = 0.654) and sulphur (CCC = 0.708) and depth to bedrock. Sentinel-2 bands SWIR (B11, B12), NIR (B09, B8A), Landsat SWIR bands, and vertical depth derived from 30 m resolution DTM, were the overall most important 30 m resolution covariates. Climatic data images—SM2RAIN, bioclimatic variables and MODIS Land Surface Temperature—however, remained as the overall most important variables for predicting soil chemical variables at continental scale. This publicly available 30-m Soil Information System of Africa aims at supporting numerous applications, including soil and fertilizer policies and investments, agronomic advice to close yield gaps, environmental programs, or targeting of nutrition interventions.

Abstract Background Migraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models. Methods Acute sleep deprivation was achieved using the “gentle handling method”, chosen to minimize stress and avoid confounding bias. Sleep deprivation was started with onset of light (diurnal lighting conditions), and assessment of CSD was performed at the end of a 6 h or 12 h sleep deprivation period. The effect of chronic sleep deprivation on CSD was assessed 6 weeks or 12 weeks after lesioning of the hypothalamic ventrolateral preoptic nucleus. All experiments were done in a blinded fashion with respect to sleep status. During 60 min of continuous topical KCl application, we assessed the total number of CSDs, the direct current shift amplitude and duration of the first CSD, the average and cumulative duration of all CSDs, propagation speed, and electrical CSD threshold. Results Acute sleep deprivation of 6 h (n = 17) or 12 h (n = 11) duration significantly increased CSD frequency compared to controls (17 ± 4 and 18 ± 2, respectively, vs. 14 ± 2 CSDs/hour in controls; p = 0.003 for both), whereas other electrophysiological properties of CSD were unchanged. Acute total sleep deprivation over 12 h but not over 6 h reduced the electrical threshold of CSD compared to controls (p = 0.037 and p = 0.095, respectively). Chronic partial sleep deprivation in contrast did not affect CSD susceptibility in rats. Conclusions Acute but not chronic sleep deprivation enhances CSD susceptibility in rodents, possibly underlying its negative impact as a migraine trigger and exacerbating factor. Our findings underscore the importance of CSD as a therapeutic target in migraine and suggest that headache management should identify and treat associated sleep disorders.

Isolation guidelines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are largely derived from data collected prior to the emergence of the delta variant. We followed a cohort of ambulatory patients with postvaccination breakthrough SARS-CoV-2 infections with longitudinal collection of nasal swabs for SARS-CoV-2 viral load quantification, whole-genome sequencing, and viral culture. All delta variant infections in our cohort were symptomatic, compared with 64% of non-delta variant infections. Symptomatic delta variant breakthrough infections were characterized by higher initial viral load, longer duration of virologic shedding by PCR, greater likelihood of replication-competent virus at early stages of infection, and longer duration of culturable virus compared with non-delta variants. The duration of time since vaccination was also correlated with both duration of PCR positivity and duration of detection of replication-competent virus. Nonetheless, no individuals with symptomatic delta variant infections had replication-competent virus by day 10 after symptom onset or 24 hours after resolution of symptoms. These data support US CDC isolation guidelines as of November 2021, which recommend isolation for 10 days or until symptom resolution and reinforce the importance of prompt testing and isolation among symptomatic individuals with delta breakthrough infections. Additional data are needed to evaluate these relationships among asymptomatic and more severe delta variant breakthrough infections.

Current understanding of sea turtle nesting, hatching, and emergence events has been largely limited to observable events on the surface of the sand, though recent approaches using audio or visual equipment have allowed scientists to better understand some underground nest phenomena. We used a technology-based approach to define motion-related Caretta caretta hatching and emergence nest events. We describe a novel low-cost, accelerometer-based system called TurtleSense that can detect movement and temperature within sea turtle nests remotely. TurtleSense is successfully able to specifically detect motion within sea turtle nests over the entire course of incubation. This system allows for the identification of infertile nests and the detection of four predictable sequential developmental activity patterns in viable nests, including a hatch and posthatch period, the timing of which can be used to tightly predict hatchling emergence events almost to the day. TurtleSense provides a much better understanding about what is happening in the nest before emergence and allows for the generation of a theory of the mechanism that triggers mass emergence. Our results suggest that motion plays a large role in hatchling communication and that the timing of emergence events may be related to the cessation of movement within the nest. Current management of sea turtle nesting events is primarily driven by counting the number of days since the nest was laid, with further safeguards placed at the nest upon subsequent visual observation of depression or emergence events. Use of TurtleSense technology can impact nest management and conservation efforts, allowing organizations to use this motion data to more tightly predict emergence dates for sea turtle hatchlings and to use viability data to inform nest management decisions.

