A Review of Pediatric Cardiomyopathy.

Though pediatric cardiomyopathy is rare in children, there is significant associated morbidity and mortality. Etiology varies from inborn errors of metabolism to familial genetic mutations and myocyte injury. Major classes include dilated, hypertrophic, restrictive, and non-compaction. Diagnosis generally involves a combination of clinical history and echocardiography. The use of cross-sectional imaging is gaining popularity. Management varies between subtype and may involve a combination of medical and surgical interventions depending on clinical status.

Clinical Relevance of Physical Function Outcomes in Cancer Cachexia.

Managing clinical manifestations of cancer/treatment burden on functional status and quality of life remains paramount across the cancer trajectory, particularly for patients with cachexia who display reduced functional capacity. However, clinically relevant criteria for classifying functional impairment at a single point in time or for classifying meaningful functional changes subsequent to disease and/or treatment progression are lacking. This unmet clinical need remains a major obstacle to the development of therapies for cancer cachexia. This review aims to describe current literature-based evidence for clinically meaningful criteria for (1) functional impairment at a single timepoint between cancer patients with or without cachexia and (2) changes in physical function over time across interventional studies conducted in patients with cancer cachexia. The most common functional assessment in cross-sectional and interventional studies was hand grip strength (HGS). We observed suggestive evidence that an HGS deficit between 3 and 6 kg in cancer cachexia may display clinical relevance. In interventional studies, we observed that long-duration multimodal therapies with a focus on skeletal muscle may benefit HGS in patients with considerable weight loss. Future studies should derive cohort-specific clinically relevant criteria to confirm these observations in addition to other functional outcomes and investigate appropriate patient-reported anchors.

Lifecycle of surgical devices: Global, environmental, and regulatory considerations.

BACKGROUND: Technological advancements, improved surgical access, and heightened demand for surgery have fueled unprecedented device and supply turnover impelling wealthy hospitals to upgrade continually and sell, donate, recycle, or dispose of used, expired, antiquated, or surplus goods. This paper reviews the issues related to device and supply lifecycles and discusses the opportunities and challenges they present for sustainable surgical growth in low- and middle-income (LMICs) countries. OBSERVATIONS: This review found, in LMICs countries, regulatory disparities persist that limit effective harmonization secondary to highly variable national policies and a lack of prioritized enforcement. Heterogeneity in the regulatory landscape, specifically in the classification, nomenclature, and identification of medical devices, encumbers effective regulation and distribution. Once devices are sold, donated, or reused in LMICs countries, complexities arise in regulatory compliance, maintenance, and appropriate use of these technologies. At the end of the lifecycle, waste management poses significant obstacles with limited resources hindering the implementation of best practices. CONCLUSION: There are major disparities in access to quality surgical equipment and supplies around the world. Improved communication between relevant stakeholders and harmonization of manufacture and disposal regulations will be needed to ensure adequate and appropriate responses to these challenges. TRIAL REGISTRATION NUMBER: Not applicable.

Applying the Hybrid Concept as a Bridge to Transplantation in Infants Without Hypoplastic Left Heart Syndrome.

Therapies to support small infants in decompensated heart failure that are failing medical management are limited. We have used the hybrid approach, classically reserved for high-risk infants with single ventricle physiology, in patients with biventricular physiology with left ventricular failure. This approach secures systemic circulation, relieves left atrial hypertension, protects the pulmonary vasculature, and allows the right ventricle to support cardiac output. This approach can be used as a bridge to transplantation in select individuals. Infants without single ventricle congenital heart disease who were treated with the hybrid approach between 2008 and 2021 were included in analysis. Eight patients were identified. At the time of hybrid procedure, the median weight was 3.2 kg (range 2.4-3.6 kg) and the median age was 18 days (range 1-153 days). Seventy five percent were mechanically ventilated and 88% were on inotropic support. The median duration from hybrid procedure to transplant was 63 days (range 4-116 days). All patients experienced a good outcome (delisted for improvement or transplanted). The hybrid procedure is an appropriate therapeutic bridge to transplantation in a carefully selected subset of critically ill infants without single ventricle congenital heart disease in whom alternate therapies may confer increased risk for morbidity and mortality.

