Prevalence of Wasting and its Associated Factors among Children Under 5 Years of Age in India: Findings from the Comprehensive National Nutrition Survey.

BACKGROUND: The burden of wasting among under five children in India, has not reduced in the last decade. OBJECTIVES: We used child-level data from the latest nationally representative Comprehensive National Nutritional Survey (CNNS) to estimate the prevalence of wasting at the national and state level in India. METHODS: We explored the association of wasting with maternal, child and household factors using multivariable logistic regression for the age group of 0-5, 6-23 and 24-59 months. RESULTS: The overall prevalence of wasting was 17.3%, ranging from 5.8% to 29.1% across states, 23.3% in children 0-5 months, 19.6 % in children 6-23 months and 15.4 % in children 24-59 months of age. Higher birthweight i.e., every 100g increase (0-5 months aOR = 0.96, 6-23 months aOR = 0.94, 24-59 months aOR = 0.96), higher maternal BMI (0-5 months aOR = 0.51, 6-23 months aOR = 0.62, 24-59 months aOR = 0.67), increasing child age in months (0-5 months aOR = 0.84) and female sex of the child (24-59 months aOR = 0.82) was found to have significantly lower odds of wasting. The odds of wasting were significantly higher for poorest wealth quintile (0-5 months aOR = 1.99, 6-23 months aOR = 2.13), maternal unemployment (0-5 months aOR = 2.25), and lower levels of maternal education (6-23 months aOR = 1.74). CONCLUSIONS: Our analyses showed that burden of wasting continues to remain high in India. Preventive interventions must target reduction of low birthweight. Early identification and management of wasting should be done, especially during the first six months of life who are not part of current therapeutic feeding programme.

An arch worth revisiting: a study on the feline humeral supracondylar foramen and its evolutionary significance.

The supracondylar foramen with a (seemingly) osseous peripheral arch noticed on the medio-distal feline humeri had remained disputed among anatomists. Some scholars have argued in favor of homology between this foramen and the supracondyloid foramen formed in presence of the ligament of Struthers in humans. Other theories include its presence as a retinaculum holding the median nerve and brachial artery to their anatomical position in a flexed elbow. Unfortunately, these theories lack investigative rigor. The emergence of non-invasive imaging modalities, such as micro-computed tomography, has enabled researchers to inspect the internal anatomy of bones without dismantling them. Thus, a micro-computed tomographic investigation was conducted on three feline (Felis catus) humeri specimens while the internal anatomy of the supracondylar foramina was examined. Unlike the humerus, the thin peripheral arch of the feline supracondylar foramen failed to elicit any osseous trabeculae or foci of calcification. While adhering to the humeral periosteum at its origin, the non-osseous arch, typical of a muscular tendon, attaches into the bony saddle related to the medial humeral epicondyle suggestive of a tendon or aponeurotic extension of a (vestigial) brachial muscle, with the coracobrachialis longus emerging to be the most likely candidate.

Experimental testing combined with inverse-FE for mechanical characterisation of penile tissues.

Erectile dysfunction (ED) predominantly affects men in their 40-70s and can lead to poor quality of life. One option for ED treatment is surgical implantation of an inflatable penile prosthesis (IPP). However, they can be associated with negative outcomes including infection, migration or fibrosis. To improve outcomes, the interaction between the IPP device and surrounding tissues needs further investigation and this could be achieved using pre-clinical testbeds, but they need to be informed by extensive tissue testing. In this study, an experimental approach is adopted to characterise the mechanics of horse penile tissue and establish a testing protocol for penile tissue. The whole penis segments were tested in plate compression tests to obtain whole penis behaviour which is necessary for validation of a pre-clinical testbed, whilst tensile and compression tests were performed on individual penile tissues, namely corpus cavernosa and tunica albuginea. The second part of the paper deals with the development of a computational model employing an inverse finite element approach to estimate the material parameters of each tissue layer. These material parameters are in good agreement with the experimental results obtained from the individual tissue layers and whole organ tissue tests. This paper presents the first study proposing realistic nonlinear elastic material parameters for penile tissues and offers a validated testbed for IPPs. STATEMENT OF SIGNIFICANCE: Erectile Dysfunction (ED) affects over half the male population aged 40-70 potentially leading to poor quality of life. Patients not responding to conventional treatments of ED, are advised to use penile prostheses which can create an erection using implanted inflatable cylinders. A significant drawback of such prostheses, however, is the substantial tissue damage they can induce during their usage. Preclinical testbeds, including computational and bench-top models, could offer an efficient means of improving device designs to mitigate this damage but such testbeds require extensive knowledge of penile tissue properties. In this study, the authors determine penile tissue mechanics and apply an inverse FE approach to characterise the penile material properties required to validate preclinical models of the penis.

