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Population health initiatives often rely on cold outreach to close gaps in preventive care, such as overdue screenings or immunizations. Tailoring messages to diverse patient populations remains challenging, as traditional A/B testing requires large sample sizes to test only two alternative messages. With increasing availability of large language models (LLMs), programs can utilize tiered testing among both LLM and manual human agents, presenting the dilemma of identifying which patients need different levels of human support to cost-effectively engage large populations. Using microsimulations, we compared both the statistical power and false positive rates of A/B testing and Sequential Multiple Assignment Randomized Trials (SMART) for developing personalized communications across multiple effect sizes and sample sizes. SMART showed better cost-effectiveness and net benefit across all scenarios, but superior power for detecting heterogeneous treatment effects (HTEs) only in later randomization stages, when populations were more homogeneous and subtle differences drove engagement differences., Competing Interests: Competing interests S.B. and S.Y.P. receive stock options and salaries from Waymark, which engages in patient outreach. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Objectives: To compare rates and analyze health facility determinants of emergency department visits and hospitalizations for ambulatory care-sensitive conditions (ACSCs) among Medicaid patients by geographical location., Study Design: Retrospective cross-sectional analysis of 48.3 million patients receiving Medicaid and their acute care visits across 34 states and the District of Columbia in 2019., Methods: Descriptive analyses of county-level variations in emergency department visits and hospitalizations (acute care) for ACSCs, and multivariate regressions of proximity to and density of health facility infrastructure as correlates to utilization and spending. Regression models were adjusted for county-level poverty rates, chronic disease rates, and state fixed effects., Results: Among the studied patient population receiving Medicaid, nearly 40% of acute care visits were for ACSCs, with variations across and within states. Rates ranged from 17.8 per 1000 member-months in Vermont to 39.0 in Mississippi, and from 5.9 to 77.9 between counties within states. Longer distances to the nearest urgent care center and primary care shortage area designation correlated to higher acute care visits for ACSCs (+4.3 per 1000 member-months for every 100 miles; 95% CI, 2.9-5.7; P < .001; +1.5 per 1000 member-months if shortage area; 95% CI, 0.4-2.6; P = .006). Counties with more rural health clinics had fewer acute care visits for ACSCs (-3.4 fewer visits per rural clinic per 1000 population; 95% CI, -4.6 to -2.2; P < .001). Among 6 states with additional spending data, 4.2% of total Medicaid spending was attributable to acute care visits for ACSCs., Conclusions: Our evaluation revealed more than 13-fold variation in acute care utilization for ACSCs between Medicaid counties within the same state. Proximity to urgent care facilities and density of rural health clinics were major explanatory variables for these variations, underscoring the importance of local health infrastructure in reducing acute care utilization for ACSCs.