A systematic review of self and observer assessment of pain and related functioning in youth with brain-based developmental disabilities.

ABSTRACT: Pain experiences of youth with brain-based developmental disabilities are often overlooked and/or misinterpreted, increasing the risk for poor or inadequate pain assessment and management. Ample measures exist to assess acute and chronic pain, yet their utility and frequency of use in youth with brain-based developmental disabilities is unclear and available measures do not have strong measurement properties for this diverse group. This systematic review identified the scope of self-reported and observer-reported pain assessment in studies of youth (aged 3-24 years) with brain-based developmental disabilities (phase 1) and summarized other measures of pain-related functioning for acute and chronic pain (ie, physical, emotional, social, sleep, and quality of life, within the subset of quantitative studies focused primarily on pain, phase 2). A comprehensive search for English-language studies was conducted in August 2022 in Web of Science, CINAHL, MEDLINE, Cochrane CENTRAL, EMBASE, and APA PsychINFO (PROSPERO registration: CRD42021237444). A total of 17,029 unique records were screened. Of the 707 articles included in phase 1, most assessed chronic pain (n = 314; 62.0%) and primarily used observer-report (n = 155; 31%) over self-report (n = 67; 13%). Of the 137 articles included in phase 2, other outcomes assessed alongside pain intensity included motor ability (16.8%), adaptive functioning (11%), quality of life (8%), pain interference (6.6%), mental health (5.8%), and communication ability (2.9%). Cerebral palsy was the most common population in both phase 1 (n = 343; 48.5%) and phase 2 (n = 83; 59.7%). This review provides a foundational understanding of pain assessment in brain-based developmental disabilities and highlights continued inequities in holistic pain assessment for this population.

Unpacking reappraisal: a systematic review of fMRI studies of distancing and reinterpretation.

In recent decades, a substantial volume of work has examined the neural mechanisms of cognitive reappraisal. Distancing and reinterpretation are two frequently used tactics through which reappraisal can be implemented. Theoretical frameworks and prior evidence have suggested that the specific tactic through which one employs reappraisal entails differential neural and psychological mechanisms. Thus, we were motivated to assess the neural mechanisms of this distinction by examining the overlap and differentiation exhibited by the neural correlates of distancing (specifically via objective appraisal) and reinterpretation. We analyzed 32 published functional magnetic resonance imaging (fMRI) studies in healthy adults using multilevel kernel density analysis. Results showed that distancing relative to reinterpretation uniquely recruited right bilateral dorsolateral PFC (DLPFC) and left posterior parietal cortex, previously associated with mentalizing, selective attention and working memory. Reinterpretation relative to distancing uniquely recruited left bilateral ventrolateral PFC (VLPFC), previously associated with response selection and inhibition. Further, distancing relative to reinterpretation was associated with greater prevalence of bilateral amygdala attenuation during reappraisal. Finally, a behavioral meta-analysis showed efficacy for both reappraisal tactics. These results are consistent with prior theoretical models for the functional neural architecture of reappraisal via distancing and reinterpretation and suggest potential future applications in region-of-interest specification and neural network analysis in studies focusing on specific reappraisal tactics.

Genetic counseling practices among outpatient obstetric providers in the Northeast.