The Exonuclease TREX1 Constitutes an Innate Immune Checkpoint Limiting cGAS/STING-Mediated Antitumor Immunity.

The DNA exonuclease three-prime repair exonuclease 1 (TREX1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. As tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here, we show that in tumor cells, TREX1 restricts spontaneous activation of the cGAS/STING pathway, and the subsequent induction of a type I IFN response. As a result, TREX1 deficiency compromised in vivo tumor growth in mice. This delay in tumor growth depended on a functional immune system, systemic type I IFN signaling, and tumor-intrinsic cGAS expression. Mechanistically, we show that tumor TREX1 loss drove activation of CD8+ T cells and NK cells, prevented CD8+ T-cell exhaustion, and remodeled an immunosuppressive myeloid compartment. Consequently, TREX1 deficiency combined with T-cell-directed immune checkpoint blockade. Collectively, we conclude that TREX1 is essential to limit tumor immunogenicity, and that targeting this innate immune checkpoint remodels the tumor microenvironment and enhances antitumor immunity by itself and in combination with T-cell-targeted therapies. See related article by Toufektchan et al., p. 673.

Transcriptional priming and chromatin regulation during stochastic cell fate specification.

Stochastic cell fate specification, in which a cell chooses between two or more fates with a set probability, diversifies cell subtypes in development. Although this is a vital process across species, a common mechanism for these cell fate decisions remains elusive. This review examines two well-characterized stochastic cell fate decisions to identify commonalities between their developmental programmes. In the fly eye, two subtypes of R7 photoreceptors are specified by the stochastic ON/OFF expression of a transcription factor, spineless. In the mouse olfactory system, olfactory sensory neurons (OSNs) randomly select to express one copy of an olfactory receptor (OR) gene out of a pool of 2800 alleles. Despite the differences in these sensory systems, both stochastic fate choices rely on the dynamic interplay between transcriptional priming, chromatin regulation and terminal gene expression. The coupling of transcription and chromatin modifications primes gene loci in undifferentiated neurons, enabling later expression during terminal differentiation. Here, we compare these mechanisms, examine broader implications for gene regulation during development and posit key challenges moving forward. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.

Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells.

Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.

The inseparability of context and clinical reasoning.

Early descriptions of clinical reasoning have described a dual process model that relies on analytical or nonanalytical approaches to develop a working diagnosis. In this classic research, clinical reasoning is portrayed as an individual-driven cognitive process based on gathering information from the patient encounter, forming mental representations that rely on previous experience and engaging developed patterns to drive working diagnoses and management plans. Indeed, approaches to patient safety, as well as teaching and assessing clinical reasoning focus on the individual clinician, often ignoring the complexity of the system surrounding the diagnostic process. More recent theories and evidence portray clinical reasoning as a dynamic collection of processes that takes place among and between persons across clinical settings. Yet, clinical reasoning, taken as both an individual and a system process, is insufficiently supported by theories of cognition based on individual clinicals and lacks the specificity needed to describe the phenomenology of clinical reasoning. In this review, we reinforce that the modern healthcare ecosystem - with its people, processes and technology - is the context in which health care encounters and clinical reasoning take place.

Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer.

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

Retinoic acid signaling regulates spatiotemporal specification of human green and red cones.

Trichromacy is unique to primates among placental mammals, enabled by blue (short/S), green (medium/M), and red (long/L) cones. In humans, great apes, and Old World monkeys, cones make a poorly understood choice between M and L cone subtype fates. To determine mechanisms specifying M and L cones, we developed an approach to visualize expression of the highly similar M- and L-opsin mRNAs. M-opsin was observed before L-opsin expression during early human eye development, suggesting that M cones are generated before L cones. In adult human tissue, the early-developing central retina contained a mix of M and L cones compared to the late-developing peripheral region, which contained a high proportion of L cones. Retinoic acid (RA)-synthesizing enzymes are highly expressed early in retinal development. High RA signaling early was sufficient to promote M cone fate and suppress L cone fate in retinal organoids. Across a human population sample, natural variation in the ratios of M and L cone subtypes was associated with a noncoding polymorphism in the NR2F2 gene, a mediator of RA signaling. Our data suggest that RA promotes M cone fate early in development to generate the pattern of M and L cones across the human retina.

