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Abstract Background Vitamin C deficiency, or scurvy, is rare but poses risks for children with poor diets, limited resources, or malabsorption issues. It may also be common in children with restrictive or selective dietary habits in children with global developmental delay, autism spectrum disorder, and physical disabilities. Symptoms include fatigue, irritability, joint and muscle pain, joint swellings, edema, swollen gums, easy bruising, and delayed wound healing. Early recognition and prompt intervention are essential to prevent the progression of symptomatic vitamin C deficiency in children. Case presentation We present a case of a 13-year-old boy with developmental delay secondary to Lennox Gastaut syndrome referred for suspected recurrent, severe, and atypical IgA vasculitis. He presented with irritability, loss of appetite, petechial and ecchymotic lower limb lesions, unilateral gum swelling, severe arthritis, peripheral oedema, severe weight loss, anaemia, and raised inflammatory markers. Multiple investigations were performed before the diagnosis of scurvy was made. A surgical finding of friable gingival tissue with multiple loose teeth, a skin biopsy with follicular hyperkeratosis and extravasated perifollicular red blood cells, and a typical X-ray finding led to the diagnosis of scurvy. Conclusion Scurvy should be given careful consideration as a differential diagnosis in patients presenting with musculoskeletal issues, mucocutaneous complaints, and constitutional symptoms such as malaise, asthenia, irritability, and loss of appetite. A focused and detailed dietary history looking for a lack of good sources of vitamin C can be an easy indicator of this differential. Imaging studies revealing the typical features can also help make the diagnosis. Pathology of the skin revealing pathognomonic features can add to the certainty of the diagnosis. In the absence of all else, the rapid response to treatment with an appropriate dose of vitamin C has a diagnostic and therapeutic role.

Knowledge of anticipatory stress responses before sports competitions is limited, thus this study examined the relationship between anticipatory stress in terms of salivary cortisol secretion in athletes on the morning of a competition and a comparison baseline day. Thirty-seven athletes collected three saliva samples over a 45-min period post-awakening (0, 30 and 45 min). Anticipatory stress was expressed as Area Under the Curve compared to ground (AUCg; total cortisol secretion). There was no significant difference in AUCg between baseline and competition days. However, a mixed two-factor ANOVA with day and sport type (individual vs. team) revealed a significant main effect of sport type (p

ABSTRACT The vaginal microbiome has been linked to negative health outcomes including preterm birth. Specific taxa, including Gardnerella spp., have been identified as risk factors for these conditions. Historically, microbiome analysis methods have treated all Gardnerella spp. as one species, but the broad diversity of Gardnerella has become more apparent. We explore the diversity of Gardnerella clades and genomic species in the vaginal microbiome of pregnant women and their associations with microbiome composition and preterm birth. Relative abundance of Gardnerella clades and genomic species and other taxa was quantified in shotgun metagenomic sequencing data from three distinct cohorts of pregnant women. We also assessed the diversity and abundance of Gardnerella variants in 16S rRNA gene amplicon sequencing data from seven previously conducted studies in differing populations. Individual microbiomes often contained multiple Gardnerella variants, and the number of clades was associated with increased microbial load, or the ratio of non-human reads to human reads. Taxon co-occurrence patterns were largely consistent across Gardnerella clades and among cohorts. Some variants previously described as rare were prevalent in other cohorts, highlighting the importance of surveying a diverse set of populations to fully capture the diversity of Gardnerella. The diversity of Gardnerella both across populations and within individual vaginal microbiomes has long been unappreciated, as has been the intra-species diversity of many other members of the vaginal microbiome. The broad genomic diversity of Gardnerella has led to its reclassification as multiple species; here we demonstrate the diversity of Gardnerella found within and between vaginal microbiomes.IMPORTANCEThe present study shows that single microbiomes can contain all currently known species of Gardnerella and that multiple similar species can exist within the same environment. Furthermore, surveys of demographically distinct populations suggest that some species appear more commonly in certain populations. Further studies in broad and diverse populations will be necessary to fully understand the ecological roles of each Gardnerella sp., how they can co-exist, and their distinct impacts on microbial communities, preterm birth, and other health outcomes.

Despite the availability of potent antiviral therapy and increasingly long prophylaxis courses, cytomegalovirus (CMV) infection continues to negatively affect outcomes after cardiothoracic transplant (CT). CMV antiviral stewardship (AVS) represents an opportunity to implement organ-specific prophylaxis, treatment, and monitoring algorithms while optimizing care of the allograft and patient. Within the nuanced context of heart and lung transplant recipients, CMV prophylaxis, monitoring, and treatment strategies are reviewed for efficacy and safety. These insights highlight opportunities for CMV AVS programs to combine organ- and patient-specific data while implementing CMV guidelines, appropriately adopted to local context by local experts, with concurrent and retrospective evaluation for each patient and the transplant program. By applying concepts of CMV AVS currently practiced in abdominal transplant, CT programs can work to improve graft and patient outcomes related to CMV, including ongoing challenges such as atherosclerosis and impaired endothelial function in heart transplant recipients and chronic lung allograft dysfunction in lung transplant recipients. While implementation of CMV AVS is not without challenges, it also represents an opportunity for multidisciplinary teams to foster the development of CMV-specific cell-mediated immunity and improve long-term outcomes.

Background: Inadequate pain control after lung transplantation increases perioperative complications. Standard opioid-based regimens are associated with adverse effects and epidural catheters that reduce opioid use are limited by contraindications and technical challenges. We report the use of intercostal nerve cryoablation to enhance perioperative pain control as part of an opioid-sparing protocol for lung transplant recipients (LTR). Methods: We conducted a retrospective cohort study of LTRs from January 1, 2016 to December 31, 2021, before (precryo) and after (postcryo) initiation of an opioid-sparing protocol utilizing intraoperative intercostal nerve cryoablation. The precryo cohort included consecutive patients treated with opioids and selective use of epidural catheters. The postcryo cohort received intercostal nerve cryoablation at levels 3 to 7, scheduled acetaminophen, gabapentin, and tramadol. Additional opioids or epidural catheters were used for breakthrough pain. Results: In total, 49 precryo and 40 postcryo patients were analyzed. Baseline demographics were similar aside from a shift to performing more bilateral lung transplants in the postcryo cohort (57% vs 95%, p