BACKGROUND: The American College of Obstetricians and Gynecologists recommends all pregnant people be offered genetic screening and diagnostic testing regardless of risk factors. Previous studies have demonstrated disparities in referrals for genetic testing by race outside of pregnancy, but limited data exist regarding genetic counseling practices during pregnancy. OBJECTIVE: This study aimed to describe how patient, provider, and practice demographics influence the offering of diagnostic prenatal genetic testing by outpatient prenatal care providers. STUDY DESIGN: This was a multicenter anonymous survey study conducted between October 2021 and March 2022. Outpatient prenatal care providers, including family medicine and obstetrics attendings, residents, maternal-fetal medicine fellows, nurse practitioners, physician assistants, and midwives, were surveyed about their genetic counseling practices and practice demographics. The primary outcome was the proportion of respondents who answered "yes, all patients" to the survey question "Do you offer diagnostic genetic testing to all patients?" The secondary outcomes included the association between patient and practice demographics and offering diagnostic testing. Diagnostic testing was defined as chorionic villus sampling or amniocentesis. Screening genetic tests were defined as sequential screen, quadruple screen, cell-free DNA screening, or "other." The chi-square test or Fisher exact test was used as appropriate. For the outcome answers of diagnostic testing, logistic regression was performed to assess the association between the answer of diagnostic genetic testing and the current training level of providers, race and ethnicity, and insurance status variables. Multivariable analysis was performed to adjust for confounders. RESULTS: A total of 635 outpatient prenatal care providers across 7 sites were sent the survey. Overall, 419 providers responded for a total response rate of 66%. Of the providers who responded, most were attendings (44.9%), followed by residents (37.5%). Providers indicated the race, insurance status, and primary language of their patient population. Screening genetic testing was offered by 98% of providers. Per provider report, 37% offered diagnostic testing to all patients, 18% did not offer it at all, and 44% only offered it if certain patient factors were present. Moreover, 54.8% of attendings reported universally offering diagnostic testing. On univariable analysis, residents were less likely to offer diagnostic testing than attendings (odds ratio, 0.18; 95% confidence interval, 0.11-0.30). Providers who serve non-Hispanic Black, Hispanic Black, and other Hispanic patients were less likely to report offering diagnostic testing than other patient populations. Providers who served non-Hispanic Whites were more likely to offer diagnostic testing (odds ratio, 2.26; 95% confidence interval, 1.51-3.39). Patient populations who were primarily privately insured were more likely to be offered diagnostic testing compared with primarily publicly insured patients (odds ratio, 6.25; 95% confidence interval, 3.60-10.85). Providers who served a primarily English-speaking population were more likely to offer diagnostic genetic testing than other patient populations (odds ratio, 0.43; 95% confidence interval, 0.26-0.69). On multivariable analysis, the factors that remained significantly associated with offering diagnostic testing included level of training (resident odds ratio, 0.33; 95% confidence interval, 0.17-0.62; P=.0006; advanced practice provider odds ratio, 0.34; 95% confidence interval, 0.15-0.82; P=.02), having at least one-third of the patient population identify as "other Hispanic" (odds ratio, 0.42; 95% confidence interval, 0.23-0.77; P=.005), and having private insurance instead of public insurance (primarily private insured odds ratio, 2.84; 95% confidence interval, 1.20-6.74; P=.02). CONCLUSION: Although offering genetic screening and diagnostic testing to all patients is recommended, no provider group universally offers diagnostic testing. Providers who serve populations from a racial and ethnic minority, those with public insurance, and those whose primary language is not English are less likely to report universally offering diagnostic genetic testing.

Perinatal depression before and during the COVID-19 pandemic in New York City.

