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Peru is a historically unique and culturally diverse Latin American country. As a low-to-middle-income country (LMIC), Peru faces health implications from the spread of communicable diseases as well as a growing rate of noncommunicable diseases, both of which have been worsened by the recent COVID-19 pandemic’s impact on the national health system. Over the past two decades, the country has aimed to improve health access for its population through various efforts described in this review. Despite this, there are notable neurological health disparities that exist today. This narrative review investigates such disparities through the leading neurological contributors to the national burden of disease in the country, including migraine headaches, cerebrovascular disease, and dementia. Public health disparities that contribute to other major neurological diseases in the country, including epilepsy, neurocysticercosis, Chagas disease, multiple sclerosis, traumatic brain injury, traumatic and non-traumatic spinal cord injuries are also investigated. We also explore potential solutions for overcoming the various neurological health disparities covered in this review that may be applied through public policies, as well as in similar LMICs in Latin America. By overcoming such disparities, the country may be able to successfully address the major contributors of neurological disease burden and create a healthcare environment that can sustainably and equitably improve health outcomes for Peruvian people.

The nuclear receptor subfamily 5, Group A, Member 1 (NR5A1) gene encodes steroidogenic factor 1 (SF1), which is necessary for development of steroid hormone-producing tissues including the gonad and adrenal gland. An induced pluripotent stem cell line (iPSC) LCHi002-B was generated from a participant with differences (disorders) of sex development (DSD) and multiple genetic variants including a large deletion in NR5A1, and three single nucleotide changes in DYNC2H1, PDE4D, and ZFPM2. The line presented typical morphology, expressed stem cell markers, differentiated into three germ layers, had normal karyotype, was mycoplasma-free, and carried mutations in NR5A1, DYNC2H1, PDE4D, and ZFPM2.

Abstract Background Monoclonal antibody (mAb) treatment for COVID-19 is associated with improved clinical outcomes. However, there is limited information regarding the impact of treatment on symptoms and the prevalence of post-COVID Conditions (PCC). Understanding of the association between time to mAb infusion and the development of PCC is also limited. Methods This longitudinal study was conducted among patients with COVID-19 who received mAb infusions at a Federally Qualified Health Center in San Diego, CA. A series of telephone interviews were conducted at baseline and follow-up (14 days and 28+ days). A comprehensive symptom inventory was completed and physical and mental health status were measured using PROMIS-29 and PHQ-2. Pearson’s Chi-squared tests and independent two-sample t-tests were performed to test for association between time to mAb infusion and outcomes at follow-up. A Poisson regression model was used to analyze whether time to mAb infusion predicts risk of developing PCC. Results Participants (N = 411) were 53% female, ranged in age from 16 to 92 years (mean 50), and a majority (56%) were Latino/Hispanic. Cross-sectional findings revealed a high symptom burden at baseline (70% of patients had cough, 50% had fever, and 44% had headache). The prevalence of many symptoms decreased substantially by the final follow-up survey (29% of patients had cough, 3% had fever, and 28% had headache). Longitudinal findings indicated that 10 symptoms decreased in prevalence from baseline to final follow-up, 2 remained the same, and 14 increased. The severity of symptoms and most patient-reported physical and mental health measure scores decreased over time. The prevalence of PCC was 69% when PCC was defined as ≥ 1 symptom at final follow-up. Time to mAb infusion was not significantly associated with any outcome at follow-up. Time to infusion was not associated with PCC status at final follow-up in the crude or adjusted Poisson regression models. Conclusions The prevalence of PCC was high among this patient population following COVID-19 mAb treatment. Time to mAb infusion did not predict the development of PCC. Further research in these areas is essential to answer urgent clinical questions about effective treatments of COVID-19.

Abstract Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2− metastatic breast cancer (MBC) patients. However, 30–40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.

Abstract Salinization and eutrophication are nearly ubiquitous in watersheds with human activity. Despite the known impacts of the freshwater salinization syndrome (FSS) to organisms, we demonstrate a pronounced knowledge gap on how FSS alters wetland biogeochemistry. Most experiments assessing FSS and biogeochemistry pertain to coastal saltwater intrusion. The few inland wetland studies mostly add salt as sodium chloride. Sodium chloride alone does not reflect the ionic composition of inland salinization, which derives from heterogeneous sources, producing spatially and temporally variable ionic mixtures. We develop mechanistic hypotheses for how elevated ionic strength and changing ionic composition alter urban wetland sediment biogeochemistry, with the prediction that FSS diminishes nutrient removal capacity via a suite of related direct and indirect processes. We propose that future efforts specifically investigate inland urban wetlands, a category of wetland heavily relied on for its biogeochemical processing ability that is likely to be among the most impacted by salinization.

Worldwide consumer support of disadvantaged producers from developing countries has been encouraged through a variety of options, including the acquisition of Fairtrade-certified products. Prior studies showed that consumers’ purchases of Fairtrade products are driven by moral incentives and economic factors. Among the economic factors, only cursory research attention has been paid to a key aspect influencing purchases: the specific price of the Fairtrade item as compared to the price of non-Fairtrade items in the same product category. The price difference between Fairtrade and non-Fairtrade items can range anywhere from 0% to 70% or higher. This aspect is becoming ever more important in light of recent calls toward setting a price premium level of 100%, up to 200% in some categories, to reflect the changes in producers’ working conditions and living standards triggered by the global pandemic. Our studies suggest that such increases may not have the desired outcome. We hypothesize a negative relationship between the price premium and consumers’ willingness to pay (WTP) for Fairtrade items, testing this proposition in six cross-cultural studies. Our studies involve surveys administered to cross-sectional samples of consumers from the United States, from Canada, and samples of students from large North American universities. The surveys assessed consumers’ willingness to buy Fairtrade products using 7-point Likert scales (1 = “very unlikely to choose the Fairtrade product”; 7 = “very likely to choose the Fairtrade product” at the specified price premium level), for various product categories. Linear mixed-effects models for repeated measures (within-participants data) were employed for the key analyses. The significant finding of a negative relationship between the price premium and WTP supports our Hypothesis in each study, underscoring that as the Fairtrade premium is set at increasing levels (from 0% to 2%, 10%, and 25% higher price for the Fairtrade items), consumers’ average willingness to pay is significantly diminished, decreasing from 6.43 (MWTPat0%premium) to 5.56 (MWTPat2%premium) to 4.19 (MWTPat10%premium) to 2.95 (MWTPat25%premium) in Study 1; from 6.15 (MWTPat0%premium) to 5.37 (MWTPat2%premium) to 4.08 (MWTPat10%premium) to 2.98 (MWTPat25%premium) in Study 2; from 6.16 (MWTPat0%premium) to 5.34 (MWTPat2%premium) to 3.89 (MWTPat10%premium) to 2.27 (MWTPat25%premium) in Study 3, and from 6.39 (MWTPat0%premium) to 5.62 (MWTPat2%premium) to 4.45 (MWTPat10%premium) to 3.22 (MWTPat25%premium) in Study 4. These findings highlight actionable policy implications of marketing Fairtrade products to consumers, with a focus on the price component of the marketing mix. From a theoretical perspective, our research sheds light on the less-than-straightforward consequence of Fairtrade premium increases: we propose and show that the economic model is more applicable than the contributions/donations model in the context of Fairtrade. We emphasize that Fairtrade should not be regarded conceptually as just a special case of social contributions, because general helping theory is not able to account for the particularities of Fairtrade. Also, the impact of the price premium level on Fairtrade purchases is shown to have a different direction compared to the field of cause-related marketing purchases, revealing notable conceptual and empirical distinctions between these fields.

