Impact of steroids on the immune profiles of children with asthma living in the inner-city.

Background: Inner-city asthma is associated with high morbidity and systemic steroid use. Chronic steroid use impacts immune function; however, there is a lack of data with regard to the extent of immunosuppression in patients with asthma and who are receiving frequent systemic steroids. Objective: To identify the impact of frequent systemic steroid bursts on the immune function of children with asthma who live in the inner city. Methods: Children ages 3-18 years with asthma were divided into study (≥2 systemic steroid bursts/year) and control groups (0-1 systemic steroid bursts/year). Lymphocyte subsets; mitogen proliferation assay; total immunoglobulin G (IgG) value, and pneumococcal and diphtheria/tetanus IgG values were evaluated. Results: Ninety-one participants were enrolled (study group [n = 42] and control group [n = 49]). There was no difference in adequate pneumococcal IgG value, diphtheria/tetanus IgG value, mitogen proliferation assays, lymphocyte subsets, and IgG values between the two groups. Children who received ≥2 steroid bursts/year had a significantly lower median pneumococcal IgG serotype 7F value. Most of the immune laboratory results were normal except for the pneumococcal IgG value. Most of the participants (n/N = 72/91 [79%]) had an inadequate pneumococcal IgG level (<7/14 serotypes ≥1.3 µg/mL). The participants with inadequate pneumococcal IgG level and who received a pneumococcal polysaccharide vaccine 23 (PPSV23) boost had a robust response. There was no significant difference in infection, steroid exposure, asthma severity, or morbidities between those with adequate versus inadequate pneumococcal IgG values. Conclusion: Children with asthma who live in the inner city and receive ≥2 steroid bursts/year do not have a significantly different immune profile from those who receive ≤1 steroid bursts/year do not have a significantly different immune profile from those who do not. Although appropriately vaccinated, most participants had an inadequate pneumococcal IgG level, regardless of steroid exposure and asthma severity. These children may benefit from PPSV23.

Acceptability and tolerability of long-acting injectable cabotegravir or rilpivirine in the first cohort of virologically suppressed adolescents living with HIV (IMPAACT 2017/MOCHA): a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study.

BACKGROUND: Long-acting injectable cabotegravir and rilpivirine have demonstrated safety, acceptability, and efficacy in adults living with HIV-1. The IMPAACT 2017 study (MOCHA study) was the first to use these injectable formulations in adolescents (aged 12-17 years) living with HIV-1. Herein, we report acceptability and tolerability outcomes in cohort 1 of the study. METHODS: In this a secondary analysis of a phase 1/2, multicentre, open-label, non-comparative dose-finding study, with continuation of pre-study oral combination antiretroviral treatment (ART), 55 adolescents living with HIV-1 were enrolled to receive sequential doses of either long-acting cabotegravir or rilpivirine and 52 received at least two injections. Participants had a body weight greater than 35 kg and BMI less than 31·5 kg/m2 and had been on stable ART for at least 90 consecutive days with an HIV-1 viral load of less than 50 copies per mL at a participating IMPAACT study site. Participants had to be willing to continue their pre-study ART during cohort 1. The primary objectives of the study were to confirm doses for oral and injectable cabotegravir and for injectable rilpivirine in adolescents living with HIV. This analysis of participant-reported outcomes included a face scale assessment of pain at each injection and a Pediatric Quality of Life Inventory (PedsQL) at baseline and week 16 for participants in the USA, South Africa, Botswana, and Thailand. A subset of 11 adolescents and 11 parents or caregivers in the USA underwent in-depth interviews after receipt of one or two injections. This trial is registered at ClinicalTrials.gov, NCT03497676. FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled into cohort 1. Using the six-point face scale, 43 (83%) of participants at week 4 and 38 (73%) at week 8 reported that the injection caused "no hurt" or "hurts little bit", while only a single (2%) participant for each week rated the pain as one of the two highest pain levels. Quality of life was not diminished by the addition of one injectable antiretroviral. In-depth interviews revealed that parents and caregivers in the USA frequently had more hesitancy than adolescents about use of long-acting formulations, but parental acceptance was higher after their children received injections. INTERPRETATION: High acceptability and tolerability of long-acting cabotegravir or rilpivirine injections suggests that these are likely to be favoured treatment options for some adolescents living with HIV. FUNDING: National Institutes of Health and ViiV Healthcare.

Safety and pharmacokinetics of oral and long-acting injectable cabotegravir or long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017/MOCHA): a phase 1/2, multicentre, open-label, non-comparative, dose-finding study.