Background: Common Variable Immunodeficiency Disorders (CVID) encompass a spectrum of immunodeficiency characterised by recurrent infections and diverse non-infectious complications (NICs). This study aimed to describe the clinical features and variation in NICs in CVID with and without interstitial lung disease (ILD) from a large UK national registry population., Methods: Retrospective, cross-sectional data from a UK multicentre database (previously known as UKPIN), categorising patients into those with CVID-ILD and those with NICs related to CVID but without pulmonary involvement (CVID-EP; EP= extra-pulmonary involvement only)., Results: 129 patients were included. Chronic lung diseases, especially CVID-ILD, are prominent complications in complex CVID, occurring in 62% of the cohort. Bronchiectasis was common (64% of the cohort) and associated with greater pulmonary function impairment in patients with CVID-ILD compared to those without bronchiectasis. Lymphadenopathy and the absence of gastrointestinal diseases were significant predictors of ILD in complex CVID. Although the presence of liver disease did not differ significantly between the groups, nearly half of the CVID-ILD patients were found to have liver disease. Patients with CVID-ILD were more likely to receive immunosuppressive treatments such as rituximab and mycophenolate mofetil than the CVID-EP group, indicating greater need for treatment and risk of complications., Conclusion: This study highlights the significant burden of CVID-ILD within the CVID population with NICs only. The lungs emerged as the most frequently affected organ, with ILD and bronchiectasis both highly prevalent. These findings emphasise the necessity of a comprehensive and multidisciplinary approach in managing CVID patients, considering their susceptibility to various comorbidities and complications., Competing Interests: LM received speaker fees and travel grants from Takeda, BioCryst and CSL. MA received honoraria from Takeda and Biocryst for educational activities in the past. No direct conflicts with this work. TG received consulting, advisory work and educational support from BioCryst, CSL Behring, KalVista, Novartis, Octapharma, Pharming, Pharvaris and Takeda. AH received support for attending meetings from Biocryst, Pharming and Takeda. NH has received honoraria from Dr Falk and Advanz Pharma for educational activities and has consultancy agreements with Mirum Pharma and Signant Health, none of which relate to this work. SB received grant support from CSL Behring and personal fees or travel expenses from Grifols, Pharming, GSK, CSL Behring, Baxalta US Inc and Biotest. CS: Received honoraria and educational support from BioCryst, CSL Behring, Pharming and Takeda. JH received grant support, and payment for educational and advisory work to his institution from pharmaceutical companies that make medicines to treat respiratory disease and immunodeficiency. Personal payment for educational and advisory work, and support to attend meetings from the same. SGo received Takeda sponsored meetings in the last 12 months and was paid to co-lead a workshop relating to immunodeficiency. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bintalib, Grigoriadou, Patel, Mutlu, Sooriyakumar, Vaitla, McDermott, Drewe, Steele, Ahuja, Garcez, Gompels, Grammatikos, Herwadkar, Ayub, Halliday, Burns, Hurst and Goddard.)

States have turned to novel Medicaid financing to pay for community health worker (CHW) programs, often through fee-for-service or capitated payments. We sought to estimate Medicaid payment rates to ensure CHW program sustainability. A microsimulation model was constructed to estimate CHW salaries, equipment, transportation, space, and benefits costs across the U.S. Fee-for-service rates per 30-min CHW visit (code 98960) and capitated rates were calculated for financial sustainability. The mean CHW hourly wage was $23.51, varying from $15.90 in Puerto Rico to $31.61 in Rhode Island. Overhead per work hour averaged $43.65 nationwide, and was highest for transportation among other overhead categories (65.1% of overhead). The minimum fee-for-service rate for a 30-min visit was $53.24 (95% CI $24.80, $91.11), varying from $40.44 in South Dakota to $70.89 in Washington D.C. The minimum capitated rate was $140.18 per member per month (95% CI $105.94, $260.90), varying from $113.55 in South Dakota to $176.58 in Washington D.C. Rates varied minimally by metro status but more by panel size. Higher Medicaid fee-for-service and capitated rates than currently used may be needed to support financial viability of CHW programs. A revised payment estimation approach may help state officials, health systems and plans discussing CHW program sustainability., (© 2024. The Author(s).)

Hereditary angioedema is a potentially life-threatening autosomal dominant condition, causing attacks of angioedema due to failure to regulate bradykinin. Nearly all cases of hereditary angioedema are caused by mutations in the gene encoding C1 inhibitor, SERPING1 . C1 inhibitor is a multifunctional protein produced in the liver that regulates the kallikrein-kinin system at multiple points. An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema., (Copyright © 2024 Massachusetts Medical Society.)

Abstract: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients receiving Medicaid often experience social risk factors for poor health and limited access to primary care, leading to high utilization of emergency departments and hospitals (acute care) for non-emergent conditions. As programs proactively outreach Medicaid patients to offer primary care, they rely on risk models historically limited by poor-quality data. Following initiatives to improve data quality and collect data on social risk, we tested alternative widely-debated strategies to improve Medicaid risk models. Among a sample of 10 million patients receiving Medicaid from 26 states and Washington DC, the best-performing model tripled the probability of prospectively identifying at-risk patients versus a standard model (sensitivity 11.3% [95% CI 10.5, 12.1%] vs 3.4% [95% CI 3.0, 4.0%]), without increasing "false positives" that reduce efficiency of outreach (specificity 99.8% [95% CI 99.6, 99.9%] vs 99.5% [95% CI 99.4, 99.7%]), and with a ~ tenfold improved coefficient of determination when predicting costs (R 2 : 0.195-0.412 among population subgroups vs 0.022-0.050). Our best-performing model also reversed the lower sensitivity of risk prediction for Black versus White patients, a bias present in the standard cost-based model. Our results demonstrate a modeling approach to substantially improve risk prediction performance and equity for patients receiving Medicaid., (© 2024. The Author(s).)