Abstract Cellular agriculture, that is, the production of cultured meat and microbial proteins, has been developed to provide food security for a growing world population. The use of green energy technologies is recommended to ensure the sustainability of changing traditional agriculture to a cellular one. Here, we use a global dynamic model and life-cycle assessment to analyze scenarios of replacing traditional livestock products with cellular agriculture from 2020 to 2050. Our findings indicate that a transition to cellular agriculture by 2050 could reduce annual greenhouse gas emissions by 52%, compared to current agriculture emissions, reduce demand for phosphorus by 53%, and use 83% less land than traditional agriculture. A maximum 72% replacement of livestock products with cellular agriculture using renewable energy is possible based on the 2050 regional green energy capacities. A complete transition can be achieved but requires 33% of the global green energy capacities in 2050. Further, the accelerated demand for critical materials will not exceed their primary production capacities, except for tellurium. We conclude that a transition to cellular agriculture is possible with environmental benefits and provide a benchmark to study different alternatives to animal-based diets.

Abstract Emerging nature restoration agendas are increasing the pressure on rural communities to coexist with expanding wildlife, including large carnivores. There are different interpretations of coexistence, stemming from divergent ways of conceptualising and relating to nature. Yet there is limited understanding of how and why certain interpretations become dominant, and how this influences conservation policy and practice. This question is highly relevant for the management of wolves in Spain. Until recently, the national strategy allowed certain regional autonomy in creating and enacting coexistence policy, including through culling and sport hunting. However, in 2021, the national government declared wolves strictly protected throughout the country, despite strong contestations about whether and why it was necessary. We studied the discursive processes that co‐produced this policy shift. First, we explored interpretations among communities that share, or will share, space with wolves, using qualitative field data. Second, we triangulated local interpretations with framings in public media to identify prominent discourses about coexistence. Third, we traced how these discourses interacted with Spanish conservation policy: who was heard and why. We highlight three prominent discourses: wolf protectionism, traditionalism and pragmatism, each proposing a distinct pathway to coexistence with wolves. Through our policy analysis, we illuminate a dominance of protectionism within national politics, which justified a centralised technocratic pathway while downplaying place‐based approaches. The resulting coexistence policy was highly contested and appears to have increased social conflict over wolves. Our findings reveal knowledge hierarchies within Spanish policy frameworks that promotes ‘mainstream’ conservationists' narrow interpretation of what nature and coexistence should be. This has perpetuated an apolitical approach that is focussed on mediating direct impacts from wolves, rather than conflicting worldviews, and that undermines efforts to promote dialogue and local stewardship. While our research is centred on Spain, the findings are of broad relevance since they reveal structural barriers that constrain the incorporation of diverse knowledge systems into conservation policy, and subsequent transformations towards socially just and locally adapted coexistence programmes. Read the free Plain Language Summary for this article on the Journal blog.

Abstract The increasing use of additive manufacturing (AM) techniques (e.g., 3D-printing) offers many advantages but at the same time presents some challenges. One concern is the possible exposure and health risk related to metal containing particles of different sizes. Using the nickel-based alloys Hastelloy X (HX) and Inconel 939 (IN939) as a case, the aim of this cross-disciplinary study was to increase the understanding on possible health hazards and exposure. This was done by performing in-depth characterization of virgin, reused and condensate powders, testing in vitro toxicity (cytotoxicity, genotoxicity, oxidative stress), and measuring occupational airborne exposure. The results showed limited metal release from both HX and IN939, and slightly different surface composition of reused compared to virgin powders. No or small effects on the cultured lung cells were observed when tested up to 100 µg/mL. Particle background levels in the printing facilities were generally low, but high transient peaks were observed in relation to sieving. Furthermore, during post processing with grinding, high levels of nanoparticles (> 100,000 particles/cm3) were noted. Urine metal levels in AM operators did not exceed biomonitoring action limits. Future studies should focus on understanding the toxicity of the nanoparticles formed during printing and post-processing.

Abstract Metal additive manufacturing (AM) is gaining traction but raises worker health concerns due to micron‐sized powders, including fine inhalable particles. This study explored particle and surface characteristics, electrochemical properties, metal release in artificial lysosomal fluid (ALF), and potential toxicity of virgin and sieved virgin Fe‐based powders, stainless steel (316L), Fe, and two tooling steels. Virgin particles ranged in size from 1 to 100 µm, while sieved particles were within the respirable size range (

Background: Females are typically less fatigable than males during sustained isometric contractions at lower isometric contraction intensities. This sex difference in fatigability becomes more variable during higher intensity isometric and dynamic contractions. While less fatiguing than isometric or concentric contractions, eccentric contractions induce greater and longer lasting impairments in force production. However, it is not clear how muscle weakness influences fatigability in males and females during sustained isometric contractions. Methods: We investigated the effects of eccentric exercise-induced muscle weakness on time to task failure (TTF) during a sustained submaximal isometric contraction in young (18–30 years) healthy males (n = 9) and females (n = 10). Participants performed a sustained isometric contraction of the dorsiflexors at 35° plantar flexion by matching a 30% maximal voluntary contraction (MVC) torque target until task failure (i.e., falling below 5% of their target torque for ≥2 s). The same sustained isometric contraction was repeated 30 min after 150 maximal eccentric contractions. Agonist and antagonist activation were assessed using surface electromyography over the tibialis anterior and soleus muscles, respectively. Results: Males were ∼41% stronger than females. Following eccentric exercise both males and females experienced an ∼20% decline in maximal voluntary contraction torque. TTF was ∼34% longer in females than males prior to eccentric exercise-induced muscle weakness. However, following eccentric exercise-induced muscle weakness, this sex-related difference was abolished, with both groups having an ∼45% shorter TTF. Notably, there was ∼100% greater antagonist activation in the female group during the sustained isometric contraction following exercise-induced weakness as compared to the males. Conclusion: This increase in antagonist activation disadvantaged females by decreasing their TTF, resulting in a blunting of their typical fatigability advantage over males.