BACKGROUND: Combined intramuscular long-acting cabotegravir and long-acting rilpivirine constitute the first long-acting combination antiretroviral therapy (ART) regimen approved for adults with HIV. The goal of the IMPAACT 2017 study (MOCHA [More Options for Children and Adolescents]) was to assess the safety and pharmacokinetics of these drugs in adolescents. METHODS: In this phase 1/2, multicentre, open-label, non-comparative, dose-finding study, virologically suppressed adolescents (aged 12-17 years; weight ≥35 kg; BMI ≤31·5 kg/m2) with HIV-1 on daily oral ART were enrolled at 15 centres in four countries (Botswana, South Africa, Thailand, and the USA). After 4-6 weeks of oral cabotegravir (cohort 1C) or rilpivirine (cohort 1R), participants received intramuscular long-acting cabotegravir or long-acting rilpivirine every 4 weeks or 8 weeks per the adult dosing regimens, while continuing pre-study ART. The primary outcomes were assessments of safety measures, including all adverse events, until week 4 for oral cabotegravir and until week 16 for long-acting cabotegravir and long-acting rilpivirine, and pharmacokinetic measures, including the area under the plasma concentration versus time curve during the dosing interval (AUC0-tau) and drug concentrations, at week 2 for oral dosing of cabotegravir and at week 16 for intramuscular dosing of cabotegravir and rilpivirine. Enrolment into cohort 1C or cohort 1R was based on the participant's pre-study ART, meaning that masking was not done. For pharmacokinetic analyses, blood samples were drawn at weeks 2-4 after oral dosing and weeks 4-16 after intramuscular dosing. Safety outcome measures were summarised using frequencies, percentages, and exact 95% CIs; pharmacokinetic parameters were summarised using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03497676, and is closed to enrolment. FINDINGS: Between March 19, 2019, and Nov 25, 2021, 55 participants were enrolled: 30 in cohort 1C and 25 in cohort 1R. At week 16, 28 (97%, 95% CI 82-100) of the 29 dose-evaluable participants in cohort 1C and 21 (91%; 72-99) of the 23 dose-evaluable participants in cohort 1R had reported at least one adverse event, with the most common being injection-site pain (nine [31%] in cohort 1C; nine [39%] in cohort 1R; none were severe). One (4%, 95% CI 0-22) participant in cohort 1R had an adverse event of grade 3 or higher, leading to treatment discontinuation, which was defined as acute rilpivirine-related allergic reaction (self-limiting generalised urticaria) after the first oral dose. No deaths or life-threatening events occurred. In cohort 1C, the week 2 median cabotegravir AUC0-tau was 148·5 (range 37·2-433·1) µg·h/mL. The week 16 median concentrations for the every-4-weeks and every-8-weeks dosing was 3·11 µg/mL (range 1·22-6·19) and 1·15 µg/mL (<0·025-5·29) for cabotegravir and 52·9 ng/mL (31·9-148·0) and 39·1 ng/mL (27·2-81·3) for rilpivirine, respectively. These concentrations were similar to those in adults. INTERPRETATION: Study data support using long-acting cabotegravir or long-acting rilpivirine, given every 4 weeks or 8 weeks, per the adult dosing regimens, in virologically suppressed adolescents aged 12 years and older and weighing at least 35 kg. FUNDING: The National Institutes of Health and ViiV Healthcare.

Increased mortality in infants with abnormal T-cell receptor excision circles.

BACKGROUND: T-Cell Receptor Excision Circles based newborn screening (TREC-NBS) allows for early detection of T-cell lymphopenia in infants with primary immunodeficiency disorders (PIDD). The utility of abnormal TREC-NBS in infants without PIDD is not well studied. We sought to evaluate the association of abnormal TREC-NBS with mortality. METHODS: 365,207 TREC-NBS from October 2011 to December 2014 were reviewed. 467 newborns had abnormal screens and did not meet the criteria for a PIDD diagnosis. Cases were matched to controls (1:3) based on gestational age, birth weight, neonatal intensive care unit status (NICU), and race. Data were obtained through NBS, birth and death certificates records from the Michigan Department of Health and Human Services (MDHHS) databases. RESULTS: Infants with abnormal TREC-NBS had higher mortality even when PIDD was ruled-out. Transient abnormal TREC-NBS was not associated with higher mortality, but unresolved or late abnormal TREC-NBS was associated with higher mortality. Infants with late abnormal TREC-NBS had severe prematurity, lower birth weight, lower Apgar scores, and higher percentage of congenital anomalies. CONCLUSION: Infants with abnormal TREC-NBS may be at a higher risk of morbidity and mortality and should be carefully followed, especially if discharged home before a repeat screen can be completed. IMPACT: This study explores the risk factors and mortality for newborns with secondary T-cell lymphopenia captured on T-Cell Receptor Excision Circles based newborn screening (TREC-NBS). Abnormal TREC-NBS allows for prompt life-saving interventions for primary immunological conditions such as Severe Combined Immunodeficiency (SCID), but can also be associated with non-immunologic conditions. Unresolved and late abnormal TREC-NBS is associated with higher mortality even without primary immunodeficiency, likely detected in infants with more severe prematurity, lower birth weight, and congenital anomalies. TREC-NBS positive infants with secondary T-cell lymphopenia require special attention and close monitoring.