BACKGROUND: To meet the rising demand for cancer care in low- and middle-income countries (LMICs), educational partnerships are needed. The Geisel School of Medicine at Dartmouth (GSMD) Hematology-Oncology Fellowship Program (HOFP) piloted a bi-annual elective in Rwanda supervised by GSMD faculty. OBJECTIVE: Exchange of knowledge and collaborations regarding treatment of advanced cancer in a low-resource setting. METHODS: Program objectives were implemented by GSMD HOFP, Rwandan Ministry of Health, the NGO Partners In Health, and the Butaro Hospital Cancer Center of Excellence (BCCOE) in Butaro, Rwanda. Education, organizational changes, research projects, and funding sources were tracked. Fellows were evaluated using American College of Graduate Medical Education clinical competencies. RESULTS: The two-year pilot program was 100% enrolled. Ten educational, research, and organizational projects were implemented. Three grant proposals are in process. Fifty percent of participating Fellows plan to pursue careers in Global Health. The Hematology-Oncology (HO) Fellows gained perspective on cancer care capacity-building in a LMIC, and confidence in teaching. BCCOE staff gained knowledge and mentorship, ideas for quality improvement, and increased expertise with treatment protocols. Rwandan and U.S. colleagues valued the solidarity generated by the regular exchange, and a long-term commitment is planned. CONCLUSION: A Global Oncology Fellowship elective is feasible and has a qualitative impact on care delivery and collaboration in LMICs influencing Fellows’ career choices and professional growth of colleagues at partner sites. Long-term partnerships complement the task-sharing approach to cancer care. Financial sustainability requires formal institutional support for faculty participation.

Optogenetic tools have revolutionized the study of receptor-mediated processes, but such tools are lacking for RNA-controlled systems. In particular, light-activated regulatory RNAs are needed for spatiotemporal control of gene expression. To fill this gap, we used in vitro selection to isolate a novel riboswitch that selectively binds the trans isoform of a stiff-stilbene (amino-tSS)–a rapidly and reversibly photoisomerizing small molecule. Structural probing revealed that the RNA binds amino-tSS about 100-times stronger than the cis photoisoform (amino-cSS). In vitro and in vivo functional analysis showed that the riboswitch, termed Werewolf-1 (Were-1), inhibits translation of a downstream open reading frame when bound to amino-tSS. Photoisomerization of the ligand with a sub-millisecond pulse of light induced the protein expression. In contrast, amino-cSS supported protein expression, which was inhibited upon photoisomerization to amino-tSS. Reversible photoregulation of gene expression using a genetically encoded RNA will likely facilitate high-resolution spatiotemporal analysis of complex RNA processes.

Low crop yields in Sub-Saharan Africa are associated with low fertilizer use. To better understand patterns of, and opportunities for, fertilizer use, location specific fertilizer price data may be relevant. We compiled local market price data for urea fertilizer, a source of inorganic nitrogen, in 1729 locations in eighteen countries in two regions (West and East Africa) from 2010-2018 to understand patterns in the spatial variation in fertilizer prices. The average national price was lowest in Ghana (0.80 USD kg-1), Kenya (0.97 USD kg-1), and Nigeria (0.99 USD kg-1). Urea was most expensive in three landlocked countries (Burundi: 1.51, Uganda: 1.49, and Burkina Faso: 1.49 USD kg-1). Our study uncovers considerable spatial variation in fertilizer prices within African countries. We show that in many countries this variation can be predicted for unsampled locations by fitting models of prices as a function of longitude, latitude, and additional predictor variables that capture aspects of market access, demand and environmental conditions. Predicted within-country urea price variation (as a fraction of the median price) was particularly high in Kenya (0.77-1.12), Nigeria (0.83-1.34), Senegal (0.73-1.40), Tanzania (0.90-1.29) and Uganda (0.93-1.30), but much lower in Burkina Faso (0.96-1.04), Burundi (0.95-1.05), and Togo (0.94-1.05). The correlation coefficient of the country level models was between 0.17 to 0.83 (mean 0.52) and the RMSE varies from 0.005 to 0.188 (mean 0.095). In 10 countries, predictions were at least 25% better than a null-model that assumes no spatial variation. Our work indicates new opportunities for incorporating spatial variation in prices into efforts to understand the profitability of agricultural technologies across rural areas in Sub-Saharan Africa.