We report the discovery and characterization of a small planet, TOI-1408 c, on a 2.2 day orbit located interior to a previously known hot Jupiter, TOI-1408 b ( P = 4.42 days, M = 1.86 ± 0.02 M _Jup , R = 2.4 ± 0.5 R _Jup ) that exhibits grazing transits. The two planets are near 2:1 period commensurability, resulting in significant transit timing variations (TTVs) for both planets and transit duration variations for the inner planet. The TTV amplitude for TOI-1408 c is 15% of the planet’s orbital period, marking the largest TTV amplitude relative to the orbital period measured to date. Photodynamical modeling of ground-based radial velocity (RV) observations and transit light curves obtained with the Transiting Exoplanet Survey Satellite and ground-based facilities leads to an inner planet radius of 2.22 ± 0.06 R _⊕ and mass of 7.6 ± 0.2 M _⊕ that locates the planet into the sub-Neptune regime. The proximity to the 2:1 period commensurability leads to the libration of the resonant argument of the inner planet. The RV measurements support the existence of a third body with an orbital period of several thousand days. This discovery places the system among the rare systems featuring a hot Jupiter accompanied by an inner low-mass planet.

Abstract Partnerships between organizations that engage in land protection are promoted as a way to improve the efficiency of limited conservation budgets. However, limited empirical exploration of the types of organizations involved in partnering and their organizational objectives precludes a holistic understanding of how to integrate partnering into planning for improved conservation outcomes. Using data on protected areas from California, United States, we explored the frequency and extent of partnering between managing organizations. In addition, we analyzed mission statements of partnering and non‐partnering organizations to explore whether organizational objectives were related to observed partnering behavior. We estimated that partnerships managed about 7 million acres, comprising 8% of total protected land area, in California. Furthermore, the organizations that we observed partnering tended to use more environmental themed language in their mission statements, while non‐partnering organizations tended to use language with socioeconomic themes. These results provide empirical evidence of partnering and support further exploration of it as a potentially important mechanism to improve conservation outcomes. In addition, they suggest that current partnering patterns and future opportunities to expand partnerships in protected land management likely depend on organizations pursuing wildlife and nature focused conservation objectives, and to a lesser extent socioeconomic objectives.

BackgroundGoal management training (GMT), a metacognitive rehabilitation method that has been demonstrated to improve executive function (EF) in adults with acquired brain injury (ABI), could potentially be effective for children in the chronic phase of ABI. In a previously published randomised controlled trial (RCT), the efficacy of a paediatric adaptation of GMT (pGMT) compared to a psychoeducative control intervention (paediatric Brain Health Workshop, pBHW) was investigated. Comparable improvements in EF in both groups were found at 6-month follow-up. However, a specific effect of pGMT could not be conclusively proven. The present study reports 2-year follow-up data (T4; T1: baseline, T2: post-intervention, T3: 6-month follow-up, and T4: 2-year follow-up) from this original RCT.MethodsA total of 38 children and adolescents and also their parents completed questionnaires tapping into daily life EF. Explorative analyses were conducted comparing the 2-year follow-up data (T4) with the baseline (T1) and 6-month follow-up data (T3) for T4-participants in the two intervention groups (pGMT; n = 21, pBHW; n = 17), and we also assessed T4-participants vs. non-responders (n = 38) in the RCT. Primary outcome measures were the Behavioural Regulation Index (BRI) and the Metacognition Index (MI) derived from the Behaviour Rating Inventory of Executive Function (BRIEF) parent report.ResultsNo difference between intervention groups was found (BRI, F = 2.25, p = 0.143, MI, F = 1.6, p = 0.213), and no time*group interaction (BRI, F = 0.07, p = 0.976, MI, F = 0.137, p = 0.937) could be seen at the 2-year follow-up. Nevertheless, both pGMT and the pBHW groups improved daily EF as measured by parental reports over time from the baseline to T4 (p = 0.034). T4 participants and non-responders shared similar baseline characteristics.ConclusionOur results extend the findings from the 6-month follow-up previously published. Both pGMT and pBHW groups sustained their improvements in daily life EFs from the baseline, but additional effectiveness of pGMT relative to pBHW was not found.

Exacerbated inflammatory responses are a hallmark of severe coronavirus disease 2019 (COVID-19). Zileuton (Zi) is a selective inhibitor of 5-lipoxygenase, an enzyme involved in the production of several inflammatory/pro-resolving lipid mediators. Herein, we investigated the effect of Zi treatment in a severe acute respiratory syndrome (SARS) model. Mouse hepatitis virus (MHV)3-infected mice treated with Zi significantly improved the clinical score, weight loss, cardiopulmonary function, and survival rates compared with infected untreated animals. The protection observed in Zi-treated mice was associated with a lower inflammatory score, reduced dendritic cell-producing tumor necrosis factor (TNF), and increased neutrophil-producing interleukin (IL)-10 in the lungs three days after infection (dpi). At 5 dpi, the lungs of treated mice showed an increase in Th2-, Treg CD4+-, and Treg CD8+-producing IL-10 and reduced Th1 infiltrating cells. Furthermore, similar results were found upon Zi treatment after SARS-CoV-2 infection in transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2), significantly improving the clinical score, weight loss, and lung inflammatory score compared with untreated animals. Our data suggest that Zi protects against developing severe lung disease during SARS induced by betacoronavirus without affecting the host’s capacity to deal with infection.

Abstract The Ophthalmology Student Interest Group at Indiana University School of Medicine provides a free student-run eye screening clinic for an underserved community in Indianapolis. Patients with abnormal findings are referred to the ophthalmology service of the local county hospital for further evaluation. This retrospective chart review studied 180 patients referred from our free eye clinic to follow up at the ophthalmology service of a local county hospital from October 2013 to February 2020. This study investigated factors impacting follow-up of patients by analyzing demographics, medical history, insurance coverage, and final diagnoses at follow-up. Thirty-five (19.4%) of 180 patients successfully followed up at the local county hospital with an average time to follow-up of 14.4 (± 15.9) months. Mean patient age was 51 (± 13.6) with nearly equal numbers of males and females. The most common diagnoses at follow-up included refractive error (51.4%), cataract (45.7%), and glaucoma (28.6%). Patients with diabetes diagnoses or Healthy Indiana Plan insurance coverage had increased probability of follow-up. This study reveals gaps in timely follow-up to the local county hospital, demonstrating the current limitations of our free clinic in connecting patients to more definitive care and the need for an improved referral process.