Detecting changes in the transmission rate of a stochastic epidemic model.

Throughout the course of an epidemic, the rate at which disease spreads varies with behavioral changes, the emergence of new disease variants, and the introduction of mitigation policies. Estimating such changes in transmission rates can help us better model and predict the dynamics of an epidemic, and provide insight into the efficacy of control and intervention strategies. We present a method for likelihood-based estimation of parameters in the stochastic susceptible-infected-removed model under a time-inhomogeneous transmission rate comprised of piecewise constant components. In doing so, our method simultaneously learns change points in the transmission rate via a Markov chain Monte Carlo algorithm. The method targets the exact model posterior in a difficult missing data setting given only partially observed case counts over time. We validate performance on simulated data before applying our approach to data from an Ebola outbreak in Western Africa and COVID-19 outbreak on a university campus.

Fitting a stochastic model of intensive care occupancy to noisy hospitalization time series during the COVID-19 pandemic.

Intensive care occupancy is an important indicator of health care stress that has been used to guide policy decisions during the COVID-19 pandemic. Toward reliable decision-making as a pandemic progresses, estimating the rates at which patients are admitted to and discharged from hospitals and intensive care units (ICUs) is crucial. Since individual-level hospital data are rarely available to modelers in each geographic locality of interest, it is important to develop tools for inferring these rates from publicly available daily numbers of hospital and ICU beds occupied. We develop such an estimation approach based on an immigration-death process that models fluctuations of ICU occupancy. Our flexible framework allows for immigration and death rates to depend on covariates, such as hospital bed occupancy and daily SARS-CoV-2 test positivity rate, which may drive changes in hospital ICU operations. We demonstrate via simulation studies that the proposed method performs well on noisy time series data and apply our statistical framework to hospitalization data from the University of California, Irvine (UCI) Health and Orange County, California. By introducing a likelihood-based framework where immigration and death rates can vary with covariates, we find, through rigorous model selection, that hospitalization and positivity rates are crucial covariates for modeling ICU stay dynamics and validate our per-patient ICU stay estimates using anonymized patient-level UCI hospital data.

COVID-19 and Pregnancy: Interrelationships With Asthma and Allergy.

Pregnant individuals are at higher risk of complications from respiratory viruses such as coronavirus-19 disease (COVID-19). Altered lung function, vaccine hesitancy, and resistance to taking necessary medications because of a lack of safety data in pregnancy make this population especially vulnerable to the effects of COVID-19. Like many medical conditions, the treatment of allergic conditions, including asthma and allergic rhinitis, were affected during the pandemic, with decreased numbers of in-person visits and interruptions in medical treatment. There were initially no data to allow pregnant women with asthma know whether the condition put them at higher risk of complications from COVID-19. There are now increasing data for the efficacy and safety of vaccines for COVID-19 in at-risk populations, including pregnant women. Vaccine studies show no increased risk for spontaneous abortion, congenital anomalies, or pregnancy complications. Furthermore, infants of individuals vaccinated during pregnancy have been shown to obtain protective antibodies via the placenta, providing protection against COVID-19 after birth. Although overall risks are low, pregnant women who become infected with COVID-19 are at higher risk for maternal and pregnancy complications. Antiviral treatment is available for pregnant women with mild to moderate symptoms of COVID-19, with reassuring safety data to date. Dexamethasone is the mainstay of inpatient therapy.

The prevalence, characteristics, and risk factors of external cervical resorption: a retrospective practice-based study.