Bruton's tyrosine kinase (BTK) is a non-receptor bound kinase involved in pro-inflammatory signalling in activated macrophages, however, its role within adipose tissue macrophages remains unclear. We have demonstrated that BTK signalling regulates macrophage M2-like polarisation state by up-regulating subunits of mitochondrially encoded electron transport chain Complex I (ND4 and NDL4) and Complex IV (mt-CO1, mt-CO2 and mt-CO3) resulting in an enhanced rate of oxidative phosphorylation (OxPhos) in an NF-κB independent manner. Critically, BTK expression is elevated in adipose tissue macrophages from obese individuals with diabetes, while key mitochondrial genes (mtC01, mtC02 and mtC03) are decreased in inflammatory myeloid cells from obese individuals. Inhibition of BTK signalling either globally (Xid mice) or in myeloid cells (LysMCreBTK), or therapeutically (Acalabrutinib) protects HFD-fed mice from developing glycaemic dysregulation by improving signalling through the IRS1/Akt/GSK3β pathway. The beneficial effects of acalabrutinib treatment are lost in macrophage ablated mice. Inhibition of BTK signalling in myeloid cells but not B-cells, induced a phenotypic switch in adipose tissue macrophages from a pro-inflammatory M1-state to a pro-resolution M2-like phenotype, by shifting macrophage metabolism towards OxPhos. This reduces both local and systemic inflammation and protected mice from the immunometabolic consequences of obesity. Therefore, in BTK we have identified a macrophage specific, druggable target that can regulate adipose tissue polarisation and cellular metabolism that can confer systematic benefit in metabolic syndrome., (© 2024 by the American Diabetes Association.)

Background: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome., Methods: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants., Results: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving., Conclusions: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing., (© 2023. Crown.)

Objective: To examine the proportion of healthcare visits are delivered by nurse practitioners and physician assistants versus physicians and how this has changed over time and by clinical setting, diagnosis, and patient demographics., Design: Cross-sectional time series study., Setting: National data from the traditional Medicare insurance program in the USA., Participants: Of people using Medicare (ie, those older than 65 years, permanently disabled, and people with end stage renal disease), a 20% random sample was taken., Main Outcome Measures: The proportion of physician, nurse practitioner, and physician assistant visits in the outpatient and skilled nursing facility settings delivered by physicians, nurse practitioners, and physician assistants, and how this proportion varies by type of visit and diagnosis., Results: From 1 January 2013 to 31 December 2019, 276 million visits were included in the sample. The proportion of all visits delivered by nurse practitioners and physician assistants in a year increased from 14.0% (95% confidence interval 14.0% to 14.0%) to 25.6% (25.6% to 25.6%). In 2019, the proportion of visits delivered by a nurse practitioner or physician assistant varied across conditions, ranging from 13.2% for eye disorders and 20.4% for hypertension to 36.7% for anxiety disorders and 41.5% for respiratory infections. Among all patients with at least one visit in 2019, 41.9% had one or more nurse practitioner or physician assistant visits. Compared with patients who had no visits from a nurse practitioner or physician assistant, the likelihood of receiving any care was greatest among patients who were lower income (2.9% greater), rural residents (19.7%), and disabled (5.6%)., Conclusion: The proportion of visits delivered by nurse practitioners and physician assistants in the USA is increasing rapidly and now accounts for a quarter of all healthcare visits., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking., Objectives: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results., Methods: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed., Results: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts., Conclusions: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease., (Copyright © 2023. Published by Elsevier Inc.)