Reintegrating wolves in human-dominated landscapes constitutes a significant conservation challenge. After decades of studying human-wolf interactions through a conflict lens, there is growing recognition that more nuanced perspectives are needed. However, this recognition has hitherto yielded few practical changes, and few have studied what underpins successful coexistence. Here we show that disproportionate focus on and resource allocation to conflict within conservation programmes risks undermining existing convivial relationships with large carnivores. Using a coexistence lens, we studied human-wolf interactions in Sanabria-La Carballeda in Spain; the region has one of the highest densities of wolves in Europe. We explored the underlying social and ecological conditions that have permitted both wolves and people to persist in the area, studied the mutual impacts, and surveyed how interactions are influenced by broader socio-economic processes. The findings of this novel approach to studying human-wildlife interactions elucidates how areas of functional coexistence have been neglected in policy, leaving them vulnerable to depopulation, low agricultural profitability, and the loss of biocultural diversity. When institutions fail to support functional coexistence, we risk losing the knowledge, the traditions and the trust of those who have sustained Europe's large carnivores, thereby undermining transitions to more convivial human-wildlife interactions in the future.

Abstract Background The Indiana University Student Outreach Clinic (IUSOC) Eye Clinic is a monthly student-run eye clinic that provides free visual screening to the Near East Side community of Indianapolis, IN, USA. Screening includes assessments of visual acuity, intraocular pressure, peripheral visual fields, refraction, and non-mydriatic fundus photography. Methods This is a retrospective chart review of 875 patients seen at the IUSOC Eye Clinic from October 2013 to February 2020. Data on demographics, insurance coverage, ocular history, physical examination, suspected diagnosis, referral status, and glasses provided were collected and analyzed. Results 875 patients were seen at the IUSOC Eye Clinic from October 2013 to February 2020. 39.2% of the patients seen at the clinic reported being uninsured. 61.4% of patients were found to have visual acuity of 20/40 or worse, while 51.3% of patients were found to have a near visual acuity of 20/40 or worse. 20.3% of patients were referred to the local county hospital for further evaluation by an ophthalmologist, 14.4% of patients received free glasses prescriptions, and 27.9% of patients received free reading glasses. Common reasons for referral for further ophthalmology evaluation included glaucoma, decreased visual acuity, and diabetic retinopathy. An estimated value of services provided over the seven years of the clinic was 1271 relative value units. Conclusion The IUSOC Eye Clinic fills an important role in advancing ocular health and preventing irreversible blindness in an underserved Indianapolis community. Additionally, the clinic demonstrates an educational model for involving medical student volunteers.

With the increasing adoption rate of electric vehicles, power peaks caused by many cars simultaneously charging on the same low-voltage grid can cause local overloading and power outages. Smart charging solutions should spread this load, but there is a residual risk of incidental peaks. A decentralized and autonomous technology called GridShield is being developed to reduce the likelihood of a transformer’s fuse blowing when other congestion solutions have failed. It serves as a measure of last resort to protect the grid against local power failures from unpredicted congestion by temporarily limiting the virtual capacity of charging stations. This paper describes the technical development and demonstrates how GridShield can keep a transformer load below a critical limit using simulations and real-world tests. It optimizes grid capacity while ensuring grid reliability.

Sensitization to a contact allergen brings with it a lifelong risk to develop allergic contact dermatitis. Inflammation is an important part of the skin sensitizing mechanism, and understanding how different haptens stimulate the immune system, as well as the role played by different cell types present in skin, may be helpful for developing optimized in vitro models for risk assessment of new chemicals or mixtures. The aim of this study was to compare the cytokine profile following exposure of cells representing keratinocytes (HaCaT), monocytes (THP-1) and a co-culture of these cells to three clinically important skin sensitizers: cobalt (II) chloride (CoCl2), methylisothiazolinone (MI) and p-phenylenediamine (PPD). Secretion of ten pro-inflammatory cytokines was measured using multiplexing. The results showed that the cytokine response differed substantially between the three cell assays. CoCl2 caused an increase of IL-8 in HaCaT cells, while the induction of also IL-13 and IL-1β was observed in THP-1 cells and co-cultures. MI induced six cytokines in HaCaT cells but only IL-1β in the THP-1 cells and four cytokines in the co-culture. Interestingly, the IL-1β response was massive in the co-culture. PPD caused release of IL-1β in all three models as well as IL-8 in the co-culture. Control experiments with two non-sensitizers and irritants (lactic acid and sodium dodecyl sulfate) showed no effect on IL-8 or IL-1β in the co-culture. Taken together, results from this exploratory analysis show unique cytokine profiles dependent on the type of hapten and cell model. Importantly, all three haptens triggered secretion of IL-1β and IL-8 in a co-culture of HaCaT cells and THP-1 cells, representing the most robust test system.

Genotoxicity is an important endpoint to assess for understanding the risks associated with nanoparticles (NPs). Most genotoxicity studies performed on NPs have focused on primary genotoxicity analyzed by comet- or micronuclei (MN) assay using microscopic scoring. Here, we established a protocol for a more efficient version of MN assessment using flow cytometry and, importantly, both primary and secondary (inflammation-driven) genotoxicity was assessed. Human bronchial epithelial cells (HBEC-3kt) were exposed to nickel oxide (NiO) NPs directly or indirectly. The indirect exposure was done to assess secondary genotoxicity, and in this case immune cells (THP-1 derived macrophages) were exposed on inserts and the HBEC were cultured in the lower compartment. The results in monocultures showed that no increased MN formation was observed in the HBEC cells but instead a clear MN induction was noted in THP-1 cells indicating higher sensitivity. No MN formation was either observed when the HBEC were indirectly exposed, but an increase in DNA strand breaks was detected using the comet assay. Taken together, the present study emphasizes the feasibility of assessing primary and secondary genotoxicity and, furthermore, shows a clear MN induction in THP-1 monoculture following NiO NPs exposure.