OBJECTIVES: External cervical root resorption (ECR) is a poorly understood and aggressive form of resorption. The purpose of this study was to examine the prevalence, characteristics, and risk factors associated with the occurrence of ECR in patients seeking endodontic care from private practice settings. MATERIALS AND METHODS: Records of 343 patients with 390 teeth diagnosed with ECR were identified from 3 private endodontic practices from 2008 to 2022. The patients' demographic information, systemic conditions, and dental history were recorded. The characteristics of the cases including Heithersay classification, pulpal and periapical status, and their management were documented. The association between case severity and potential predisposing factors was examined using chi-square analysis. RESULTS: The overall prevalence of ECR among patients seeking endodontic care was low (< 1%). However, there was a greater than twofold increase in the pooled prevalence from 2016 to 2021 (0.99%) compared to the data from 2010 to 2015 (0.46%). The most commonly affected teeth were anterior teeth (48.7%). Class II (30.0%) and class III (45.4%) defects were the most often identified. Patients with a history of trauma or orthodontic treatment were significantly more likely to be diagnosed with severe cervical resorption (class III or IV) (p < 0.05). CONCLUSIONS: There has been an increase in the prevalence of ECR in patients seeking endodontic care. A history of orthodontic treatment and traumatic dental mechanical injuries may predict the severity of resorption. CLINICAL RELEVANCE: The upward trend in the occurrence of ECR warrants close monitoring of the patients at high risk of developing the condition to facilitate early detection and management.

Safety and immunogenicity of the live-attenuated varicella vaccine in pediatric solid organ transplant recipients: A systematic review and meta-analysis.

This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients.

Sustainable general practice.

BACKGROUND: Climate change is a health emergency, and general practitioners have an important role in both mitigation and adaptation to the effects of climate change. Climate change is already impacting health in a myriad of ways, including death and illness from increasingly frequent extreme weather events, disruptions to food systems and changes in vector-borne diseases. General practice can demonstrate leadership by embracing sustainability as part of a primary care ethos aligning it with quality care. OBJECTIVE: The aim of this article is to outline the steps required to achieve and promote sustainability from practice operations through to clinical care and advocacy. DISCUSSION: Achieving sustainability requires not just a consideration of energy use or waste, but also a fundamental re-evaluation of the purpose and practice of medicine. A planetary health perspective requires us to recognise our connectedness to and dependence on the health of nature. It demands a change to models of healthcare that are sustainable, prioritise prevention and are inclusive of the social and environmental dimensions to health.

Asthma in Pregnancy.

This JAMA Insights in the Women's Health series examines the management of asthma during pregnancy, including diagnosis, treatment, and the handling of exacerbations.

MASP2 inhibition by narsoplimab suppresses endotheliopathies characteristic of transplant-associated thrombotic microangiopathy: in vitro and ex vivo evidence.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endotheliopathy complicating up to 30% of allogeneic hematopoietic stem cell transplants (alloHSCT). Positive feedback loops among complement, pro-inflammatory, pro-apoptotic, and coagulation cascade likely assume dominant roles at different disease stages. We hypothesized that mannose-binding lectin-associated serine protease 2 (MASP2), principal activator of the lectin complement system, is involved in the microvascular endothelial cell (MVEC) injury characteristic of TA-TMA through pathways that are susceptible to suppression by anti-MASP2 monoclonal antibody narsoplimab. Pre-treatment plasmas from 8 of 9 TA-TMA patients achieving a complete TMA response in a narsoplimab clinical trial activated caspase 8, the initial step in apoptotic injury, in human MVEC. This was reduced to control levels following narsoplimab treatment in 7 of the 8 subjects. Plasmas from 8 individuals in an observational TA-TMA study, but not 8 alloHSCT subjects without TMA, similarly activated caspase 8, which was blocked in vitro by narsoplimab. mRNA sequencing of MVEC exposed to TA-TMA or control plasmas with and without narsoplimab suggested potential mechanisms of action. The top 40 narsoplimab-affected transcripts included upregulation of SerpinB2, which blocks apoptosis by inactivating procaspase 3; CHAC1, which inhibits apoptosis in association with mitigation of oxidative stress responses; and pro-angiogenesis proteins TM4SF18, ASPM, and ESM1. Narsoplimab also suppressed transcripts encoding pro-apoptotic and pro-inflammatory proteins ZNF521, IL1R1, Fibulin-5, aggrecan, SLC14A1, and LOX1, and TMEM204, which disrupts vascular integrity. Our data suggest benefits to narsoplimab use in high-risk TA-TMA and provide a potential mechanistic basis for the clinical efficacy of narsoplimab in this disorder.