The urologic oncology patient who refuses blood transfusion can present unique challenges in perioperative blood management. Since blood loss and associated transfusion can be expected in many complex urologic oncology surgeries, a multidisciplinary approach may be required for optimal outcomes. Through collaboration with the hematologist, anesthesiologist, and urologist, various techniques can be employed in the perioperative phases to minimize blood loss and the need for transfusion. We review the risks and benefits of these techniques and offer recommendations specific to the urologic oncology patient., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Preoperative nutritional status is an important and modifiable risk factor of a patient's recovery and outcome after radical cystectomy. There are multiple malnutrition screening tools and treatment options. In this review, we discuss the best indicators of this condition and how to optimize nutrition status prior to radical cystectomy.

Objective: Individuals with substance use disorder (SUD) smoke cigarettes at a rate that is more than double the rate of the general population. Tobacco dependence treatment (TDT) is effective at reducing smoking, yet it is unclear whether expanding insurance coverage of these services increases TDT use among Medicaid beneficiaries with SUD., Data Source: 2009-2013 Medicaid data in all 50 states and Washington DC., Study Design: We conducted a retrospective analysis of the 2009-2013 de-identified Medicaid Analytic Extract (MAX) claims for a 100% national sample of fee-for-service (FFS) Medicaid adult beneficiaries. Using a difference-in-difference-in-differences analysis, we assessed the association of full TDT coverage on TDT medication use and tobacco cessation counseling services between beneficiaries with and without SUD. We adjusted for age, sex, race/ethnicity, diagnosis of co-occurring chronic illness, state tobacco taxes, and state and year fixed effects., Data Collection/extraction Methods: We excluded patients not continuously enrolled in Medicaid for 12 months during the calendar year, adults aged 65 and older (given their dual enrollment in Medicaid and Medicare), minors aged 12-17, and pregnant women (for whom different TDT coverage policies apply)., Principal Findings: We separately modeled the association between full coverage of (1) counseling, (2) over-the-counter nicotine replacement therapy, and (3) prescription cessation medications on TDT medication treatment and counseling services. We found that each coverage led to increases in any TDT medication treatment and counseling services for beneficiaries with SUD. The effects of each coverage on medication treatment were greater for beneficiaries with SUD compared to beneficiaries without SUD (ranging from 4.9 to 6.1 percentage point difference)., Conclusion: Coverage of tobacco cessation counseling, over-the-counter nicotine replacement therapy, and prescription cessation medications holds promise for reducing the wide disparities in rates of smoking between those with and without SUD., (© 2022 Health Research and Educational Trust.)

Background: Individuals with primary and secondary immunodeficiency (PID/SID) were shown to be at risk of poor outcomes during the early stages of the SARS-CoV-2 pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients., Objectives: To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed following the deployment of vaccination and therapeutics in the context of the emergence of novel viral variants of concern., Methods: The outcomes of two cohorts of patients with PID and SID were compared: the first, infected between March and July 2020, prior to vaccination and treatments, the second after these intervention became available between January 2021 and April 2022., Results: 22.7% of immunodeficient patients have been infected at least once with SARS-CoV-2 since the start of the pandemic, compared to over 70% of the general population. Immunodeficient patients were typically infected later in the pandemic when the B.1.1.529 (Omicron) variant was dominant. This delay was associated with receipt of more vaccine doses and higher pre-infection seroprevalence. Compared to March-July 2020, hospitalization rates (53.3% vs 17.9%, p<0.0001) and mortality (Infection fatality rate 20.0% vs 3.4%, p=0.0003) have significantly reduced for patients with PID but remain elevated compared to the general population. The presence of a serological response to vaccination was associated with a reduced duration of viral detection by PCR in the nasopharynx. Early outpatient treatment with antivirals or monoclonal antibodies reduced hospitalization during the Omicron wave., Conclusions: Most individuals with immunodeficiency in the United Kingdom remain SARS-CoV-2 infection naïve. Vaccination, widespread availability of outpatient treatments and, possibly, the emergence of the B.1.1.529 variant have led to significant improvements in morbidity and mortality followings SARS-CoV-2 infection since the start of the pandemic. However, individuals with PID and SID remain at significantly increased risk of poor outcomes compared to the general population; mitigation, vaccination and treatment strategies must be optimized to minimize the ongoing burden of the pandemic in these vulnerable cohorts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shields, Tadros, Al-Hakim, Nell, Lin, Chan, Goddard, Dempster, Dziadzio, Patel, Elkalifa, Huissoon, Duncan, Herwadkar, Khan, Bethune, Elcombe, Thaventhiran, Klenerman, Lowe, Savic, Burns and Richter.)