Background:. A technique of a free nipple graft with an inframammary incision and no vertical incision offers promising postoperative results as a safe and aesthetic alternative. Methods:. This was a retrospective chart review of patients who presented to a single surgeon for breast reduction surgery using a free nipple graft with an inframammary incision from June 1999 to March 2021. Baseline patient demographics and clinical information along with postoperative complications were recorded and compared between patients who presented for concomitant reconstruction or just reduction. A narrative literature review on surgical techniques and outcomes was also conducted. Results:. From the literature search, there have been minimal prior mentions of breast reductions using a free nipple graft with an inframammary incision and no vertical incision. Fifty-five cases were identified for breast reduction surgery in the author’s 22-year study period, of which 46 had adequate clinical documentation and follow-up. An estimated 22 patients had either both or one breast reconstructed with opposite side breast reduction, and 24 patients underwent breast reduction alone with free nipple grafting. No implants were used in any of the patients. Conclusions:. The free nipple graft technique with an inframammary incision can be performed on patients with excessively large or ptotic breasts. It is possible to reduce the volume of the breast and obtain good projection with this method. Furthermore, avoidance of the vertical incision reduces breakdown at the T-junction and is aesthetically beneficial.

Judi Porter,1,2 Lauren Hanna2,3 1Deakin University, Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Geelong, Victoria, Australia; 2Department of Nutrition, Dietetics & Food, Monash University, Notting Hill, Victoria 3168, Australia; 3Department of Nutrition and Dietetics, Monash Health, Clayton, Victoria, AustraliaCorrespondence: Judi PorterDeakin University, Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Geelong, Victoria, AustraliaTel +61 3 9902 0659Email judi.porter@deakin.edu.auAbstract: Malnutrition in hospitalized patients remains a significant problem. Protected Mealtimes is a complex, inter-professional ward-based intervention that was first introduced in the United Kingdom to address this issue. Now implemented internationally, the approach still remains in key policy documents including the National Health Service Essence of Care. This review aims to synthesize the nutrition, satisfaction and quality of life patient/resident outcomes that arise from the implementation of Protected Mealtimes in hospitals and residential aged care facilities and to consider fidelity issues that have been reported in previous research. A defined search strategy was implemented in seven databases to identify full text papers of original research that evaluated Protected Mealtimes implementation. After screening, data were extracted from eight studies (7 quantitative and 1 qualitative study) that were conducted in hospitals. There was no research identified from the aged care sector. There were few positive outcomes that resulted from Protected Mealtimes implementation, many fidelity issues with the intervention were reported. It is apparent that Protected Mealtimes provide few, if any, benefits for hospitalized patients. It is a complex, multi-pronged initiative that has limited fidelity and limited outcomes. As such, we recommend that disinvestment by policy makers for hospitals should be considered, with the implementation of other evidence based mealtime initiatives. We provide no recommendation for disinvestment in the aged care sector, since the approach has not been evaluated against any of the eligible outcomes of this review.Keywords: disinvestment, hospitals, policy, Protected Mealtimes

Abstract Background: Integration of clinical skills during graduate training in dual-degree programs remains a challenge. The present study investigated the availability and self-perceived efficacy of clinical continuity strategies for dual-degree trainees preparing for clinical training. Methods: Survey participants were MD/DO-PhD students enrolled in dual-degree-granting institutions in the USA. The response rate was 95% of 73 unique institutions surveyed, representing 56% of the 124 MD-PhD and 7 DO-PhD recognized training programs. Respondents were asked to indicate the availability and self-perceived efficacy of each strategy. Results: Reported available clinical continuity strategies included clinical volunteering (95.6%), medical grand rounds (86.9%), mentored clinical experiences (84.2%), standardized patients/ practice Objective Structured Clinical Examinations (OSCEs) (70.3%), clinical case reviews (45.9%), clinical journal clubs (38.3%), and preclinical courses/review sessions (37.2%). Trainees rated standardized patients (µ = 6.98 ± 0.356), mentored clinical experiences (µ = 6.94 ± 0.301), clinical skills review sessions (µ = 6.89 ± 0.384), preclinical courses/review sessions (µ = 6.74 ± 0.482), and clinical volunteering (µ = 6.60 ± 0.369), significantly (p < 0.050) higher than clinical case review (µ = 5.34 ± 0.412), clinical journal club (µ = 4.75 ± 0.498), and medicine grand rounds (µ = 4.45 ± 0.377). Further, 84.4% of respondents stated they would be willing to devote at least 0.5–1 hour per week to clinical continuity opportunities during graduate training. Conclusion: Less than half of the institutions surveyed offered strategies perceived as the most efficacious in preparing trainees for clinical reentry, such as clinical skills review sessions. Broader implementation of these strategies could help better prepare dual-degree students for their return to clinical training.

Neurodevelopmental disorders such as those linked to intellectual disabilities or autism spectrum disorder are thought to originate in part from genetic defects in synaptic proteins. Single gene mutations linked to synapse dysfunction can broadly be separated in three categories: disorders of transcriptional regulation, disorders of synaptic signaling and disorders of synaptic scaffolding and structures. The recent developments in super-resolution imaging technologies and their application to synapses have unraveled a complex nanoscale organization of synaptic components. On the one hand, part of receptors, adhesion proteins, ion channels, scaffold elements and the pre-synaptic release machinery are partitioned in subsynaptic nanodomains, and the respective organization of these nanodomains has tremendous impact on synaptic function. For example, pre-synaptic neurotransmitter release sites are partly aligned with nanometer precision to postsynaptic receptor clusters. On the other hand, a large fraction of synaptic components is extremely dynamic and constantly exchanges between synaptic domains and extrasynaptic or intracellular compartments. It is largely the combination of the exquisitely precise nanoscale synaptic organization of synaptic components and their high dynamic that allows the rapid and profound regulation of synaptic function during synaptic plasticity processes that underlie adaptability of brain function, learning and memory. It is very tempting to speculate that genetic defects that lead to neurodevelopmental disorders and target synaptic scaffolds and structures mediate their deleterious impact on brain function through perturbing synapse nanoscale dynamic organization. We discuss here how applying super-resolution imaging methods in models of neurodevelopmental disorders could help in addressing this question.