Abstract Background Little research is available regarding vaccination attitudes among those recently diagnosed with COVID-19. This is important to investigate, particularly among those experiencing mild-to-moderate illness, given the ongoing need to improve uptake of both initial vaccine series and booster doses, and the divergent ways such an experience could impact attitudes. Methods From September 3 – November 12, 2021, all patients enrolled in Baylor Scott & White’s “COVID-19 Digital Care Journey for Home Monitoring” were invited to participate in an online survey that included questions about vaccination status and attitudes/opinions regarding COVID-19 and the COVID-19 vaccines. Following an item asking about accordance of COVID-19 vaccination with religious/personal beliefs, participants were asked to describe those beliefs and how they relate to taking/not taking the vaccine. Results Of 8,075 patients age ≥ 18 years diagnosed with COVID-19 and invited to join the survey during the study period, 3242 (40.2%) were fully vaccinated. In contrast, among the 149 who completed the questionnaire, 95(63.8%) reported full vaccination. Responses differed significantly between vaccination groups. The vaccinated group strongly agreed that COVID-19 is a major public health problem, the vaccines are safe and effective, and their decision to vaccinate included considering community benefit. The unvaccinated group responded neutrally to most questions addressing safety and public health aspects of the vaccine, while strongly disagreeing with statements regarding vaccine effectiveness and other preventative public health measures. The vaccinated group strongly agreed that taking the vaccine accorded with their religious/personal beliefs, while the unvaccinated group was neutral. In qualitative analysis of the free text responses “risk perception/calculation” and “no impact” of religious/personal beliefs on vaccination decisions were frequent themes/subthemes in both groups, but beliefs related to the “greater good” were a strong driver among the vaccinated, while statements emphasizing “individual choice” were a third frequent theme for the unvaccinated. Conclusion Our results show that two of the three factors that drive vaccine hesitancy (complacency, and lack of confidence in the vaccines) are present among unvaccinated adults recently diagnosed with COVID-19. They also show that beliefs emphasizing the importance of the greater good promote public health participation.

Abstract Sea ice modulates the energy exchange between the atmosphere and the ocean through its kinematics. Marginal ice zone (MIZ) dynamics are complex and are not well resolved in routine observations. Here, we investigate sea ice dynamics in the Greenland Sea MIZ using in situ and remote sensing Lagrangian drift datasets. These datasets provide a unique view into ice dynamics spanning spatial scales. We find evidence of tidal currents strongly affecting sub‐daily ice motion. Velocity anomalies show abrupt transitions aligned with gradients in seafloor topography, indicating changes in ocean currents. Remote‐sensed ice floe trajectories derived from moderate resolution satellite imagery provide a view of small‐scale variability across the Greenland continental shelf. Ice floe trajectories reveal a west‐east increasing velocity gradient imposed by the East Greenland Current, with maximum velocities aligned along the continental shelf edge. These results highlight the importance of small scale ocean variability for ice dynamics in the MIZ.

ABSTRACT Staphylococcus aureus can produce β-lactamases capable of hydrolyzing penicillins and first-generation cephalosporins. The propensity of type A and type C β-lactamase-producing S. aureus (TAPSA and TCPSA) to hydrolyze cefazolin at a high inoculum is termed the cefazolin inoculum effect (CIE). Strains with a CIE have a theoretical risk of causing treatment failure and are unable to be detected routinely by most laboratories. We developed a high-performing yet straightforward β-lactamase disc test that identifies and differentiates both TAPSA and TCPSA and is suitable for routine diagnostic laboratory workflows. Clinical isolates of S. aureus resistant to penicillin were identified, and their blaZ genes were sequenced. MICs were determined at low and high inocula (5 × 105 CFU/mL and 5 × 107 CFU/mL), and isolates demonstrating a CIE were characterized. A semimechanistic model was established to describe differential hydrolysis patterns, and candidate models were iteratively assessed using area-under-the-curve analysis from competitor receiver operating characteristic (ROC) curves. Biomarker thresholds were derived from Youdon index-derived optimal cutoff values. Genetic analysis of 99 isolates identified 26 TAPSA isolates and 45 TCPSA isolates. The model best differentiating TAPSA from non-TAPSA utilized cefazolin-to-cephalothin ratio analysis (sensitivity, 96.2%; specificity, 98.6%). The model best differentiating TCPSA from non-TCPSA incorporated cefazolin, cephalothin, and oxacillin (sensitivity, 88.6%; specificity, 96.6%). TAPSA and TCPSA can be differentiated using three antibiotic discs on a single agar plate. The test has potential value in typing the β-lactamase type from isolates from patients that are candidates for or have failed cefazolin therapy. IMPORTANCE The key significance of this article is that it details a straightforward method of performing a disc test that can differentiate Staphylococcus aureus isolates that are likely to be associated with a cefazolin inoculum effect and theoretical risk of cefazolin treatment failure from isolates that are less likely to be associated with a cefazolin inoculum effect.

Background: Gut microbiota (GM) modulation has been considered a nutritional approach to manage obesity. Reduced Firmicutes/Bacteroidetes ratio (F/B) is associated with reduced energy harvesting capacity from the diet, ameliorates endotoxemia and inflammation, and restores gut hormone signaling related to hypothalamic control of energy homeostasis. As anti-obesogenic and anti-inflammatory properties have been attributed to Ginkgo biloba extract (GbE), the present study investigated whether GbE supplementation for two weeks modulates the GM composition of obese rats. Method: Fifty-six 2-month-old male Wistar rats were submitted to a lard-rich diet-induced obesity protocol for 60 days (high-fat diet, HFD). Following the obesity-inducing period, rats were gavaged daily with GbE at 500 mg/kg (HFD+G group), or saline (HFD group), for 14 days. A 3rd group (pair-fed group, PF) was performed by mimicking the HFD group (saline administration) but with its food intake matched to the HFD+G group. Rats were euthanized on the 14th supplementation day. Stool DNA was extracted and amplified with V3–V4 region primers of the 16S rRNA gene. Results: In comparison to both HFD and PF groups, GbE supplementation increased the number of Bacteroidetes colon community and concomitantly reduced the abundance of Firmicutes, reducing the F/B ratio. Hierarchical clustering showed that communities of the HFD+G group were less likely related to HFD and PF groups. Conclusion: As GbE modulated the GM structure and diversity in GbE-supplemented obese rats, our results show that GbE possesses phytotherapeutic potential to modulate obesity by improving GM and lessening the consequences of obesity-related GM dysbiosis.

IntroductionIn Krabbe disease (KD), mutations in β-galactosylceramidase (GALC), a lysosomal enzyme responsible for the catabolism of galactolipids, leads to the accumulation of its substrates galactocerebroside and psychosine. This neurologic condition is characterized by a severe and progressive demyelination together with neuron-autonomous defects and degeneration. Twitcher mice mimic the infantile form of KD, which is the most common form of the human disease. The Twitcher CNS and PNS present demyelination, axonal loss and neuronal defects including decreased levels of acetylated tubulin, decreased microtubule stability and impaired axonal transport.MethodsWe tested whether inhibiting the α-tubulin deacetylase HDAC6 with a specific inhibitor, ACY-738, was able to counteract the early neuropathology and neuronal defects of Twitcher mice.ResultsOur data show that delivery of ACY-738 corrects the low levels of acetylated tubulin in the Twitcher nervous system. Furthermore, it reverts the loss myelinated axons in the sciatic nerve and in the optic nerve when administered from birth to postnatal day 9, suggesting that the drug holds neuroprotective properties. The extended delivery of ACY-738 to Twitcher mice delayed axonal degeneration in the CNS and ameliorated the general presentation of the disease. ACY-738 was effective in rescuing neuronal defects of Twitcher neurons, stabilizing microtubule dynamics and increasing the axonal transport of mitochondria.DiscussionOverall, our results support that ACY-738 has a neuroprotective effect in KD and should be considered as an add-on therapy combined with strategies targeting metabolic correction.