Recently, the World Health Organization (WHO) approved RTS, S/AS01 (RTS, S) as the world's first malaria vaccine for partial malaria protection in young children at risk. While this immunization drive begins during the unprecedented pandemic of the SARS-CoV-2 Virus, the WHO has also approved 7 Vaccines in 2021 for the vaccination of children at risk. This article explores the quandary that would occur to the officials in charge of carrying out large vaccination campaigns against these two deadly infectious illnesses in several regions including the continent of Africa. The article also outlines the priorities for resolving this dilemma, offers evidence-based solutions, and provides a summary of recent significant events and their consequences. While providing the latest data, a discussion on the causation of the dilemma with clear recommendations for possible solutions has been explored as well., Competing Interests: NA., (© 2022 The Authors.)

Background: Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood., Objectives: COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination., Methods: Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs., Results: A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine., Conclusion: SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection., (© 2022. The Author(s).)

Background: Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity., Objectives: To determine the immunogenicity of the third primary SARS-CoV-2 immunisation in a heterogeneous cohort of patients with antibody deficiency., Methods: Participants enrolled in the COV-AD study were sampled before and after their third vaccine dose. Serological and cellular responses were determined using ELISA, live-virus neutralisation and ELISPOT assays., Results: Following a two-dose schedule, 100% of healthy controls mounted a serological response to SARS-CoV-2 vaccination, however, 38.6% of individuals with antibody deficiency remained seronegative. A third primary SARS-CoV-2 vaccine significantly increased anti-spike glycoprotein antibody seroprevalence from 61.4% to 76.0%, the magnitude of the antibody response, its neutralising capacity and induced seroconversion in individuals who were seronegative after two vaccine doses. Vaccine-induced serological responses were broadly cross-reactive against the SARS-CoV-2 B.1.1.529 variant of concern, however, seroprevalence and antibody levels remained significantly lower than healthy controls. No differences in serological responses were observed between individuals who received AstraZeneca ChAdOx1 nCoV-19 and Pfizer BioNTech 162b2 during their initial two-dose vaccine schedule. SARS-CoV-2 infection-naive participants who had received a heterologous vaccine as a third dose were significantly more likely to have a detectable T cell response following their third vaccine dose (61.5% vs 11.1%)., Conclusion: These data support the widespread use of third primary immunisations to enhance humoral immunity against SARS-CoV-2 in individuals with antibody deficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shields, Faustini, Hill, Al-Taei, Tanner, Ashford, Workman, Moreira, Verma, Wagg, Heritage, Campton, Stamataki, Drayson, Klenerman, Thaventhiran, Elkhalifa, Goddard, Johnston, Huissoon, Bethune, Elcombe, Lowe, Patel, Savic, Richter, Burns and the COV-AD consortium.)

Nurse practitioners (NPs) and physician assistants (PAs) represent a growing share of the health care workforce, but much of the care they provide cannot be observed in claims data because of indirect (or "incident to") billing, a practice in which visits provided by an NP or PA are billed by a supervising physician. If NPs and PAs bill directly for a visit, Medicare and many private payers pay 85 percent of what is paid to a physician for the same service. Some policy makers have proposed eliminating indirect billing, but the possible impact of such a change is unknown. Using a novel approach that relies on prescriptions to identify indirectly billed visits, we estimated that the number of all NP or PA visits in fee-for-service Medicare data billed indirectly was 10.9 million in 2010 and 30.6 million in 2018. Indirect billing was more common in states with laws restricting NPs' scope of practice. Eliminating indirect billing would have saved Medicare roughly $194 million in 2018, with the greatest decrease in revenue seen among smaller primary care practices, which are more likely to use this form of billing.