Wolf populations are recovering across Europe and readily recolonize most areas where humans allow their presence. Reintegrating wolves in human-dominated landscapes is a major challenge, particularly in places where memories and experience of coexistence have been lost. Despite the observed expansion trends, little has been done to prepare communities for the return of these apex predators, or to understand what fosters and perpetuates coexistence. In this study, we present a theoretical framework for resilient coexistence based on four conditions: Effective institutions, large carnivore persistence, social legitimacy, and low levels of risk and vulnerability, nested within the social-ecological systems (SES) concept. To empirically show how the conditions can be manifested and interconnected, and how this knowledge could be used to improve local coexistence capacities, the framework is applied in a case study of human–wolf relations in Spain. We examined three traditionally pastoral landscapes at different states of cohabitation with wolves: uninterrupted presence, recent recolonization, and imminent return. We found that both the perceptions of wolves and the capacity to coexist with them diverged across these states, and that this was largely determined by a diversity of vulnerabilities that have not been recognized or addressed within current management regimes, such as economic precarity and weak legitimacy for governing institutions. Our results illustrate the importance of working in close contact with communities to understand local needs and enhance adaptive capacities in the face of rural transitions, beyond those directly related to wolves. The framework complements emerging tools for coexistence developed by researchers and practitioners, which offer guidance on the process of situational analysis, planning, and resource allocation needed to balance large carnivore conservation with local livelihoods.

Among the various nanomaterials present in society, many contain metals or metal compounds [...]

Burnout is common among students and can negatively influence their motivation, performance, and wellbeing. However, there is currently little consensus regarding how to intervene effectively. Consequently, we provide the first systematic review and meta-analysis of studies examining the effectiveness of interventions aimed at reducing burnout in students. A systematic literature search returned 17 studies (10 randomized controlled trials and 7 quasi-experimental trials), which included 2,462 students from secondary and tertiary levels of education. These studies used a range of interventions (e.g., mindfulness, rational emotive behavior therapy, cognitive behavioral therapy). When the effects were aggregated across interventions, there was evidence for their effectiveness in reducing total burnout (g+ = 0.90, p = 0.02, 95% CI: [0.04, 1.75], k = 14). However, we also found evidence for moderation and nonsignificant effects when certain symptoms, designs, and intervention-types were examined. The strongest evidence for effectiveness was for randomized controlled trials, rational emotive behavior therapy, and mindfulness-based interventions. This review provides initial evidence for the efficacy of interventions in reducing burnout in students, but we note that a more systematic examination of particular intervention types, especially those designed to target the organisational-level, would be useful, and to have the most impact in informing policy, so too are studies examining the cost effectiveness of such interventions.

Abstract Essentials Cancer is associated with increased risk of developing venous thrombosis. Cancer patients were studied for ADAMTS‐13 and VWF levels and occurrence of venous thrombosis. Increased VWF in cancer patients is associated with a higher risk of venous thrombosis. Low levels of ADAMTS‐13 and/or increased VWF in cancer patients are associated with worse survival. Background Cancer‐associated venous thromboembolism (VTE) is an important complication in the course of a malignant disease. Low ADAMTS‐13 (a disintegrin‐like and metalloproteinase with thrombospondin type 1 motif 13) and increased von Willebrand Factor (VWF) levels in cancer patients have been described numerously. Objectives Investigation of the influence of ADAMTS‐13 and VWF on the probability of VTE and survival in malignancy. Patients/Methods In the framework of the ongoing prospective Cancer and Thrombosis Study (CATS) ADAMTS‐13 activity and VWF antigen levels were investigated in cancer patients. Results In total, 795 patients with various tumor types (364 female/431 male, median age 62 years) were included; of those, 56 developed VTE and 359 patients died during a median follow‐up time of 730 days. The hazard ratio (HR) of VTE per doubling of VWF level was 1.56 (95% confidence interval [CI] 1.13‐2.16) in multivariable competing risk analysis. ADAMTS‐13 levels showed no correlation with the incidence of VTE in univariate competing risk analysis. The HR of mortality per doubling of VWF level was 1.46 (95% CI 1.28‐1.66) and per SD increment of ADAMTS‐13was 0.90 (95% CI 0.81‐1.00) in multivariable Cox regression analysis. Patients with VWF >75th percentile and concomitant low (

Lung cancer, one of the most common and deadly forms of cancer, is in some cases associated with exposure to certain types of particles. With the rise of nanotechnology, there is concern that some engineered nanoparticles may be among such particles. In the absence of epidemiological evidence, assessment of nanoparticle carcinogenicity is currently performed on a time-consuming case-by-case basis, relying mainly on animal experiments. Non-animal alternatives exist, including a few validated cell-based methods accepted for regulatory risk assessment of nanoparticles. Furthermore, new approach methodologies (NAMs), focused on carcinogenic mechanisms and capable of handling the increasing numbers of nanoparticles, have been developed. However, such alternative methods are mainly applied as weight-of-evidence linked to generally required animal data, since challenges remain regarding interpretation of the results. These challenges may be more easily overcome by the novel Adverse Outcome Pathway (AOP) framework, which provides a basis for validation and uptake of alternative mechanism-focused methods in risk assessment. Here, we propose an AOP for lung cancer induced by nanosized foreign matter, anchored to a selection of 18 standardized methods and NAMs for in silico- and in vitro-based integrated assessment of lung carcinogenicity. The potential for further refinement of the AOP and its components is discussed in relation to available nanosafety knowledge and data. Overall, this perspective provides a basis for development of AOP-aligned alternative methods-based integrated testing strategies for assessment of nanoparticle-induced lung cancer.