Abstract Context‐specific research is needed on the relationship between household animal production and nutrition outcomes to inform programmes intervening in small‐scale animal production. We examined associations between household animal/fishpond ownership and animal source food (ASF) consumption among 6‐ to 12‐month‐old infants enroled in the control arm of a cluster‐randomised controlled trial in rural Bangladesh. We measured ASF consumption using a 7‐day food frequency questionnaire at 6, 9 and 12 months and assessed household animal/fishpond ownership at 12 months. We developed negative binomial regression models with random intercepts for infant and cluster, controlling for infant age and sex, maternal age, socioeconomic status and season. Models were stratified by a dichotomised maternal decision‐making score. Compared with infants in households without each animal type, those with 4–10 and ≥11 poultry consumed eggs 1.3 (95% confidence interval [CI]: 1.1, 1.6) and 1.6 (95% CI: 1.3, 2.0) times more, respectively; 2–3 and ≥4 dairy‐producing animals consumed dairy 1.9 (95% CI: 1.3, 2.7) and 2.0 (95% CI: 1.3, 3.1) times more, respectively; and ≥12 meat‐producing animals consumed meat 1.4 (95% CI: 1.0, 1.8) times more. It was unclear whether there was an association between fishpond ownership and fish consumption. Our results did not suggest that maternal decision‐making power was a modifier in the relationship between animal/fishpond ownership and ASF consumption. In this South Asian context, strategies intervening in household animal production may increase infant consumption of eggs, dairy and meat, but not necessarily fish. Research is needed on the role of market access and other dimensions of women's empowerment.

Summary: Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

Fibromyalgia (FM) is a chronic muscle pain disorder that shares several clinical features with other related rheumatologic disorders. This study investigates the feasibility of using surface-enhanced Raman spectroscopy (SERS) with gold nanoparticles (AuNPs) as a fingerprinting approach to diagnose FM and other rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), osteoarthritis (OA), and chronic low back pain (CLBP). Blood samples were obtained on protein saver cards from FM (n = 83), non-FM (n = 54), and healthy (NC, n = 9) subjects. A semi-permeable membrane filtration method was used to obtain low-molecular-weight fraction (LMF) serum of the blood samples. SERS measurement conditions were standardized to enhance the LMF signal. An OPLS-DA algorithm created using the spectral region 750 to 1720 cm−1 enabled the classification of the spectra into their corresponding FM and non-FM classes (Rcv > 0.99) with 100% accuracy, sensitivity, and specificity. The OPLS-DA regression plot indicated that spectral regions associated with amino acids were responsible for discrimination patterns and can be potentially used as spectral biomarkers to differentiate FM and other rheumatic diseases. This exploratory work suggests that the AuNP SERS method in combination with OPLS-DA analysis has great potential for the label-free diagnosis of FM.

Engagement strategies are central to the success of community and citizen science (CCS) initiatives; however, relatively little has been written on approaches that support project growth. Here, we assess the four components of the Mountain Rain or Snow engagement strategy (recruitment, training, activation, and retention) as the project transitioned from one region to four to increase participation in documenting precipitation phase. To scale up, we replicated the structure from our single-region effort in new regions while using place-based text messaging with observers across broad geographic areas and a localized approach to building partnerships. We use two sources of data—a participant feedback survey of 443 respondents and participant analytics of 877 new sign-ups and 13,017 observations submitted during the study—to evaluate success relative to project goals established at the outset of the expansion process. The Mountain Rain or Snow engagement strategy met project-wide goals for growing our observer network, for data collection, and for maintaining observer satisfaction with communication tools. We did not meet region-level goals for recruitment and activation in one location. Diverse partnerships and approaches to amplification supported recruitment success for this project. Survey data show that 85% of respondents found our novel approach to training helpful, and 82% found activation text messages helpful to understand when and how to participate. Feedback on communication preferences show that there was unmet demand for text messaging. Our evaluation found that a consistent structure across regions coupled with place-based messaging enhanced engagement while scaling up.

Diabetes is a chronic degenerative disease that carries multiple complications. One of the most important complications is the diabetic cutaneous complications, such as skin lesions, ulcerations, and diabetic foot, which are present in 30%–70% of the patients. Currently, the treatments for wound healing include growth factors and cytokines, skin substitutes, hyperbaric oxygen therapy, and skin grafts. However, these treatments are ineffective due to the complex mechanisms involved in developing unhealed wounds. Considering the aforementioned complications, regenerative medicine has focused on this pathology using stem cells to improve these complications. However, it is essential to mention that there is a poor biomolecular understanding of diabetic skin and the effects of treating it with stem cells. For this reason, herein, we investigated the employment of pluripotent stem cells (PSC) in the wound healing process by carrying out morphometric, histological, and Fourier-transform infrared microspectroscopy (FTIRM) analysis. The morphometric analysis was done through a photographic follow-up, measuring the lesion areas. For the histological analysis, hematoxylin & eosin and picrosirius red stains were used to examine the thickness of the epidermis and the cellularity index in the dermis as well as the content and arrangement of collagen type I and III fibers. Finally, for the FTIRM analysis, skin cryosections were obtained and analyzed by employing a Cassegrain objective of 16× of an FTIR microscope coupled to an FTIR spectrometer. For this purpose, 20 mice were divided into two groups according to the treatment they received: the Isotonic Salt Solution (ISS) group and the PSCs group (n = 10). Both groups were induced to diabetes, and six days after diabetes induction, an excisional lesion was made in the dorsal area. Furthermore, using microscopy and FTIRM analysis, the skin healing process on days 7 and 15 post-skin lesion excision was examined. The results showed that the wound healing process over time, considering the lesion size, was similar in both groups; however, the PSCs group evidenced hair follicles in the wound. Moreover, the histological analysis evidenced that the PSCs group exhibited granulation tissue, new vessels, and better polarity of the keratinocytes. In addition, the amount of collagen increased with a good deposition and orientation, highlighting that type III collagen fibers were more abundant in the PSCs. Finally, the FTIR analysis evidenced that the PSCs group exhibited a faster wound healing process. In conclusion, the wounds treated with PSCs showed a more rapid wound healing process, less inflammatory cellular infiltration, and more ordered structures than the ISS group.

Vaccination campaigns played a crucial role in reducing the incidence of COVID-19. However, a scant number of studies evaluated the impact of vaccination on case fatality rates (CFRs), including in Brazil. Our study aimed to compare CFRs according to vaccination status among subjects living in Arapongas (Paraná State, Brazil), considering the age composition of the population. Several strategies adopted by the Arapongas City Hall to minimize the spread of the virus were also elaborated upon. We accessed the 2021 database of the Arapongas Municipal Health Department, in which a total of 16,437 confirmed cases and 425 deaths were reported. The CFR was calculated as the ratio between COVID-19 deaths and the number of confirmed cases. Differences in age composition between unvaccinated and fully vaccinated individuals were observed in our study. Considering that CFR is a crude indicator and is highly sensitive to the age composition of the population, we adopted the average age distribution of confirmed cases among the three vaccination statuses (unvaccinated, partially, and fully) as a standard age distribution. The age-standardized CFR for unvaccinated and fully vaccinated groups were 4.55% and 2.42%, respectively. Fully vaccinated individuals showed lower age-specific CFRs in all age groups above 60 years than unvaccinated populations. Our findings strengthen the role of vaccination as a critical measure for preventing deaths among infected people and is particularly important to the ongoing reassessment of public health interventions and policies.