Positive Newborn Screening for Severe Combined Immunodeficiency: What Should the Pediatrician Do?

Severe combined immunodeficiency (SCID) is a group of diseases characterized by low T-cell count and impaired T-cell function, resulting in severe cellular and humoral immune defects. If not diagnosed and treated promptly, infants affected by this condition can develop severe infections which will result in death. Delayed treatment can markedly reduce the survival outcome of infants with SCID. T-cell receptor excision circle (TREC) levels are measured on newborn screening to promptly identify infants with SCID. It is important for primary care providers and pediatricians to understand the approach to managing infants with positive TREC-based newborn screening as they may be the first contact for infants with SCID. Primary care providers should be familiar with providing anticipatory guidance to the family in regard to protective isolation, measures to minimize the risk of infection, and the coordination of care with the SCID coordinating center team of specialists. In this article, we use case-based scenarios to review the principles of TREC-based newborn screening, the genetics and subtypes of SCID, and management for an infant with a positive TREC-based newborn screen.

Defibrotide mitigates endothelial cell injury induced by plasmas from patients with COVID-19 and related vasculopathies.

BACKGROUND AND OBJECTIVES: COVID-19 progression is characterized by systemic small vessel arterial and venous thrombosis. Microvascular endothelial cell (MVEC) activation and injury, platelet activation, and histopathologic features characteristic of acute COVID-19 also describe certain thrombotic microangiopathies, including atypical hemolytic-uremic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and hematopoietic stem cell transplant (HSCT)-associated veno-occlusive disease (VOD). We explored the effect of clinically relevant doses of defibrotide, approved for HSCT-associated VOD, on MVEC activation/injury. METHODS: Human dermal MVEC were exposed to plasmas from patients with acute TMAs or acute COVID-19 in the presence and absence of defibrotide (5µg/ml) and caspase 8, a marker of EC activation and apoptosis, was assessed. RNAseq was used to explore potential mechanisms of defibrotide activity. RESULTS: Defibrotide suppressed TMA plasma-induced caspase 8 activation in MVEC (mean 60.2 % inhibition for COVID-19; p = 0.0008). RNAseq identified six major cellular pathways associated with defibrotide's alteration of COVID-19-associated MVEC changes: TNF-α signaling; IL-17 signaling; extracellular matrix (ECM)-EC receptor and platelet receptor interactions; ECM formation; endothelin activity; and fibrosis. Communications across these pathways were revealed by STRING analyses. Forty transcripts showing the greatest changes induced by defibrotide in COVID-19 plasma/MVEC cultures included: claudin 14 and F11R (JAM), important in maintaining EC tight junctions; SOCS3 and TNFRSF18, involved in suppression of inflammation; RAMP3 and transgelin, which promote angiogenesis; and RGS5, which regulates caspase activation and apoptosis. CONCLUSION: Our data, in the context of a recent clinical trial in severe COVID-19, suggest benefits to further exploration of defibrotide and these pathways in COVID-19 and related endotheliopathies.

The Aetion Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation Initiative: Oncology.

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real-world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and regulatory decision making. In the oncology setting, studies leveraging RWD offer distinct advantages that are complementary to randomized controlled trials (RCTs). They also permit the conduct of investigations that may not be possible through prospective designs due to ethics or feasibility. Despite its promise, the use of RWD for the generation of clinical evidence remains controversial due to concerns of unmeasured confounding and other sources of bias that must be carefully addressed in the study design and analysis. To facilitate a better understanding of when RWD can provide reliable conclusions on drug effectiveness, we seek to conduct 10 RWD-based studies that emulate RCTs in oncology using a systematic, protocol-driven approach described herein. Results of this investigation will help inform clinical, scientific, and regulatory stakeholders on the applications of RWD in the context of product labeling expansion, drug safety, and comparative effectiveness in oncology.

Selective sweeps in SARS-CoV-2 variant competition.

The main mathematical result in this paper is that change of variables in the ordinary differential equation (ODE) for the competition of two infections in a Susceptible-Infected-Removed (SIR) model shows that the fraction of cases due to the new variant satisfies the logistic differential equation, which models selective sweeps. Fitting the logistic to data from the Global Initiative on Sharing All Influenza Data (GISAID) shows that this correctly predicts the rapid turnover from one dominant variant to another. In addition, our fitting gives sensible estimates of the increase in infectivity. These arguments are applicable to any epidemic modeled by SIR equations.