Background The ophthalmology residency match is highly competitive, and fourth-year medical students frequently complete away rotations at other institutions hoping to increase their chances of matching. Objective The study aimed to determine the impact of away rotations on the ophthalmology residency selection process and to provide recommendations to faculty for counseling fourth-year medical students as they prepare for the ophthalmology match. Methods A survey was sent in June 2020 to program directors (PDs), medical student educators (MSEs), and residents at 119 accredited ophthalmology residency programs via the Association of University Professors of Ophthalmology e-mail listserv. The 43 PDs and 38 MSEs who responded were asked questions about their views regarding away rotations and visiting students during the residency selection process. The 83 resident respondents were asked about their interview and match success after completing away rotations. Categorical variables were analyzed by Chi-square test. Results The majority of PDs and MSEs typically recommend that fourth-year medical students complete away rotations (p = 0.022 and p = 0.194, respectively). The majority believe that an away rotation will increase the chance of the applicant matching with the host institution (p = 0.004 and p = 0.001, respectively). The vast majority of PDs were more likely to offer an interview to a visiting student compared with another equally qualified applicant (p

Background The fundus examination is an essential part of any ophthalmologic evaluation. However, medical students and primary care physicians often lack confidence with direct ophthalmoscopy. Virtual reality simulators are being employed in medical education to teach this technically challenging examination. Objective To compare medical student ratings of the Eyesi Direct Ophthalmoscope Simulator and traditional small group teaching methods for learning direct ophthalmoscopy skills. Methods All medical students at Indiana University School of Medicine traditionally learn direct ophthalmoscopy in their first 2 years during a small group session led by a physician instructor. Students who later enrolled in ophthalmology clinical electives during 2019 and 2020 were invited to additionally complete the Eyesi Direct Ophthalmoscope Simulator virtual reality curriculum. A voluntary, anonymous survey was sent between June and August 2020 to students who had completed both the traditional and Eyesi simulator sessions. Students were asked to rate their confidence in performing direct ophthalmoscopy following each session, and to indicate which teaching method was superior and why. Chi-square analysis was used to compare categorical variables. Results Students' confidence ratings for performing direct ophthalmoscopy were significantly higher following completion of the Eyesi simulator session compared with the traditional small group session (p

Gemtuzumab-ozogamicin (GO) is a humanized anti-CD33 antibody, which is conjugated to a cytotoxic calicheamicin. It is used to treat acute myeloid leukemia (AML) in combination with chemotherapy. We describe here two GO-treated acute myeloid leukemia (AML) cases: both patients suffered from a toxic syndrome, which manifested as impaired hemoglobin-haptoglobin scavenging and accumulation of hemolysis-related products. Our observations and earlier reports indicated that the reaction was caused by GO-targeted destruction of CD33 + CD163+ monocytes/macrophages, which are responsible for the clearance of hemoglobin-haptoglobin complexes. The rise of plasma lactate dehydrogenase was an early sign of the reaction, and both patients had high levels of free plasma hemoglobin, but plasma haptoglobin and bilirubin levels were paradoxically normal. Symptoms included septic fever and abnormalities in cardiac tests and in the case of the first patient, severe neurological symptoms which required intensive care unit admittance. Therapeutic plasma exchanges supported the patients until the recovery of normal hematopoiesis. The symptoms may be easily confounded with infectious complications-related organ damage. Regarding the increasing use of gemtuzumab-ozogamicin and other emerging CD33-targeted cell therapies, we want to highlight this mostly unknown and probably underdiagnosed toxicity.

B cell responses are a crucial part of the adaptive immune response to viral infection. Infection by salmonid alphavirus subtype 3 (SAV3) causes pancreas disease (PD) in Atlantic salmon (Salmo salar) and is a serious concern to the aquaculture industry. In this study, we have used intraperitoneal (IP) infection with SAV3 as a model to characterize local B cell responses in the peritoneal cavity (PerC) and systemic immune tissues (head kidney/spleen). Intraperitoneal administration of vaccines is common in Atlantic salmon and understanding more about the local PerC B cell response is fundamental. Intraperitoneal SAV3 infection clearly induced PerC B cell responses as assessed by increased frequency of IgM+ B cells and total IgM secreting cells (ASC). These PerC responses were prolonged up to nine weeks post-infection and positively correlated to the anti-SAV3 E2 and to neutralizing antibody responses in serum. For the systemic immune sites, virus-induced changes in B cell responses were more modest or decreased compared to controls in the same period. Collectively, data reported herein indicated that PerC could serve as a peripheral immunological site by providing a niche for prolonged maintenance of the ASC response in Atlantic salmon.

Cellular reproduction defines life, yet our textbook-level understanding of cell division is limited to a small number of model organisms centered around humans. The horizon on cell division variants is expanded here by advancing insights on the fascinating cell division modes found in the Apicomplexa, a key group of protozoan parasites. The Apicomplexa display remarkable variation in offspring number, whether karyokinesis follows each S/M-phase or not, and whether daughter cells bud in the cytoplasm or bud from the cortex. We find that the terminology used to describe the various manifestations of asexual apicomplexan cell division emphasizes either the number of offspring or site of budding, which are not directly comparable features and has led to confusion in the literature. Division modes have been primarily studied in two human pathogenic Apicomplexa, malaria-causing Plasmodium spp. and Toxoplasma gondii, a major cause of opportunistic infections. Plasmodium spp. divide asexually by schizogony, producing multiple daughters per division round through a cortical budding process, though at several life-cycle nuclear amplifications stages, are not followed by karyokinesis. T. gondii divides by endodyogeny producing two internally budding daughters per division round. Here we add to this diversity in replication mechanisms by considering the cattle parasite Babesia bigemina and the pig parasite Cystoisospora suis. B. bigemina produces two daughters per division round by a “binary fission” mechanism whereas C. suis produces daughters through both endodyogeny and multiple internal budding known as endopolygeny. In addition, we provide new data from the causative agent of equine protozoal myeloencephalitis (EPM), Sarcocystis neurona, which also undergoes endopolygeny but differs from C. suis by maintaining a single multiploid nucleus. Overall, we operationally define two principally different division modes: internal budding found in cyst-forming Coccidia (comprising endodyogeny and two forms of endopolygeny) and external budding found in the other parasites studied (comprising the two forms of schizogony, binary fission and multiple fission). Progressive insights into the principles defining the molecular and cellular requirements for internal vs. external budding, as well as variations encountered in sexual stages are discussed. The evolutionary pressures and mechanisms underlying apicomplexan cell division diversification carries relevance across Eukaryota.

Abstract During embryogenesis, differentiation of pluripotent cells into somatic cell types depends both on signaling cues and intrinsic gene expression programs. While the molecular underpinnings of pluripotency are well mapped, much less is known on how mouse embryonic stem cells (mESCs) differentiate. Using RNA‐Seq profiling during specification to the three germ layers, we showed that mESCs switched on condition‐specific gene expression programs from the onset of the differentiation procedure and that primed pluripotency did not constitute an obligatory intermediate state. After inferring the gene network controlling mESC differentiation, we tested the role of the highly connected nodes by deleting them in a triple knock‐in Sox1‐Brachyury‐Eomes mESC line reporting on ectoderm, mesoderm, and endoderm fates. This led to the identification of regulators of mESC differentiation that acted at several levels: Sp1 as a global break on differentiation, Nr5a2 controlling ectoderm specification, and notably Fos:Jun and Zfp354c as opposite switches between ectoderm and mesendoderm fate.