Abstract To increase the number of direct observations of rain and snow, we started a citizen science project that crowdsources precipitation phase reports from volunteers using a smartphone app. We focused on the Lake Tahoe region of California and Nevada, USA which forms part of the rain‐snow transition zone, an area where both solid and liquid precipitation occur in winter months. In two study years, we received 2,495 reports, of which 2,248 (90.1%) passed our quality control checks. Snow was the most frequent phase (64.0%), followed by rain (21.0%) and mixed precipitation (15.0%). We compared these values to estimates from 14 common precipitation phase partitioning methods that use near‐surface meteorology as well as to two remote sensing products from the Global Precipitation Measurement mission (GPM). We found the meteorology‐based methods tended to underestimate snowfall on average (60.9%) with a sizable standard deviation of 18%. The Integrated Multi‐satellitE Retrievals for GPM level 3 probabilityLiquidPrecipitation product also underestimated snowfall (57.5%) relative to the crowdsourced data, while the Dual‐frequency Precipitation Radar level 2A phaseNearSurface product had little spatiotemporal overlap with the observations. We also found slight differences in the rain‐snow line elevations measured by a freezing‐level radar versus those estimated from the crowdsourced data, with the former being 165 m lower than the latter on average. These findings underscore the importance of collecting ground‐truth observations of precipitation phase in the rain‐snow transition zone. We hope future studies will consider the use of crowdsourced data for improved insights into and better representation of hydrometeorological processes.

Abstract Under-ice eddies are prevalent in the major circulation system in the western Arctic Ocean, the Beaufort Gyre. Theoretical studies hypothesize that the eddy-driven overturning and the ice-ocean drag are crucial mechanisms of the gyre equilibration in response to atmospheric winds. However, due to severe weather conditions and limitations of remote sensing instruments, there are only sparse eddy observations in the ice-covered Arctic Ocean. Hence, the evolution of the under-ice eddy field, its impact on the gyre variability, and their mutual response to the ongoing Arctic warming remain uncertain. Here, we infer the characteristics of the under-ice eddy field by establishing its tight connection to the angular velocities of isolated spinning sea ice floes in marginal ice zones. Using over two decades of satellite observations of marginal ice zones in the western Arctic Ocean, we identified and tracked thousands of floes and used idealized eddy modeling to infer the interannual evolution of the eddy energetics underneath the ice. We find that the eddy field is strongly correlated to the strength of the Beaufort Gyre on interannual timescales, which provides the major observational evidence consistent with the hypothesis of the gyre equilibration by eddies. The inferred trends over the past two decades signify that the gyre and its eddy field have been intensifying as the sea ice cover has been declining. Our results imply that with continuing sea ice decline, the eddy field and the Beaufort Gyre will keep intensifying and leading to enhanced transport of freshwater and biogeochemical tracers.

Purpose: There are currently limited treatment options for aniridia. In this context, 3D printed iris implants may provide a cost-effective, cosmetically acceptable alternative for patients with aniridia. The purpose of this study was to develop a proof-of-concept workflow for manufacturing 3D printed iris implants using a silicone ink palette that aesthetically matches iris shades, identified in slit lamp images. Methods: Slit lamp iris photos from 11 healthy volunteers (3 green; 4 blue; 4 brown) were processed using k-means binning analyses to identify two or three prominent colors each. Candidate silicone inks were created by precisely combining pigments. A crowdsourcing survey software was used to determine color matches between the silicone ink swatches and three prominent iris color swatches in 2 qualifying and 11 experimental workflows. Results: In total, 54 candidate silicone inks (20 brown; 16 green; 18 blue) were developed and analyzed. Survey answers from 29 individuals that had passed the qualifying workflow were invited to identify “best matches” between the prominent iris colors and the silicone inks. From this color-match data, brown, blue, and green prototype artificial irises were printed with the silicone ink that aesthetically matched the three prominent colors. The iris was printed using a simplified three-layer five-branch starburst design at scale (12.8 mm base disc, with 3.5 mm pupil). Conclusions: This proof-of-concept workflow produced color-matched silicone prosthetic irises at scale from a panel of silicone inks using prominent iris colors extracted from slit lamp images. Future work will include printing a more intricate iris crypt design and testing for biocompatibility.

Sweet corn is frequently consumed in the US and contains carbohydrates as major macronutrients. This study examined the effects of blanching, freezing, and canning on carbohydrates in sweet corn. Fresh bi-color sweet corn was picked in the field and processed immediately into frozen and canned samples. Simple sugars, starch, and dietary fiber (DF) (including total DF (TDF), insoluble DF (IDF) and two fractions of soluble DF (SDF)) were measured according to the AOAC methods. Additional glycomic analysis including oligosaccharides, monosaccharide composition of total polysaccharides (MCTP) and glycosidic linkage of total polysaccharides (GLTP) were analyzed using UHPLC-MS. Sucrose is the major simple sugar, and IDF is the main contributor to TDF. Sucrose and total simple sugar concentrations were not altered after blanching or freezing but were significantly reduced in canned samples. Kestose was the only oligosaccharide identified in sweet corn and decreased in all heat-treated or frozen samples. Starch content decreased in frozen samples but increased in canned samples. While two SDF fractions did not differ across all samples, blanching, freezing and canning resulted in increases in TDF and IDF. Six monosaccharides were identified as major building blocks of the total polysaccharides from MCTP analysis. Glucose and total monosaccharide concentrations increased in two canned samples. GLTP was also profoundly altered by different food processing methods. This study provided insights into the changes in the content and quality of carbohydrates in sweet corn after food processing. The data are important for accurate assessment of the carbohydrate intake from different sweet corn products.

Diabetes is one of the top 5 non-communicable diseases that occur worldwide according to the World Health Organization. Despite not being a fatal disease, a late diagnosis as well as poor control can cause a fatal outcome, because of that, several studies have been carried out with the aim of proposing additional techniques to the gold standard to assist in the diagnosis and control of this disease in a non-invasive way. Considering the above, and in order to provide a solid starting point for future researches, we share a primary research dataset with 1040 saliva samples obtained by Fourier Transform Infrared Spectroscopy considering the Attenuated Total Reflectance method. Database include: gender, age, individuals (patients) with/without diabetes, the glucose value, and the result to the A1C test for the diabetic population. We believe that sharing dataset as is could increase experimentation, research, and analysis of spectra through different strategies broaden its range of applicability by chemists, doctors, physicists, computer scientists, among others, to identify the effects that the virus causes in the body and to propose possible clinical treatments as well as to develop devices that allow us to assist in the characterization of possible carriers.

IMPORTANCE:. The need to understand how Community-based disparities impact morbidity and mortality in pediatric critical illness, such as traumatic brain injury. Test the hypothesis that ZIP code-based disparities in hospital utilization, including length of stay (LOS) and hospital costs, exist in a cohort of children with traumatic brain injury (TBI) admitted to a PICU using the Child Opportunity Index (COI). DESIGN:. Multicenter retrospective cohort study. SETTING:. Pediatric Health Information System (PHIS) database. PATIENTS:. Children 0–18 years old admitted to a PHIS hospital with a diagnosis of TBI from January 2016 to December 2020 requiring PICU care. To identify the most severely injured children, a study-specific definition of “Complicated TBI” was created based on radiology, pharmacy, and procedure codes. INTERVENTIONS:. None. Main Outcomes and Measures:. Using nationally normed ZIP code-level COI data, patients were categorized into COI quintiles. A low COI ZIP code has low childhood opportunity based on weighted indicators within educational, health and environmental, and social and economic domains. Population-averaged generalized estimating equation (GEE) models, adjusted for patient and clinical characteristics examined the association between COI and study outcomes, including hospital LOS and accrued hospital costs. The median age of this cohort of 8,055 children was 58 months (interquartile range [IQR], 8–145 mo). There were differences in patient demographics and rates of Complicated TBI between COI levels. The median hospital LOS was 3.0 days (IQR, 2.0–6.0 d) and in population-averaged GEE models, children living in very low COI ZIP codes were expected to have a hospital LOS 10.2% (95% CI, 4.1–16.8%; p = 0.0142) longer than children living in very high COI ZIP codes. For the 11% of children with a Complicated TBI, the relationship between COI and LOS was lost in multivariable models. COI level was not predictive of accrued hospital costs in this study. CONCLUSIONS:. Children with TBI requiring PICU care living in low-opportunity ZIP codes have higher injury severity and longer hospital LOS compared with children living in higher-opportunity ZIP codes. Additional studies are needed to understand why these differences exist.