BACKGROUND:With the growing adoption of the electronic health record (EHR) worldwide over the last decade, new opportunities exist for leveraging EHR data for detection of rare diseases. Rare diseases are often not diagnosed or delayed in diagnosis by clinicians who encounter them infrequently. One such rare disease that may be amenable to EHR-based detection is acute hepatic porphyria (AHP). AHP consists of a family of rare, metabolic diseases characterized by potentially life-threatening acute attacks and chronic debilitating symptoms. The goal of this study was to apply machine learning and knowledge engineering to a large extract of EHR data to determine whether they could be effective in identifying patients not previously tested for AHP who should receive a proper diagnostic workup for AHP. METHODS AND FINDINGS:We used an extract of the complete EHR data of 200,000 patients from an academic medical center and enriched it with records from an additional 5,571 patients containing any mention of porphyria in the record. After manually reviewing the records of all 47 unique patients with the ICD-10-CM code E80.21 (Acute intermittent [hepatic] porphyria), we identified 30 patients who were positive cases for our machine learning models, with the rest of the patients used as negative cases. We parsed the record into features, which were scored by frequency of appearance and filtered using univariate feature analysis. We manually choose features not directly tied to provider attributes or suspicion of the patient having AHP. We trained on the full dataset, with the best cross-validation performance coming from support vector machine (SVM) algorithm using a radial basis function (RBF) kernel. The trained model was applied back to the full data set and patients were ranked by margin distance. The top 100 ranked negative cases were manually reviewed for symptom complexes similar to AHP, finding four patients where AHP diagnostic testing was likely indicated and 18 patients where AHP diagnostic testing was possibly indicated. From the top 100 ranked cases of patients with mention of porphyria in their record, we identified four patients for whom AHP diagnostic testing was possibly indicated and had not been previously performed. Based solely on the reported prevalence of AHP, we would have expected only 0.002 cases out of the 200 patients manually reviewed. CONCLUSIONS:The application of machine learning and knowledge engineering to EHR data may facilitate the diagnosis of rare diseases such as AHP. Further work will recommend clinical investigation to identified patients' clinicians, evaluate more patients, assess additional feature selection and machine learning algorithms, and apply this methodology to other rare diseases. This work provides strong evidence that population-level informatics can be applied to rare diseases, greatly improving our ability to identify undiagnosed patients, and in the future improve the care of these patients and our ability study these diseases. The next step is to learn how best to apply these EHR-based machine learning approaches to benefit individual patients with a clinical study that provides diagnostic testing and clinical follow up for those identified as possibly having undiagnosed AHP.

[This corrects the article DOI: 10.1371/journal.pone.0235574.].

We present an easily calibrated spatial modeling framework for estimating location-specific fertilizer responses, using smallholder maize farming in Tanzania as a case study. By incorporating spatially varying input and output prices, we predict the expected profitability for a location-specific smallholder farmer. A stochastic rainfall component of the model allows us to quantify the uncertainty around expected economic returns. The resulting mapped estimates of expected profitability and uncertainty are good predictors of actual smallholder fertilizer usage in nationally representative household survey data. The integration of agronomic and economic information in our framework makes it a powerful tool for spatially explicit targeting of agricultural technologies and complementary investments, as well as estimating returns to investments at multiple scales.

We present an easily calibrated spatial modeling framework for estimating location-specific fertilizer responses, using smallholder maize farming in Tanzania as a case study. By incorporating spatially varying input and output prices, we predict the expected profitability for a location-specific smallholder farmer. A stochastic rainfall component of the model allows us to quantify the uncertainty around expected economic returns. The resulting mapped estimates of expected profitability and uncertainty are good predictors of actual smallholder fertilizer usage in nationally representative household survey data. The integration of agronomic and economic information in our framework makes it a powerful tool for spatially explicit targeting of agricultural technologies and complementary investments, as well as estimating returns to investments at multiple scales.