Abstract Background Genotoxicity is an important toxicological endpoint due to the link to diseases such as cancer. Therefore, an increased understanding regarding genotoxicity and underlying mechanisms is needed for assessing the risk with exposure to nanoparticles (NPs). The aim of this study was to perform an in-depth investigation regarding the genotoxicity of well-characterized Ni and NiO NPs in human bronchial epithelial BEAS-2B cells and to discern possible mechanisms. Comparisons were made with NiCl2 in order to elucidate effects of ionic Ni. Methods BEAS-2B cells were exposed to Ni and NiO NPs, as well as NiCl2, and uptake and cellular dose were investigated by transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS). The NPs were characterized in terms of surface composition (X-ray photoelectron spectroscopy), agglomeration (photon cross correlation spectroscopy) and nickel release in cell medium (ICP-MS). Cell death (necrosis/apoptosis) was investigated by Annexin V-FITC/PI staining and genotoxicity by cytokinesis-block micronucleus (cytome) assay (OECD 487), chromosomal aberration (OECD 473) and comet assay. The involvement of intracellular reactive oxygen species (ROS) and calcium was explored using the fluorescent probes, DCFH-DA and Fluo-4. Results NPs were efficiently taken up by the BEAS-2B cells. In contrast, no or minor uptake was observed for ionic Ni from NiCl2. Despite differences in uptake, all exposures (NiO, Ni NPs and NiCl2) caused chromosomal damage. Furthermore, NiO NPs were most potent in causing DNA strand breaks and generating intracellular ROS. An increase in intracellular calcium was observed and modulation of intracellular calcium by using inhibitors and chelators clearly prevented the chromosomal damage. Chelation of iron also protected against induced damage, particularly for NiO and NiCl2. Conclusions This study has revealed chromosomal damage by Ni and NiO NPs as well as Ni ionic species and provides novel evidence for a calcium-dependent mechanism of cyto- and genotoxicity.

In layered inorganic materials lattice distortions can couple to break inversion symmetry and drive improper ferroelectricity, but in perovskites, symmetry prohibits such an effect. Here, the authors use group-theoretical analysis to provide crystal engineering design principles for improper ferroelectricity in molecular perovskites.

Abstract While TLR-activated pathways are key regulators of B cell responses in mammals, their impact on teleost B cells are scarcely addressed. Here, the potential of Atlantic salmon B cells to respond to TLR ligands was shown by demonstrating a constitutive expression of nucleic-acid sensing TLRs in magnetic sorted IgM+ cells. Of the two receptors recognizing CpG in teleosts, tlr9 was the dominating receptor with over ten-fold higher expression than tlr21. Upon CpG-stimulation, IgM secretion increased for head kidney (HK) and splenic IgM+ cells, while blood B cells were marginally affected. The results suggest that CpG directly affects salmon B cells to differentiate into antibody secreting cells (ASCs). IgM secretion was also detected in the non-treated controls, again with the highest levels in the HK derived population, signifying that persisting ASCs are present in this tissue. In all tissues, the IgM+ cells expressed high MHCII levels, suggesting antigen-presenting functions. Upon CpG-treatment the co-stimulatory molecules cd83 and cd40 were upregulated, while cd86 was down-regulated under the same conditions. Finally, ifna1 was upregulated upon CpG-stimulation in all tissues, while a restricted upregulation was evident for ifnb, proposing that salmon IgM+ B cells exhibit a type I IFN-response.

Generally, fluorescence imaging needs to be done in a dark environment using molecules with spectrally separated emissions. Here, Quérard et al. develop a protocol for high-speed imaging and remote sensing of spectrally overlapping reversible photoswitchable fluorophores in ambient light.

Due to their ability to present foreign antigens and prime naïve T cells, macrophages, and dendritic cells (DCs) are referred to as professional antigen-presenting cells (APCs). Although activated macrophages may function as APCs, these cells are particularly effective at directly engaging pathogens through phagocytosis, and production of antimicrobial compounds. On the other hand, DCs possess superb antigen-presenting and costimulatory capacity and they are essential for commencement and regulation of adaptive immune responses. In in vitro models, development of mature mammalian DCs from monocytes requires sequential exposure to growth factors (including GM-CSF and IL-4) and proinflammatory stimuli such as toll-like receptor (TLR) ligands. Currently, except for IL-4/13, neither orthologs nor functional analogs of the growth factors which are essential for the differentiation of mammalian DCs (including GM-CSF and FLT3) have been identified in teleosts and data about differentiation of piscine APCs is scant. In the present study, primary salmon mononuclear phagocytes (MPs) stimulated in vitro for 5–7 days with a B-class CpG oligodeoxynucleotides (ODN 2006PS) underwent morphological differentiation and developed “dendritic” morphology, characterized by long, branching pseudopodia. Transcriptional profiling showed that these cells expressed high levels of proinflammatory mediators characteristic for M1 polarized MPs. However, the cells treated with CpGs for 7 days downregulated their surface MHCII molecules as well as their capacity to endocytose ovalbumin and exhibited attenuated allostimulatory activity. This concurred with transcriptional downregulation of costimulatory CD80/86 and upregulation of inhibitory CD274 (B7-H1) genes. Despite their exhausted allostimulatory activity, these cells were still responsive to re-stimulation with gardiquimod (a TLR7/8 ligand) and further upregulated a wide array of immune genes including proinflammatory mediators such as intereukin-1 beta and tumor necrosis factor. Overall, the presented data highlight the disparate effects TLR ligands may have on the proinflammatory status of APCs, on one side, and their antigen-presenting/costimulatory functions, on the other. These findings also indicate that despite the poor phylogenetic conservation of the growth factors involved in the differentiation of DCs, some of the processes that orchestrate the development and the differentiation of professional APCs are conserved between teleosts in mammals.