ABSTRACT Serosurveys can determine the extent and spread of a pathogen in populations. However, collection of venous blood requires trained medical staff. Dried blood spots (DBS) are a suitable alternative because they can be self-collected and stored/shipped at room temperature. As COVID-19 vaccine deployment began in early 2021, we rapidly enrolled laboratory employees in a study to evaluate IgG antibody levels following vaccination. Participants received a DBS collection kit, self-collection instructions, and a brief questionnaire. Three DBS were collected by each of 168 participants pre- and/or postvaccination and tested with a multiplex microsphere immunoassay (MIA) that separately measures IgG antibodies to SARS-CoV-2 spike-S1 and nucleocapsid antigens. Most DBS (99.6%, 507/509) were suitable for testing. Participants with prior SARS-CoV-2 infection (n = 7) generated high S antibody levels after the first vaccine dose. Naïve individuals (n = 161) attained high S antibody levels after the second dose. Similar antibody levels were seen among those vaccinated with Moderna (n = 29) and Pfizer-BioNTech (n = 137). For those receiving either mRNA vaccine, local side effects were more common after the first vaccine dose, whereas systemic side effects were more common after the second dose. Individuals with the highest antibody levels in the week prior to the second vaccine dose experienced more side effects from the second dose. Our study demonstrated that combining self-collected DBS and a multiplex MIA is a convenient and effective way to assess antibody levels to vaccination and could easily be used for population serosurveys of SARS-CoV-2 or other emerging pathogens. IMPORTANCE Serosurveys are an essential tool for assessing immunity in a population (1, 2). However, common barriers to effective serosurveys, particularly during a pandemic, include high-costs, resources required to collect venous blood samples, lack of trained laboratory technicians, and time required to perform the assay. By utilizing self-collected dried blood spots (DBS) and our previously developed high-throughput microsphere immunoassay, we were able to significantly reduce many of these common challenges. Participants were asked to self-collect three DBS before and/or after they received their COVID-19 vaccines to measure antibody levels following vaccination. Participants successfully collected 507 DBS that were tested for IgG antibodies to the spike and nucleocapsid proteins of SARS-CoV-2. When used with self-collected DBS, our relatively low-cost assay significantly reduced common barriers to collecting serological data from a population and was able to effectively assess antibody response to vaccination.

The wide range of symptoms of the coronavirus disease 2019 (COVID-19) makes it challenging to predict the disease evolution using a single parameter. Therefore, to describe the pathophysiological response to SARS-CoV-2 infection in hospitalized patients with severe COVID-19, we compared according to survival or death, the sociodemographic and clinical characteristics, the biochemical and immunological attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra from saliva samples and their correlation with chemometric findings. Herein, we demonstrate that ATR-FTIR spectroscopy allows the description of the events related to cell damage, such as lipids biogenesis and the secondary structure of proteins associated with lactate dehydrogenase and albumin levels. Moreover, humoral (IgM) and cellular (IFN-γ, TNF-α, IL-10, and IL-6) responses were also increased in patients who died from COVID-19.

Participants in the leadership breakout session at the Clinical Translational Science Awards (CTSA) virtual 2020 conference discussed and ranked six recommendations in terms of feasibility, impact, and priority for advancing Diversity, Equity, and Inclusion (DEI) efforts to elevate underrepresented populations to leadership positions in CTSAs and their broader institutions. A thematic analysis of chat and polling data identified challenges and opportunities to achieve DEI goals, with the three most promising recommendations as: cross-institutional Principal Investigator (P.I.) action-learning workgroups, transparent policies for recruiting and promoting underrepresented minorities (URM) leadership, and a clear succession plan to nurture and elevate URM leaders. Suggestions are made to improve DEI in CTSA leadership and allow for greater representation in the translational science field.

Elevated intraocular pressure (IOP) is influenced by environmental and genetic factors. Increased IOP is a major risk factor for most types of glaucoma, including primary open angle glaucoma (POAG). Investigating the genetic basis of IOP may lead to a better understanding of the molecular mechanisms of POAG. The goal of this study was to identify genetic loci involved in regulating IOP using outbred heterogeneous stock (HS) rats. HS rats are a multigenerational outbred population derived from eight inbred strains that have been fully sequenced. This population is ideal for a genome-wide association study (GWAS) owing to the accumulated recombinations among well-defined haplotypes, the relatively high allele frequencies, the accessibility to a large collection of tissue samples, and the large allelic effect size compared to human studies. Both male and female HS rats (N = 1,812) were used in the study. Genotyping-by-sequencing was used to obtain ∼3.5 million single nucleotide polymorphisms (SNP) from each individual. SNP heritability for IOP in HS rats was 0.32, which agrees with other studies. We performed a GWAS for the IOP phenotype using a linear mixed model and used permutation to determine a genome-wide significance threshold. We identified three genome-wide significant loci for IOP on chromosomes 1, 5, and 16. Next, we sequenced the mRNA of 51 whole eye samples to find cis-eQTLs to aid in identification of candidate genes. We report 5 candidate genes within those loci: Tyr, Ctsc, Plekhf2, Ndufaf6 and Angpt2. Tyr, Ndufaf6 and Angpt2 genes have been previously implicated by human GWAS of IOP-related conditions. Ctsc and Plekhf2 genes represent novel findings that may provide new insight into the molecular basis of IOP. This study highlights the efficacy of HS rats for investigating the genetics of elevated IOP and identifying potential candidate genes for future functional testing.

ObjectiveSome individuals with differences of sex development (DSD) conditions undergo medically indicated prophylactic gonadectomy. Gonads of individuals with DSD can contain germ cells and precursors and patients interested in future fertility preservation and hormonal restoration can participate in DSD-specific research protocols to cryopreserve this tissue. However, it is unclear how many providers or institutions offer gonadal tissue cryopreservation (GTC) and how widespread GTC for DSD is across the United States (US). The Pediatric Initiative Network (PIN) and Non-Oncologic Conditions committees of the Oncofertility Consortium sought to assess the current state of GTC for patients with DSD.MethodsAn electronic survey was sent to providers caring for patients with DSD via special interest groups of professional societies and research networks.ResultsThe survey was administered between November 15, 2021 and March 14, 2022. A total of 155 providers responded to the survey, of which 132 respondents care for patients with DSD, and 78 work at facilities that offer medically indicated gonadectomy to patients with DSD diagnoses. They represented 55 US institutions including 47 pediatric hospitals, and 5 international sites (Canada, Denmark, Germany, Qatar). Of individual providers, 41% offer cryopreservation after prophylactic gonadectomy for patients with DSD (32/78). At an institutional level, GTC after medically indicated gonadectomy is available at 54.4% (24/46) of institutions. GTC is offered for a variety of DSD diagnoses, most commonly 45,X/46,XY DSD (i.e., Turner Syndrome with Y-chromosome material and mixed gonadal dysgenesis), ovotesticular DSD, complete androgen insensitivity syndrome (CAIS), and complete gonadal dysgenesis. Responses demonstrate regional trends in GTC practices with 83.3% of institutions in the Midwest, 66.7% in the Northeast, 54.6% in the West, and 35.3% in the South providing GTC. All represented institutions (100%) send gonadal tissue for pathological evaluation, and 22.7% preserve tissue for research purposes.ConclusionsGTC after gonadectomy is offered at half of the US institutions represented in our survey, though a minority are currently preserving tissue for research purposes. GTC is offered for several DSD conditions. Future research will focus on examining presence and quality of germ cells to support clinical decision making related to fertility preservation for patients with DSD.