There is increasing support for HPV vaccination in the pharmacy setting, but the availability of the HPV vaccine is not well known. Additionally, little is known about perceptions of medical providers regarding referring patients to community pharmacies for HPV vaccination. The purpose of this study was to determine HPV vaccine availability in community pharmacies and to understand, among family medicine and obstetrics–gynecology providers, the willingness of and perceived barriers to referring patients for HPV vaccination in a pharmacy setting. HPV vaccine availability data were collected from pharmacies in a southern region of the United States. Family medicine and obstetrics–gynecology providers were surveyed regarding vaccine referral practices and perceived barriers to HPV vaccination in a community pharmacy. Results indicated the HPV vaccine was available in most pharmacies. Providers were willing to refer patients to a community pharmacy for HPV vaccination, despite this not being a common practice, likely due to numerous barriers reported. Pharmacist-administered HPV vaccination continues to be a commonly reported strategy for increasing HPV vaccination coverage. However, coordinated efforts to increase collaboration among vaccinators in different settings and to overcome systematic and legislative barriers to increasing HPV vaccination rates are still needed.

About 45:000 cancers are linked to HPV each year in the United States alone. The HPV vaccine prevents cancer and is highly effective, yet vaccination coverage remains low. Pharmacies can play a meaningful role in increasing HPV vaccination access due to their availability and convenience. However, little is known about pharmacists’ perceived barriers to HPV vaccination. The objective of this systematic review was to summarize existing literature on perceived barriers to administering HPV vaccination reported by pharmacists. Barriers identified from selected studies were synthesized and further grouped into patient, parental, (pharmacist’s) personal, and system/organization barrier groups. Six studies were included in this review. The cost of the HPV vaccine, insurance coverage and reimbursement were commonly reported perceived barriers. Adolescent HPV vaccination barriers related to parental concerns, beliefs, and inadequate knowledge about the HPV vaccine. Perceived (pharmacist’s) personal barriers were related to lack of information and knowledge about HPV vaccine and recommendations. At the system/organization level, barriers reported included lack of time/staff/space; difficulty in series completion; tracking and recall of patient; perceived competition with providers; and other responsibilities/vaccines taking precedence. Future strategies involving pharmacy settings in HPV-related cancer prevention efforts should consider research on multilevel pharmacy-driven interventions addressing barriers.

Head and neck squamous cell carcinoma (HNSCC) remains a morbid disease with poor prognosis and treatment that typically leaves patients with permanent damage to critical functions such as eating and talking. Currently only three targeted therapies are FDA approved for use in HNSCC, two of which are recently approved immunotherapies. In this work, we identify biological pathways involved with this disease that could potentially be targeted by current FDA approved cancer drugs and thereby expand the pool of potential therapies for use in HNSCC treatment. We analyzed 508 HNSCC patients with sequencing information from the Genomic Data Commons (GDC) database and assessed which biological pathways were significantly enriched for somatic mutations or copy number alterations. We then further classified pathways as either "light" or "dark" to the current reach of FDA-approved cancer drugs using the Cancer Targetome, a compendium of drug-target information. Light pathways are statistically enriched with somatic mutations (or copy number alterations) and contain one or more targets of current FDA-approved cancer drugs, while dark pathways are enriched with somatic mutations (or copy number alterations) but not currently targeted by FDA-approved cancer drugs. Our analyses indicated that approximately 35-38% of disease-specific pathways are in scope for repurposing of current cancer drugs. We further assess light and dark pathways for subgroups of patient tumor samples according to HPV status. The framework of light and dark pathways for HNSCC-enriched biological pathways allows us to better prioritize targeted therapies for further research in HNSCC based on the HNSCC genetic landscape and FDA-approved cancer drug information. We also highlight the importance in the identification of sub-pathways where targeting and cross targeting of other pathways may be most beneficial to predict positive or negative synergy with potential clinical significance. This framework is ideal for precision drug panel development, as well as identification of highly aberrant, untargeted candidates for future drug development.

Introduction: Our goal was to determine if the hemolysis among blood samples obtained in an emergency department and then sent to the laboratory in a pneumatic tube system was different from those in samples that were hand-carried. Methods: The hemolysis index is measured on all samples submitted for potassium analysis. We queried our hospital laboratory database system (SunQuest®) for potassium results for specimens obtained between January 2014 and July 2014. From facility maintenance records, we identified periods of system downtime, during which specimens were hand-carried to the laboratory. Results: During the study period, 15,851 blood specimens were transported via our pneumatic tube system and 92 samples were hand delivered. The proportions of hemolyzed specimens in the two groups were not significantly different (13.6% vs. 13.1% [p=0.90]). Results were consistent when the criterion was limited to gross (3.3% vs 3.3% [p=0.99]) or mild (10.3% vs 9.8% [p=0.88]) hemolysis. The hemolysis rate showed minimal variation during the study period (12.6%–14.6%). Conclusion: We found no statistical difference in the percentages of hemolyzed specimens transported by a pneumatic tube system or hand delivered to the laboratory. Certain features of pneumatic tube systems might contribute to hemolysis (e.g., speed, distance, packing material). Since each system is unique in design, we encourage medical facilities to consider whether their method of transport might contribute to hemolysis in samples obtained in the emergency department.