BACKGROUND: Quarantining and isolation during previous pandemics have been associated with higher levels of depression symptomatology. Studies in other countries found elevated rates of anxiety and/or depression among pregnant people during the COVID-19 pandemic compared with prepandemic rates. New York City was the initial epicenter of the pandemic in the United States, and the effects of the pandemic on perinatal depression in this population are not well known. OBJECTIVE: This study aimed to evaluate the rates of perinatal depression before and during the COVID-19 pandemic. STUDY DESIGN: This is a single-center retrospective cohort study of patients screened for perinatal depression with the Edinburgh Postnatal Depression Scale at 2 private academic practices in New York City. This screen is done in these practices at the time of the glucose challenge test and at the postpartum visit. Patients aged ≥18 years who completed a screen at a postpartum visit and/or glucose challenge test from February 1, 2019 to July 31, 2019 and from February 1, 2020 to July 31, 2020 were identified, and the 2019 and 2020 groups were compared. The primary outcome was a positive screen, defined as ≥13 and ≥15 for postnatal and prenatal screens, respectively. Secondary outcomes included monthly changes in rates of positive screens and factors associated with perinatal depression. Data were analyzed using Mann-Whitney U test, chi-square, or Fisher exact test, and univariate and multivariate analyses with P<.05 defined as significant. RESULTS: A total of 1366 records met the inclusion criteria; 75% of the prepandemic (2019) records were included, as opposed to 65% of pandemic (2020) records due to a lower screen completion rate in the pandemic cohort. The 2020 cohort had a higher proportion of Hispanic patients (P=.003) and higher rates of diabetes mellitus (P=.007), preterm labor (P=.03), and current or former drug use (P<.001). The 2019 cohort had higher rates of hypertension (P=.002) and breastfeeding (P=.03); 4.6% of the 2020 cohort had a suspected or confirmed COVID-19 infection. There was no difference in perinatal depression between the 2019 and 2020 cohorts (2.8% vs 2.6%; P>.99). This finding persisted after adjusting for baseline differences (adjusted odds ratio, 0.89; 95% confidence interval, 0.38-1.86; P=.76). There were no differences in rates of positive Edinburgh Postnatal Depression Scale by month. Several risk factors were associated with a positive screen, including being unmarried (P<.001), pulmonary disease (P=.02), depression (P<.001), anxiety (P=.01), bipolar disorder (P=.009), and use of anxiolytics (P=.04). CONCLUSION: There were no differences in the rates of perinatal depression between the periods before and during the COVID-19 pandemic. The rate of perinatal depression in this cohort was below the reported averages in the literature. Fewer women were screened for perinatal depression in 2020, which likely underestimated the prevalence of depression in our cohort. These findings highlight potential gaps in care in a pandemic setting.

Bidirectional processes linking social determinants of health and pediatric sickle cell anemia management: A qualitative study.

BACKGROUND: Children with sickle cell anemia (SCA) have substantial medical needs and more unmet basic needs than children with other medical conditions. Despite a recent focus on social determinants of health (SDoH), there remains an incomplete understanding of the processes linking SDoH and disease management, particularly for youth with SCA. This study elucidated these processes and identified ways to mitigate deleterious effects of adverse SDoH on SCA management. METHODS: Parents/primary caregivers (N = 27) of children with SCA (≤12 years old) participated in semi-structured interviews regarding SCA management and SDoH and completed quantitative measures of basic needs. Qualitative data were systematically coded and analyzed using applied thematic analysis. Quantitative data were presented descriptively. RESULTS: Three qualitative themes were identified. First, SCA management is bidirectionally linked with the social environment, whereby challenges of SCA management can hinder basic needs from being met, and unmet basic needs and financial hardship hinder SCA management. Second, due to limited resources, parents/caregivers are faced with difficult choices between prioritizing basic needs versus SCA management. Third, addressing material, emotional, and informational needs may improve SCA management. Quantitatively, 73% of families endorsed ≥1 basic need, including food insecurity (42%), housing instability (62%), and/or energy insecurity 19% (vs. 20%). CONCLUSION: Despite documented associations, there remains a poor understanding of the processes linking SDoH and health. Findings underscore how day-to-day conditions undermine the management of SCA treatments, symptoms, and complications, limiting treatment effectiveness. Understanding these processes may inform family-centered, health equity interventions and policies to improve living conditions, disease management, and health outcomes.

Prolonging the zone 1 aortic occlusion time to 4 hours using a partial resuscitative endovascular balloon in a swine model.