BackgroundNeutrophil extracellular traps (NETs), three-dimensional structures formed by neutrophil enzymes such as neutrophil elastase (NE) and nuclear components (DNA), have been associated with progression and metastasis in breast cancer (BC). Thus, the aim of this study was to evaluate the association of circulating NETs with clinicopathological characteristics and outcomes in early BC.MethodsA prospective cohort included women with newly diagnosed early BC. NETs were defined as the presence of NE-DNA complexes in plasma, measured by optical density. Levels of NETs were dichotomized according to the median, as low and high levels of circulating NETs. Fisher’s exact test was used to evaluate associations between NETs and clinicopathological characteristics and outcomes. Survival was assessed using the Kaplan Meier method and log-rank test.ResultsForty patients were included, 23 (57.5%) patients with low and 17 (42.5%) with high levels of circulating NETs. No associations were found between clinicopathological characteristics and circulating NETs levels. Recurrence (p = 0.99) and site of recurrence (p = 0.99) were not statistically associated with plasma NETs levels. Overall, recurrence-free survival was not statistically different between circulating levels of NETs.ConclusionsWith a short follow-up and low number of events, our results suggest that circulating levels of NETs at diagnosis of early BC are not associated with more aggressive clinicopathological characteristics, recurrence, or site of recurrence.

Abstract Information on microbiota dynamics in pulmonary tuberculosis (TB) in Africa is scarce. Here, we sequenced sputa from 120 treatment-naïve TB patients in Uganda, and investigated changes in microbiota of 30 patients with treatment-response follow-up samples. Overall, HIV-status and anti-TB treatment were associated with microbial structural and abundance changes. The predominant phyla were Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria and Actinobacteria, accounting for nearly 95% of the sputum microbiota composition; the predominant genera across time were Prevotella, Streptococcus, Veillonella, Haemophilus, Neisseria, Alloprevotella, Porphyromonas, Fusobacterium, Gemella, and Rothia. Treatment-response follow-up at month 2 was characterized by a reduction in abundance of Mycobacterium and Fretibacterium, and an increase in Ruminococcus and Peptococcus; month 5 was characterized by a reduction in Tannerella and Fusobacterium, and an increase in members of the family Neisseriaceae. The microbiota core comprised of 44 genera that were stable during treatment. Hierarchical clustering of this core’s abundance distinctly separated baseline (month 0) samples from treatment follow-up samples (months 2/5). We also observed a reduction in microbial diversity with 9.1% (CI 6–14%) of the structural variation attributed to HIV-status and anti-TB treatment. Our findings show discernible microbiota signals associated with treatment with potential to inform anti-TB treatment response monitoring.

PURPOSEWe evaluated the impact of 21-gene test results on treatment decisions for patients with early-stage breast cancer treated under the public health care system in Brazil, Sistema Único de Saúde.METHODSEligible patients treated at Hospital Pérola Byington and Santa Casa de Misericórdia de São Paulo in Brazil were required to have the following characteristics: postsurgery with hormone receptor–positive, human epidermal growth factor 2–negative, node-negative and node-positive, and T1/T2 breast cancer and patients with these characteristics were candidates for adjuvant systemic therapy. Treatment recommendations, chemotherapy plus hormonal therapy (CT + HT) or HT alone, were captured before and after 21-gene test results.RESULTSFrom August 2018 to April 2019, 179 women were enrolled. The mean age was 58 years (29-86 years), 135 (76%) were postmenopausal, and 58 (32%) had node-positive breast cancer. Most patients (61%) had a tumor > 2 cm, including 7% with tumors > 4 cm. Using Recurrence Score (RS) result cut points on the basis of the TAILORx trial, 40 (22%) had RS 0-10, 91 (51%) had RS 11-25, and 48 (27%) had RS 26-100. Before 21-gene testing, 162 of 179 (91%) patients were recommended for CT. After testing, 117 of 179 patients (65%) had changes in CT recommendation: 112 (63%) who were initially recommended CT received HT alone and five (3%) who were initially recommended HT alone received CT + HT. After 21-gene testing, 99% of physicians reported strong confidence in their treatment recommendations.CONCLUSIONThe change in clinical practice at these public hospitals was greater than expected: 66% of initial treatment recommendations were changed to omit CT with 21-gene test results. Clinicopathologic features did not correlate well with 21-gene test results and did not adequately identify those most likely to benefit from CT.

The COVID-19 pandemic started in Chile as the country was experiencing massive protests and a deep political crisis. Sanitary measures restricting movement and gatherings were implemented while the process of constitutional change responding to this crisis developed. In this context of conflict, we study why people continued participating in street protests despite the restrictions and the health risks involved. Using two surveys, we test key factors addressed in extant scholarship: biographical availability, perceived risks, and grievances. We find that grievances related to the pandemic were the most important factor, while biographical availability was much less relevant in the pandemic context. There is no evidence that perceived health risks mattered when deciding whether to join a street protest or not. These results suggest that under conditions of political crisis, grievances related to the administration of the pandemic can motivate political participation even when the latter put people's health at risk.

Climate change and the continuing increase in human population creates a growing need to tackle urban stormwater problems. One promising mitigation option is by using nature-based solutions (NBS) – especially sustainable urban stormwater management technologies that are key elements of NBS action. We used a synthesis approach to compile available information about urban stormwater retention capacity of the most common sustainable urban drainage systems (SUDS) in different climatic conditions. Those SUDS targeting stormwater management through water retention and removal solutions (mainly by infiltration, overland flow and evapotranspiration), were addressed in this study. Selected SUDS were green roofs, bioretention systems (i.e. rain gardens), buffer and filter strips, vegetated swales, constructed wetlands, and water-pervious pavements. We found that despite a vast amount of data available from real-life applications and research results, there is a lack of decisive information about stormwater retention and removal capacity of selected SUDS. The available data show large variability in performance across different climatic conditions. It is therefore a challenge to set conclusive widely applicable guidelines for SUDS implementation based on available water retention data. Adequate data were available only to evaluate the water retention capacity of green roofs (average 56±20%) and we provide a comprehensive review on this function. However, as with other SUDS, still the same problem of high variability in the performance (min 11% and max 99% of retention) remains. This limits our ability to determine the capacity of green roofs to support better planning and wider implementation across climate zones. The further development of SUDS to support urban stormwater retention should be informed by and developed concurrently with the adaptation strategies to cope with climate change, especially with increasing frequency of extreme precipitation events that lead to high volumes of stormwater runoff.

Abstract Background Unsafe abortion is a leading cause of maternal mortality. In Afghanistan, which has experienced decades of armed conflict and where abortion is highly restricted, maternal mortality is high at 638 maternal deaths per 100,000 live births. Post-abortion care (PAC) is a lifesaving package of interventions to reduce morbidity and mortality related to induced or spontaneous abortion, but is rarely provided and often of poor quality, particularly in humanitarian settings. In July 2018, we conducted a study to identify the factors that influence access to and use of PAC services at Sharana Provincial Hospital. Methods In-depth interviews (IDIs) were conducted with ten women who had received PAC services at Sharana Hospital, and eight focus group discussions (FGDs) were conducted with 40 married women and 40 married men aged 18–45 from four villages surrounding Sharana Hospital. Results PAC clients and community participants discussed similar barriers to seeking PAC, including cost, distance to the health facility, the need for male accompaniment to seek care, perceived and actual quality of care, stigma and shame. Despite the mentioned stigma around abortion, community members expressed willingness to help women to receive PAC. Conclusions Our results suggest that while some barriers are not unique to PAC, others, especially those related to stigma around abortion, may be specific to PAC. It is important for the Ministry of Public Health and its partners to prioritize addressing these barriers to ensure that women have access to this critical life-saving care.