BACKGROUND:There has been a notable expansion in routine health care in sub-Saharan Africa. While heath care is nominally free in many contexts, the time required to access services reflects an opportunity cost that may be substantial and highly gendered, reflecting the gendered nature of health care guidelines and patterns of use. The time costs of health care use, however, have rarely been systematically assessed at the population-level. METHODS:Data come from the 2015 wave of a population-based cohort study of young adults in southern Malawi during which 1,453 women and 407 men between the ages of 21 and 31 were interviewed. We calculated the time spent seeking health care over a two-month period, disaggregating findings by men, recently-pregnant women, mothers with children under two years old, and "other women". We then extrapolated the time required for specific services to estimate the time that would be needed for each subpopulation to meet government recommendations for routine health services over the course of a year. RESULTS:Approximately 60% of women and 22% of men attended at least one health care visit during the preceding two months. Women spent six times as long seeking care as did men (t = -4.414, p

The New York City HIV Care Coordination Program (CCP) combines multiple evidence-based strategies to support persons living with HIV (PLWH) at risk for, or with a recent history of, poor HIV outcomes. We assessed the comparative effectiveness of the CCP by merging programmatic data on CCP clients with population-based surveillance data on all New York City PLWH. A non-CCP comparison group of similar PLWH who met CCP eligibility criteria was identified using surveillance data. The CCP and non-CCP groups were matched on propensity for CCP enrollment within four baseline treatment status groups (newly diagnosed or previously diagnosed and either consistently unsuppressed, inconsistently suppressed or consistently suppressed). We compared CCP to non-CCP proportions with viral load suppression at 12-month follow-up. Among the 13,624 persons included, 15∙3% were newly diagnosed; among the 84∙7% previously diagnosed, 14∙2% were consistently suppressed, 28∙9% were inconsistently suppressed, and 41∙6% were consistently unsuppressed in the year prior to baseline. At 12-month follow-up, 59∙9% of CCP and 53∙9% of non-CCP participants had viral load suppression (Relative Risk = 1.11, 95%CI:1.08-1.14). Among those newly diagnosed and those consistently unsuppressed at baseline, the relative risk of viral load suppression in the CCP versus non-CCP participants was 1.15 (95%CI:1.09-1.23) and 1.32 (95%CI:1.23-1.42), respectively. CCP exposure shows benefits over no CCP exposure for persons newly diagnosed or consistently unsuppressed, but not for persons suppressed in the year prior to baseline. We recommend more targeted case finding for CCP enrollment and increased attention to viral load suppression maintenance.

Alterations in DNA damage response and repair have been observed in Huntington's disease (HD). We generated induced pluripotent stem cells (iPSC) from primary dermal fibroblasts of 5 patients with HD and 5 control subjects. A significant fraction of the HD iPSC lines had genomic abnormalities as assessed by karyotype analysis, while none of our control lines had detectable genomic abnormalities. We demonstrate a statistically significant increase in genomic instability in HD cells during reprogramming. We also report a significant association with repeat length and severity of this instability. Our karyotypically normal HD iPSCs also have elevated ATM-p53 signaling as shown by elevated levels of phosphorylated p53 and H2AX, indicating either elevated DNA damage or hypersensitive DNA damage signaling in HD iPSCs. Thus, increased DNA damage responses in the HD genotype is coincidental with the observed chromosomal aberrations. We conclude that the disease causing mutation in HD increases the propensity of chromosomal instability relative to control fibroblasts specifically during reprogramming to a pluripotent state by a commonly used episomal-based method that includes p53 knockdown.