BACKGROUND: The clinical usage of the resuscitative endovascular balloon occlusion of the aorta (REBOA) is limited by distal ischemia resulting from complete aortic occlusion. We hypothesized that animals would physiologically tolerate the prolonged partial occlusion using the novel partially occluding REBOA (pREBOA) with survivable downstream injuries. METHODS: This study used the pREBOA-PRO catheter in a previously established swine model. Female Yorkshire swine (n = 10) underwent a volume-controlled hemorrhage (40% estimated blood). After 1 hour of shock (mean arterial pressure, 28-32 mm Hg), animals were randomized to partial occlusion for either 2 hours or 4 hours. The pREBOA was inflated in zone 1 to achieve partial occlusion defined as a distal systolic blood pressure (SBP) of 20 ± 2 mm Hg. The balloon was deflated at the end of the occlusion period, and animals were resuscitated for 2 hours. Tissues were examined for gross and histologic injury. The primary endpoint was histologic organ injury, and secondary end points were hemodynamic variables and degree of distal organ ischemia. RESULTS: All animals survived to the endpoint. Both groups had similar proximal and distal SBP at baseline, with a divergence of pressures ranging from 55 mm Hg to 90 mm Hg on inflation. The lactate levels increased throughout the occlusion and decreased approximately 40% during the observation period. More animals required norepinephrine and fluid in the 4-hour group compared with the 2-hour group. There was no gross small bowel ischemia noted in the 2-hour animals. The 4-hour group had surgically resectable patchy short segment ischemia. Neither group showed nonsurvivable organ ischemia on pathology or laboratory values. CONCLUSION: This is the first study showing that the zone 1 aorta can be occluded for over 4 hours using a new pREBOA device without need for balloon titration. In conclusion, simple changes in balloon design offer reliable partial aortic occlusion, with potentially survivable and surgically manageable downstream injuries.

Spatially extended radiant heat fire model.

Recent wildfire prevalence and destruction have led to new initiatives in the search for better land management techniques and prescriptions for controlled burns. With limited data on low-intensity prescribed burns, finding models that can represent fire behavior is of great importance to learning how to control fires with more accuracy while also maintaining the purpose for the burn, be it reducing fuels or managing the ecosystem. Here we use a data set of infrared temperatures collected in the New Jersey Pine Barrens from 2017 through 2020 to develop a model for very fine-scale fire behavior (≈0.05 m^{2}). The model uses distributions from the data set to define five stages in fire behavior in a cellular automata framework. For each cell, the transition between each stage is probabilistically driven based on the radiant temperature values of the cell and its immediate neighbors in a coupled map lattice. With five distinct initial conditions, we performed 100 simulations and used the parameters derived from the data set to develop metrics for model verification. To validate the model, we also expanded it to include variables not in the data set that are important for fire behavior, e.g., fuel moisture levels and spotting ignitions. The model matches several metrics compared to the observational data set and exhibits behavioral characteristics expected from low-intensity wildfire behavior including a long and varied burn time for each cell after initial ignition, and lingering embers in the burn zone.

Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection.

Group A Streptococcus (GAS, Streptococcus pyogenes) is a professional human pathogen that commonly infects the skin. Keratinocytes are one of the first cells to contact GAS, and by inducing inflammation, they can initiate the earliest immune responses to pathogen invasion. Here, we characterized the proinflammatory cytokine repertoire produced by primary human keratinocytes and surrogate cell lines commonly used in vitro. Infection induces several cytokines and chemokines, but keratinocytes constitutively secrete IL-18 in a form that is inert (pro-IL-18) and lacks proinflammatory activity. Canonically, IL-18 activation and secretion are coupled through a single proteolytic event that is regulated intracellularly by the inflammasome protease caspase-1 in myeloid cells. The pool of extracellular pro-IL-18 generated by keratinocytes is poised to sense extracellular proteases. It is directly processed into a mature active form by SpeB, a secreted GAS protease that is a critical virulent factor during skin infection. This mechanism contributes to the proinflammatory response against GAS, resulting in T cell activation and the secretion of IFN-γ. Under these conditions, isolates of several other major bacterial pathogens and microbiota of the skin were found to not have significant IL-18-maturing ability. These results suggest keratinocyte-secreted IL-18 is a sentinel that sounds an early alarm that is highly sensitive to GAS, yet tolerant to non-invasive members of the microbiota.