Objective: To investigate structural relationships of latent constructs such as occupational wellbeing, resilience, work meaningfulness, and psychological empowerment with affective and cognitive clinical empathy among a community of physicians and advanced practice providers. Methods: We conducted a cross-sectional observational study. We gathered data by an anonymous self-administered multidimensional questionnaire disseminated electronically between March and May 2016. Participants were physicians and advanced practice providers belonging to the Health Texas Provider Network, a group private practice affiliated with the Baylor Scott and White Health system. We excluded allied health care staff (eg, nurses) and trainees (eg, residents, medical students). We pursued a 3-step strategy: (1) confirmatory factor analysis of a theory-driven measurement model, (2) a modified structural equation model from which pathways with nonsignificant path coefficients were deleted, and (3) multigroup analyses of the modified model. Results: Cognitive empathy was the strongest predictor of affective empathy. We observed modest positive associations of resilience with cognitive and affective empathy and of well-being and meaning with affective but not with cognitive empathy. Resilience, meaning, and psychological empowerment were surprisingly negatively associated with well-being, suggesting diminished self-care among practitioners. Effects of psychological empowerment on empathy and well-being were mediated by resilience and meaning. Conclusion: Cognitive empathy directly influenced affective empathy; well-being and meaningfulness exerted direct positive effects on affective but not on cognitive empathy, whereas resilience had direct positive associations with both empathy dimensions. Resilience and meaning manifested direct, negative associations with well-being, revealing clinicians’ disproportionate focus on patient care at the expense of self-care.

Abstract Background Precisely how silver nanoparticles (AgNPs) kill mammalian cells still is not fully understood. It is not clear if AgNP-induced damage differs from silver cation (Ag+), nor is it known how AgNP damage is transmitted from cell membranes, including endosomes, to other organelles. Cells can differ in relative sensitivity to AgNPs or Ag+, which adds another layer of complexity to identifying specific mechanisms of action. Therefore, we determined if there were specific effects of AgNPs that differed from Ag+ in cells with high or low sensitivity to either toxicant. Methods Cells were exposed to intact AgNPs, Ag+, or defined mixtures of AgNPs with Ag+, and viability was assessed. The level of dissolved Ag+ in AgNP suspensions was determined using inductively coupled plasma mass spectrometry. Changes in reactive oxygen species following AgNP or Ag+ exposure were quantified, and treatment with catalase, an enzyme that catalyzes the decomposition of H2O2 to water and oxygen, was used to determine selectively the contribution of H2O2 to AgNP and Ag+ induced cell death. Lipid peroxides, formation of 4-hydroxynonenol protein adducts, protein thiol oxidation, protein aggregation, and activation of the integrated stress response after AgNP or Ag+ exposure were quantified. Lastly, cell membrane integrity and indications of apoptosis or necrosis in AgNP and Ag+ treated cells were examined by flow cytometry. Results We identified AgNPs with negligible Ag+ contamination. We found that SUM159 cells, which are a triple-negative breast cancer cell line, were more sensitive to AgNP exposure less sensitive to Ag+ compared to iMECs, an immortalized, breast epithelial cell line. This indicates that high sensitivity to AgNPs was not predictive of similar sensitivity to Ag+. Exposure to AgNPs increased protein thiol oxidation, misfolded proteins, and activation of the integrated stress response in AgNP sensitive SUM159 cells but not in iMEC cells. In contrast, Ag+ cause similar damage in Ag+ sensitive iMEC cells but not in SUM159 cells. Both Ag+ and AgNP exposure increased H2O2 levels; however, treatment with catalase rescued cells from Ag+ cytotoxicity but not from AgNPs. Instead, our data support a mechanism by which damage from AgNP exposure propagates through cells by generation of lipid peroxides, subsequent lipid peroxide mediated oxidation of proteins, and via generation of 4-hydroxynonenal (4-HNE) protein adducts. Conclusions There are distinct differences in the responses of cells to AgNPs and Ag+. Specifically, AgNPs drive cell death through lipid peroxidation leading to proteotoxicity and necrotic cell death, whereas Ag+ increases H2O2, which drives oxidative stress and apoptotic cell death. This work identifies a previously unknown mechanism by which AgNPs kill mammalian cells that is not dependent upon the contribution of Ag+ released in extracellular media. Understanding precisely which factors drive the toxicity of AgNPs is essential for biomedical applications such as cancer therapy, and of importance to identifying consequences of unintended exposures.

Abstract The coronavirus disease 2019 (COVID-19) is the latest biological hazard for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though numerous diagnostic tests for SARS-CoV-2 have been proposed, new diagnosis strategies are being developed, looking for less expensive methods to be used as screening. This study aimed to establish salivary vibrational modes analyzed by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy to detect COVID-19 biological fingerprints that allow the discrimination between COVID-19 and healthy patients. Clinical dates, laboratories, and saliva samples of COVID-19 patients (N = 255) and healthy persons (N = 1209) were obtained and analyzed through ATR-FTIR spectroscopy. Then, a multivariate linear regression model (MLRM) was developed. The COVID-19 patients showed low SaO2, cough, dyspnea, headache, and fever principally. C-reactive protein, lactate dehydrogenase, fibrinogen, d-dimer, and ferritin were the most important altered laboratory blood tests, which were increased. In addition, changes in amide I and immunoglobulin regions were evidenced in the FTIR spectra analysis, and the MLRM showed clear discrimination between both groups. Specific salivary vibrational modes employing ATR-FTIR spectroscopy were established; moreover, the COVID-19 biological fingerprint in saliva was characterized, allowing the COVID-19 detection using an MLRM, which could be helpful for the development of new diagnostic devices.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan–binding receptor, Dectin-1. The patient’s PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1–dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α– and IL-1β–mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

Presentamos la experiencia de la Red Latinoamericana para la Conservación de los Murciélagos (RELCOM) y los frutos que ha cosechado. RELCOM nace 15 años, en Mérida, Yucatán, México, donde un grupo de especialistas de murciélagos y líderes en sus países, se reunieron en un congreso internacional. Hoy la RELCOM reúne a 23 Programas para la Conservación de los Murciélagos de 25 países de Latinoamérica y el Caribe. El proyecto áreas importantes para la conservación de los murciélagos (AICOMs) y sitios importantes para la conservación de los murciélagos (SICOMs) surge en 2011 y hoy cuenta con mas de 200 áreas en 21 países.

The efficacy of radiotherapy, a mainstay of cancer treatment, is strongly influenced by both cellular and non-cellular features of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are a heterogeneous population within the TME and their prevalence significantly correlates with patient prognosis in a range of cancers. Macrophages display intrinsic radio-resistance and radiotherapy can influence TAM recruitment and phenotype. However, whether radiotherapy alone can effectively “reprogram” TAMs to display anti-tumor phenotypes appears conflicting. Here, we discuss the effect of radiation on macrophage recruitment and plasticity in cancer, while emphasizing the role of specific TME components which may compromise the tumor response to radiation and influence macrophage function. In particular, this review will focus on soluble factors (cytokines, chemokines and components of the complement system) as well as physical changes to the TME. Since the macrophage response has the potential to influence radiotherapy outcomes this population may represent a drug target for improving treatment. An enhanced understanding of components of the TME impacting radiation-induced TAM recruitment and function may help consider the scope for future therapeutic avenues to target this plastic and pervasive population.