The absence of NCC does not cause significant salt wasting in NCC deficient mice under basal conditions. We hypothesized that ENaC and pendrin play important roles in compensatory salt absorption in the setting of NCC inactivation, and their inhibition and/or downregulation can cause significant salt wasting in NCC KO mice.WT and NCC KO mice were treated with a daily injection of either amiloride, an inhibitor of ENaC, or acetazolamide (ACTZ), a blocker of salt and bicarbonate reabsorption in the proximal tubule and an inhibitor of carbonic anhydrases in proximal tubule and intercalated cells, or a combination of acetazolamide plus amiloride for defined durations. Animals were subjected to daily balance studies. At the end of treatment, kidneys were harvested and examined. Blood samples were collected for electrolytes and acid base analysis.Amiloride injection significantly increased the urine output (UO) in NCC KO mice (from 1.3 ml/day before to 2.5 ml/day after amiloride, p0.05). The increase in UO in NCC KO mice was associated with a significant increase in sodium excretion (from 0.25 mmol/24 hrs at baseline to 0.35 mmol/24 hrs after amiloride injection, p80% reduction of kidney pendrin expression in both WT and NCC KO mice. However, ACTZ treatment noticeably increased urine output and salt excretion only in NCC KO mice (with urine output increasing from a baseline of 1.1 ml/day to 2.3 ml/day and sodium excretion increasing from 0.22 mmole/day before to 0.31 mmole/day after ACTZ) in NCC KO mice; both parameters were significantly higher than in WT mice. Western blot analysis demonstrated significant enhancement in ENaC expression in medulla and cortex of NCC KO and WT mice in response to ACTZ injection for 6 days, and treatment with amiloride in ACTZ-pretreated mice caused a robust increase in salt excretion in both NCC KO and WT mice. Pendrin KO mice did not display a significant increase in urine output or salt excretion after treatment with amiloride or ACTZ.1. ENaC plays an important role in salt reabsorption in NCC KO mice. 2. NCC contributes to compensatory salt reabsorption in the setting of carbonic anhydrase inhibition, which is associated with increased delivery of salt from the proximal tubule and the down regulation of pendrin. 3. ENaC is upregulated by ACTZ treatment and its inhibition by amiloride causes significant diuresis in NCC KO and WT mice. Despite being considered mild agents individually, we propose that the combination of acetazolamide and amiloride in the setting of NCC inhibition (i.e., hydrochlorothiazide) will be a powerful diuretic regimen.

Since Crohn's disease is a transmural disease, we hypothesized that examination of deep submucosal tissues directly involved in the inflammatory disease process may provide unique insights into bacterial populations transgressing intestinal barriers and bacterial populations more representative of the causes and agents of the disease. We performed deep 16s microbiota sequencing on isolated ilea mucosal and submucosal tissues on 20 patients with Crohn's disease and 15 non-inflammatory bowel disease controls with a depth of coverage averaging 81,500 sequences in each of the 70 DNA samples yielding an overall resolution down to 0.0001% of the bacterial population. Of the 4,802,328 total sequences generated, 98.9% or 4,749,183 sequences aligned with the Kingdom Bacteria that clustered into 8545 unique sequences with

Arachidonic acid (ARA) is essential in felines because conversion of dietary linoleic acid (LA) to ARA is rate-limited by low Δ6-desaturase. Dietary γ-linolenic acid (GLA) may serve as an ARA precursor by-passing this initial rate-limiting step. This possibility was investigated using twenty-six adult female domestic shorthair cats divided into three groups and fed on complete and balanced diets containing high GLA (GL), high LA (HL) or low LA (LL, control) diets, for 300 d prior to ovariohysterectomy. Plasma was obtained 1–2 d before surgery and uterine, ovarian and associated adipose tissues were reserved for lipid analysis. Fatty acid profiles of the plasma phospholipid (PL) fractions and adipose lipids were performed. In the GL group, plasma and uterine tissue PL were significantly enriched in GLA, di-homo GLA (DGLA) and ARA compared with control. However, ovarian and adipose tissue PL were only enriched in DGLA. Enrichment of uterine tissues with DGLA and ARA probably supplies the essential eicosanoid precursors for reproduction when GLA is fed consistently with an active Δ5-desaturase in uterus. By contrast, this enzyme appears less active in ovary because ARA was not higher compared with control. Earlier reports concluded that ARA was not necessary for fertilisation (an ovarian function), but required for successful pregnancy and reproduction (a uterine function). Adipose tissue DGLA may be a reservoir for ARA synthesis by other tissues upon mobilisation. Dietary GLA may meet feline ARA requirements in the absence of an animal-based preformed source of ARA.