Body mass index is negatively associated with a good perinatal outcome after in vitro fertilization among patients with polycystic ovary syndrome: a national study.

Objective: To evaluate the association between body mass index (BMI) and good perinatal outcomes after in vitro fertilization (IVF) among women with polycystic ovary syndrome (PCOS). Design: Retrospective cohort study using 2012-2015 Society for Assisted Reproductive Technology Clinic Outcomes Reporting System data. Setting: Fertility clinics. Patients: To identify patients most likely to have PCOS, we included women with a diagnosis of ovulation disorder and serum antimüllerian hormone >4.45 ng/mL. Exclusion criteria included age ≥ 41 years, secondary diagnosis of diminished ovarian reserve, preimplantation genetic testing, and missing BMI or primary outcome data. Interventions: None. Main Outcome Measures: Good perinatal outcome, defined as a singleton live birth at ≥ 37 weeks with birth weight ≥ 2,500 g and ≤ 4,000 g. Results: The analysis included 9,521 fresh, autologous IVF cycles from 8,351 women. Among women with PCOS, the proportion of cycles with a good perinatal outcome was inversely associated with BMI: underweight 25.1%, normal weight 22.7%, overweight 18.9%, class I 18.4%, class II 14.9%, and class III or super obesity 12.2%. After adjusting for confounders, women in the highest BMI category had 51% reduced odds of a good perinatal outcome compared with normal weight women (adjusted odds ratio 0.49, 95% confidence interval 0.36-0.67). Conclusions: Among women with PCOS undergoing fresh, autologous IVF, the odds of a good perinatal outcome decline with increasing BMI. Women with PCOS should be counseled that the odds of achieving a good perinatal outcome decrease as their weight increases.

Transfer of the fittest: using preimplantation genetic testing for aneuploidy to select embryo(s) most likely to lead to live birth.

Preimplantation genetic testing for aneuploidy (PGT-A) was developed to identify euploid embryos from a cohort of embryos with unknown ploidy produced during an in vitro fertilization (IVF) cycle. In recent years, the ability of PGT-A to improve IVF outcomes has come into question. The goal of this review was to summarize the major randomized controlled trials (RCTs) and nonselection studies evaluating the benefit of PGT-A to improve the live birth rates (LBRs). We argue that the LBR per transfer is more relevant to the individual patient than the cumulative LBR as a means to minimize the burden of IVF by reducing futile transfers, pregnancy losses, and ongoing aneuploidy. The early RCTs demonstrate improved implantation rates and LBRs with PGT-A for embryo selection vs. traditional morphology. However, these studies are limited by the small sample size and a bias toward good-prognosis patients. Further studies using next-generation sequencing found more variable results but did confirm an improvement in the LBRs per transfer in an older population with a higher baseline risk of aneuploidy. The largest RCT to date showed similar cumulative LBRs in the PGT-A and control groups after biopsy and sequential transfer of up to 3 blastocysts with a significant reduction in the cumulative clinical pregnancy loss rate in the PGT-A group. Nonselection studies evaluating pregnancy outcomes after transfer of euploid vs. aneuploid embryos demonstrate near-perfect negative predictive value for an aneuploid result to predict live birth. Putative mosaic embryos had similar LBRs compared with euploid embryos. The available RCTs and nonselection studies support the practice of using PGT-A to identify euploid embryos for transfer, especially in an older population, while simultaneously selecting against aneuploid embryos, without negative impact on the total reproductive potential of the cycle.