Analysis of female strangulation homicides in King County, Washington, from 1978 to 2022.

Asphyxia due to strangulation is an uncommon but important modality of homicide that tends to disproportionately involve female victims. The present study was designed to investigate the circumstances, motivations, and injuries associated with strangulation homicides of females and to measure trends in incidence over time. Electronic records of the King County Medical Examiner's Office in Seattle, Washington, were used to compile a data set of all homicides in King County from 1995 through 2022. A second data set of female homicides due to strangulation was constructed with additional records prior to 1995, supplemented with data abstracted from autopsy reports, and linked to the Washington Attorney General's Office Homicide Investigation Tracking System database. This comprehensive data set was used to analyze demographics, circumstances, motives, and injuries of female strangulation homicides from 1978 through 2016. The results found that, from 1995 through 2022, females accounted for 22.8% of 2394 homicides but 80.3% of strangulation homicides. The average annual rate of all strangulation homicides decreased until 2020. Mean ages of female decedents were 27.7 years in homicides associated with sexual assault, 36.8 years with domestic violence, and 63.9 years with robbery. Lethal assaults most often occurred in private homes, and perpetrators were usually well known to the victim. Injuries included petechiae in 83%; ligature marks in 20%; fingernail marks in 1.4%; hyoid fractures in 23%; and thyroid cartilage fractures in 31%. Fractures were more common in manual strangulation and in decedents of ages over 40 years.

Assessing Phase-Change Materials as Effective Long-Term Biosensors in Limb Prosthetics.

Monitoring and controlling the microclimate at the skin-socket interface of limb prostheses is an important, yet unresolved, clinical problem. Phase-change materials (PCMs) represent a promising biosensor technology that holds the potential to both detect and alter (i.e., stabilize) changes in the temperature of a hybrid biological/mechanical system, such as a prosthesis. The biologically inspired sensor capabilities of PCMs can enhance the internal socket conditions and offer improved comfort and suspension while minimizing skin injuries for prosthesis users. This study investigated how prosthetic liners equipped with PCM biosensors affected the long-term outcomes for prosthesis users. In this double-blinded longitudinal crossover study, a cohort of transtibial prosthesis users wore regular conventional liners for six months and PCM liners for another six months. Prosthesis utilization, physical performance, and gait symmetry were studied using Modus StepWatch, the 2-minute walk test, and the TekScan F-Scan gait test, respectively. Measured parameters from these various tests, acquired at multiple timepoints during the study, were compared pairwise between the two liners per individual. While the obtained quantitative data trends, such as the gait symmetry, favored the PCM liners, no statistically significant differences were found between the PCM and conventional gel liners in any of the study parameters.

Hydro-bio-geo-socio-chemical interactions and the sustainability of residential landscapes.

Residential landscapes are essential to the sustainability of large areas of the United States. However, spatial and temporal variation across multiple domains complicates developing policies to balance these systems' environmental, economic, and equity dimensions. We conducted multidisciplinary studies in the Baltimore, MD, USA, metropolitan area to identify locations (hotspots) or times (hot moments) with a disproportionate influence on nitrogen export, a widespread environmental concern. Results showed high variation in the inherent vulnerability/sensitivity of individual parcels to cause environmental damage and in the knowledge and practices of individual managers. To the extent that hotspots are the result of management choices by homeowners, there are straightforward approaches to improve outcomes, e.g. fertilizer restrictions and incentives to reduce fertilizer use. If, however, hotspots arise from the configuration and inherent characteristics of parcels and neighborhoods, efforts to improve outcomes may involve more intensive and complex interventions, such as conversion to alternative ecosystem types.

Biophysical Measures to Support Analysis and Communication of Existence Values.

A recent focus of ecosystem services research has been on the definition of biophysical outcomes and measures most closely linked to social welfare. There is a particular need to identify biophysical outcomes corresponding to existence values. (Values associated with existence apart from any current or future use). We review economic and ecological evidence to answer two key questions: First, what are ideal characteristics of linking indicators for existence values? Linking indicators should be: understandable, subject to direct sensory perception, represented at relevant temporal and spatial scales, comprehensive, and quantifiable in a repeatable manner. Second, what types of ecosystem outcomes are most likely to be associated with these values? We distinguish between indicators of taxa and ecological landscapes, and then multiple subcategories within each. Our fundamental conclusion is that while there are general principles informing the specification of linking indicators of existence values, there is no compact set of indicators or measures that applies universally. The case-specific nature of these issues-general guidelines notwithstanding-implies the need for sustained partnerships between social and biophysical scientists to address questions of indicator choice.