Background: Mental health impacts of the COVID-19 pandemic are well recognized, but little is known about the pandemic experience among people experiencing mental health symptoms. Methods: In June 2020, a national sample of 5023 U.S. adults, including 785 scoring ⩾10 on the PHQ-8 for symptoms of depression, completed survey measures related to their pandemic experience. Results: After adjusting for sociodemographic characteristics, aspects of the COVID-19 pandemic experience for which participants scoring PHQ-8 ⩾ 10 had the greatest increase in odds of reporting moderate/severe negative impacts included: mental health treatment access (odds ratio [OR], 95% confidence interval [CI] = 8.81, 6.70-11.57), family stress/discord (OR, 95% CI = 5.21, 4.24-6.42), food access (OR, 95% CI = 3.76, 2.97-4.77), and income/employment (OR, 95% CI = 3.19, 2.66-3.83). They were also significantly more likely to report increased use of prescription painkillers (OR, 95% CI = 8.46, 4.50-15.92) and other drugs (OR, 95% CI = 4.43, 2.85-6.89), and less trust in healthcare authorities/providers, family/friends, and employers, and more trust in websites/blogs/social media, for COVID-19 information ( P -values

Summary: BRCA1 maintains genome stability by promoting homologous recombination (HR)-mediated DNA double-strand break (DSB) repair. Mutation of mouse BRCA1-S1152, corresponding to an ATM phosphorylation site in its human counterpart, resulted in increased genomic instability and tumor incidence. In this study, we report that BRCA1-S1152 is part of a feedback loop that sustains ATM activity. BRCA1-S1152A mutation impairs recruitment of the E3 ubiquitin ligase SKP2. This in turn attenuates NBS1-K63 ubiquitination by SKP2 at DSB, impairs sustained ATM activation, and ultimately leads to deficient end resection, the commitment step in the HR repair pathway. Auto-phosphorylation of human ATM at S1981 is known to be important for its kinase activation; we mutated the corresponding amino acid residue in mouse ATM (S1987A) to characterize potential roles of mouse ATM-S1987 in the BRCA1-SKP2-NBS1-ATM feedback loop. Unexpectedly, MEFs carrying the ATM-S1987A knockin mutation maintain damage-induced ATM kinase activation, suggesting a species-specific function of human ATM auto-phosphorylation.

Introduction There is widespread use of all-terrain vehicles (ATVs) in the USA for both work-related and recreational activities. In this study, we aimed to determine the difference in injury severity, Glasgow Coma scales and length of stay between ATV-related injuries and injuries sustained from motorcycles (MOTOs) and automobiles (AUTOs).Methods We retrospectively analysed ATV, MOTO and AUTO injuries from a Level 2 Trauma Center between 01 January 2015 and 31 August 2020. Proportional odds regression analyses, as well as multivariable regression models, were used to analyse the data.Results There were significantly more male and paediatric patients that suffered ATV-related injuries compared with MOTO or AUTO injuries. Victims of ATV-related injuries were also more likely to have open fractures. Paediatric patients were less likely to sustain an injury from either AUTO or MOTO accidents compared with ATV accidents. Patients with no drug use during injury and those who used protective equipment such as seat belts and child seats were significantly associated with lower Injury Severity Scores and higher Glasgow Coma Scale scores, indicating less severe injuries.Discussion Paediatric patients are very likely to suffer sequela and long-term disability due to the severity of ATV-related injuries. Public awareness campaigns to educate our population, especially our youth, about the danger of ATV use are highly needed.

Background and aims The role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy.Methods We use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry.Results We found that patients’ regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy.Conclusions Our findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.

BackgroundMany low- and middle-income countries, including Latin America, lack access to biomarkers for the diagnosis of prodromal Alzheimer's Disease (AD; mild cognitive impairment due to AD) and AD dementia. MRI visual rating scales may serve as an ancillary diagnostic tool for identifying prodromal AD or AD in Latin America. We investigated the ability of brain MRI visual rating scales to distinguish between cognitively healthy controls, prodromal AD and AD.MethodsA cross-sectional study was conducted from a multidisciplinary neurology clinic in Lima, Peru using neuropsychological assessments, brain MRI and cerebrospinal fluid amyloid and tau levels. Medial temporal lobe atrophy (MTA), posterior atrophy (PA), white matter hyperintensity (WMH), and MTA+PA composite MRI scores were compared. Sensitivity, specificity, and area under the curve (AUC) were determined.ResultsFifty-three patients with prodromal AD, 69 with AD, and 63 cognitively healthy elderly individuals were enrolled. The median age was 75 (8) and 42.7% were men. Neither sex, mean age, nor years of education were significantly different between groups. The MTA was higher in patients with AD (p < 0.0001) compared with prodromal AD and controls, and MTA scores adjusted by age range (p < 0.0001) and PA scores (p < 0.0001) were each significantly associated with AD diagnosis (p < 0.0001) but not the WMH score (p=0.426). The MTA had better performance among ages 75 years (AUC 0.85 [0.79–0.92]). For AD diagnosis, MTA+PA had the best performance (AUC 1.00) for all age groups.ConclusionsCombining MTA and PA scores demonstrates greater discriminative ability to differentiate controls from prodromal AD and AD, highlighting the diagnostic value of visual rating scales in daily clinical practice, particularly in Latin America where access to advanced neuroimaging and CSF biomarkers is limited in the clinical setting.

Autoimmune diseases tend to cluster in families, suggesting genetic predisposition to autoimmunity associated with familial background. We have previously reported similarities in gene expression patterns and PTPN22 polymorphisms between alopecia areata (AA) patients and their healthy relatives, but not unrelated healthy controls. However, the spectrum of disease promoting (or preventing) pathways that may be activated in blood relatives of AA patients remains to be defined. Here, we investigated the extent to which cytokines associated with the Th1 and Th17 pathway are differentially expressed in the blood of patients with AA and its clinical subtypes in comparison to both healthy relatives as well as unrelated healthy controls. A comprehensive set of Th1- and Th17-related cytokines were evaluated by ELISA. We found a significant elevation of the Th17 inducer IL-23, the Th17 product IL-17A, the Th1 hallmark cytokine IFNγ, and TNFα, a Th1 cytokine with relevance to the Th17 pathway in AA patients, regardless of disease subtype, compared to healthy individuals. On further examination, we found that healthy family members grouped together with patients in terms of elevated Th1- and Th17-pathway cytokines in an inheritance-specific manner, distinct from unrelated controls. The elevation of Th17-associated cytokines in healthy controls related to AA patients indicates that Th1 and Th17 dysregulation in AA may be genetically based. Of note, one unrelated control displayed elevated levels of IL-17A and IL-23 similar to those detected in patients. One year after initial blood draw, areas of beard hair loss consistent with the diagnosis of AA were reported by this individual, indicating that the elevation in Th17-related cytokines may have predictive value.

Background: Correctional officers (COs) experience elevated rates of mental and physical ill-health as compared with other general industry and public safety occupations. The purpose of this study was to investigate demographic, mental health, job tenure, and work–family characteristics and their prospective association to burnout within and between jail officers during one year of new employment. Methods: In 2016, newly hired jail officers (N = 144) completed self-reported surveys across four time points in a one-year prospective study at a Midwestern United States urban jail. Linear mixed-effects and growth modeling examined how work–family conflict (W-FC) and depressive symptoms relate to perceptions of burnout over time. Results: Jail officer burnout increased and was related to rises in W-FC and depression symptoms. Within-person variance for W-FC (Bpooled = .52, p