Association between donor gamete use and supernumerary embryo disposition decisions.

PURPOSE: The aim of this study is to determine if donor gamete use is associated with patients' decisions regarding disposition of supernumerary embryos. METHODS: Patients who intended to undergo an IVF cycle at a single academic center signed an embryo disposition consent form to indicate their disposition preferences for any supernumerary embryos. A retrospective chart review was performed to obtain the embryo disposition declarations and demographic information. The primary outcome was the distribution of embryo disposition choices between patients who used donor gametes compared to patients who did not use donor gametes. Fisher's exact test was used to compare groups. Logistic regression models were created to determine the association between donor gamete use and disposition decision after adjusting for patient age, body mass index, and nulliparity. RESULTS: Five hundred six patients were included. Ninety-one (18.0%) patients used donor gametes [46 (9.0%) donor oocytes, 52 (10.3%) donor sperm]. Patients using donor gametes differed from those not using donor gametes when making decisions concerning death of the patient (P < 0.01), simultaneous death (P = 0.04), separation (P < 0.01), discontinuation of ART (P = 0.01), and time-limited storage (P < 0.01). Most patients, regardless of donor or autologous gamete use, awarded embryos to themselves or their partner if given the option. For patients who did not choose this option, excess embryos were generally awarded to research or discarded rather than donating to another couple. Patients using donor gametes were more likely to award embryos to research over discarding. CONCLUSION: Patients using donor gametes made different choices regarding supernumerary embryo disposition compared to patients not using donor gametes.

Isolated Right Common Carotid Artery Arising from the Right Pulmonary Artery.

Isolated aortic arch vessels arising anomalously from the pulmonary arterial system are rare congenital anomalies. Case reports of isolated arch vessels are often associated with 22q11 deletion, CHARGE syndrome, or right aortic arch. Isolation of the carotid artery may lead to cerebral steal phenomenon and ischemia or to pulmonary overcirculation. The authors report what is, to their knowledge, the first case of isolated right common carotid artery arising from the right pulmonary artery, associated with 22q11 deletion, and describe the challenging multimodality image evaluation. Keywords: Congenital, Anatomy, Carotid Arteries © RSNA, 2022.

Applied Clinical Informatics Journal: A Brief History.

In 2009, Schattauer Verlag in Stuttgart, Germany first published the Applied Clinical Informatics (ACI) Journal. ACI has served since its inception as an official journal of the International Medical Informatics Association. Later, the American Medical Informatics Association and the European Federation for Medical Informatics named ACI as an official journal. This manuscript describes the history of the journal from its inception to present day including publication measures, challenges, and successes.

Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes.

Gasdermins (GSDMs) are a family of pore-forming effectors that permeabilize the cell membrane during the cell death program pyroptosis1. GSDMs are activated by proteolytic removal of autoinhibitory carboxy-terminal domains, typically by caspase regulators1-9. However, no activator is known for one member of this family, GSDMA. Here we show that the major human pathogen group A Streptococcus (GAS) secretes a protease virulence factor, SpeB, that induces GSDMA-dependent pyroptosis. SpeB cleavage of GSDMA releases an active amino-terminal fragment that can insert into membranes to form lytic pores. GSDMA is primarily expressed in the skin10, and keratinocytes infected with SpeB-expressing GAS die of GSDMA-dependent pyroptosis. Mice have three homologues of human GSDMA, and triple-knockout mice are more susceptible to invasive infection by a pandemic hypervirulent M1T1 clone of GAS. These results indicate that GSDMA is critical in the immune defence against invasive skin infections by GAS. Furthermore, they show that GSDMs can act independently of host regulators as direct sensors of exogenous proteases. As SpeB is essential for tissue invasion and survival within skin cells, these results suggest that GSDMA can act akin to a guard protein that directly detects concerning virulence activities of microorganisms that present a severe infectious threat.