The Role of Autopsy in Quality Assurance: Pilot Study of a Method for Prospective Reporting of Diagnostic Errors Discovered at Autopsy.

ABSTRACT: Hospital autopsies frequently reveal errors in diagnosis that could have affected the patient's clinical outcome. The aims of this study were (1) to investigate the ability of autopsy at our institution to elucidate unrecognized antemortem diagnoses and (2) to pilot a method for tabulating diagnostic discrepancies on a prospective basis. The study sample consisted of 296 cases from our hybrid hospital/forensic autopsy service during the period 2016 to 2018. Discrepancies in autopsy and clinical diagnosis were reported by pathologists at the time of autopsy report generation using a standard form. The rates of major discrepancies between autopsy and clinical diagnoses were 37.5% for in-hospital cases and 25% for patients who died outside our hospital (P < 0.05). The most common discrepant category was infection. The overall rates of discrepant causes of death were 14% (in hospital) and 8% (out of hospital) (ns). Overall percentages of cases with major diagnostic discrepancies were higher in our study than have been previously reported. It is possible that the nature of our patient population plays a role in this result. This study describes an important prospective reporting tool that will allow us to track rates of medical errors and improve diagnosis and treatment of the critically ill.

Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib.

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

Single-cell transcriptome analysis of xenotransplanted human retinal organoids defines two migratory cell populations of nonretinal origin.

Human retinal organoid transplantation could potentially be a treatment for degenerative retinal diseases. How the recipient retina regulates the survival, maturation, and proliferation of transplanted organoid cells is unknown. We transplanted human retinal organoid-derived cells into photoreceptor-deficient mice and conducted histology and single-cell RNA sequencing alongside time-matched cultured retinal organoids. Unexpectedly, we observed human cells that migrated into all recipient retinal layers and traveled long distances. Using an unbiased approach, we identified these cells as astrocytes and brain/spinal cord-like neural precursors that were absent or rare in stage-matched cultured organoids. In contrast, retinal progenitor-derived rods and cones remained in the subretinal space, maturing more rapidly than those in the cultured controls. These data suggest that recipient microenvironment promotes the maturation of transplanted photoreceptors while inducing or facilitating the survival of migratory cell populations that are not normally derived from retinal progenitors. These findings have important implications for potential cell-based treatments of retinal diseases.

Spatial dimensions of water quality value in New England river networks.

Households' willingness to pay (WTP) for water quality improvements-representing their economic value-depends on where improvements occur. Households often hold higher values for improvements close to their homes or iconic areas. Are there other areas where improvements might hold high value to individual households, do effects on WTP vary by type of improvement, and can these areas be identified even if they are not anticipated by researchers? To answer these questions, we integrated a water quality model and map-based, interactive choice experiment to estimate households' WTP for water quality improvements throughout a river network covering six New England states. The choice experiment was implemented using a push-to-web survey over a sample of New England households. Voting scenarios used to elicit WTP included interactive geographic information system (GIS) maps that illustrated three water quality measures at various zoom levels across the study domain. We captured data on how respondents maneuvered through these maps prior to answering the value-eliciting questions. Results show that WTP was influenced by regionwide quality improvements and improvements surrounding each respondent's home, as anticipated, but also by improvements in individualized locations identifiable via each respondent's map interactions. These spatial WTP variations only appear for low-quality rivers and are focused around particular areas of New England. The study shows that dynamic map interactions can convey salient information for WTP estimation and that predicting spatial WTP heterogeneity based primarily on home or iconic locations, as typically done, may overlook areas where water quality has high value.

Activating and repressing gene expression between chromosomes during stochastic fate specification.

DNA elements act across long genomic distances to regulate gene expression. During transvection in Drosophila, DNA elements on one allele of a gene act between chromosomes to regulate expression of the other allele. Little is known about the biological roles and developmental regulation of transvection. Here, we study the stochastic expression of spineless (ss) in photoreceptors in the fly eye to understand transvection. We determine a biological role for transvection in regulating expression of naturally occurring ss alleles. We identify DNA elements required for activating and repressing transvection. Different enhancers participate in transvection at different times during development to promote gene expression and specify cell fates. Bringing a silencer element on a heterologous chromosome into proximity with the ss locus "reconstitutes" the gene, leading to repression. Our studies show that transvection regulates gene expression via distinct DNA elements at specific timepoints in development, with implications for genome organization and architecture.