Objective: Because of limited access to psychiatrists, patients with acute mental illness in some emergency departments (EDs) may wait days for a consultation in the ED or as a medical-surgical admission. The study assessed whether telepsychiatry improves access to care and decreases ED wait times and hospital admissions., Methods: ED visits with a primary diagnosis of mental illness were identified from 2010-2018 Medicare claims. A total of 134 EDs across 22 states that implemented telepsychiatry between 2013 and 2016 were matched 1:1 with control EDs without telepsychiatry on several characteristics, including availability of in-person psychiatrist consultations. Outcomes included patients' likelihood of admission to a medical-surgical or psychiatric bed, mental illness spending, prolonged ED length of stay (LOS) (two or more midnights in the ED), 90-day mortality, and outpatient follow-up care. Using a difference-in-difference design, changes in outcomes between the 3 years before telepsychiatry adoption and the 2 years after were examined., Results: There were 172,708 ED mental illness visits across the 134 matched ED pairs in the study period. Telepsychiatry adoption was associated with increased admissions to a psychiatric bed (differential increase, 4.3 percentage points; p<0.001), decreased admissions to a medical-surgical bed (differential decrease, 2.0 percentage points; p<0.001), increased likelihood of a prolonged ED LOS (differential increase, 3.0 percentage points; p<0.001), and increased mental illness spending (differential increase, $292; p<0.01)., Conclusions: Telepsychiatry adoption was associated with a lower likelihood of admission to a medical-surgical bed but an increased likelihood of admission to a psychiatric bed and a prolonged ED LOS.

Background: Preoperative malnourishment has been consistently associated with poor outcomes after radical cystectomy and other major abdominal surgeries. Most enhanced recovery after surgery (ERAS) studies have examined preoperative nutrition and its relationship to outcomes after gastrointestinal surgery. Although numerous studies have demonstrated the benefits of using an ERAS protocol, this study in unique in comparing 2 ERAS protocols, with and without a nutrition component., Methods: A formalized preoperative nutrition protocol (PNP) recommending use of preoperative immunonutrition and carbohydrate drink was introduced in June 2018. A total of 78 consecutive patients who drank both beverages were compared with 92 historical controls. Multivariable logistic regression analyses were sequentially performed to determine if preoperative nutrition was associated with binary outcome variables (30-day complication, infectious complication, and readmission within 30 days)., Results: The preoperative nutrition group and control group were statistically similar in distribution of age, sex, American Society of Anesthesiologists physical status classification, clinical stage, and body mass index. Return of bowel function was found to occur earlier in the preoperative nutrition group than in the control group (3.12 vs 3.74 days; relative risk, 0.82; CI, 0.73-0.93; P = .0029). Complications within 30 days were similar in both groups (63.6% vs 55.4%; P = 0.36). Infectious complications (42.9% vs 37%; P = .53) and readmission within 30 days (22.1% vs 15.2%; P = .34) were also similar in both groups., Conclusions: Use of a PNP including immunonutrition and carbohydrate drink may be associated with earlier return of bowel function after radical cystectomy., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Genetic variants in PIK3CD, PIK3R1 and NFKB1 cause the primary immune deficiencies, activated PI3Kδ syndrome (APDS) 1, APDS2 and NFκB1 haploinsufficiency, respectively. We have identified a family with known or potentially pathogenic variants NFKB1, TNFRSF13B and PIK3R1. The study's aim was to describe their associated immune and cellular phenotypes and compare with individuals with monogenic disease. NFκB1 pathway function was measured by immunoblotting and PI3Kδ pathway activity by phospho-flow cytometry. p105/p50 expression was absent in two individuals but elevated pS6 only in the index case. Transfection of primary T cells demonstrated increased basal pS6 signalling due to mutant PIK3R1, but not mutant NFKB1 or their wildtype forms. We report on the presence of pathogenic variant NFKB1, with likely modifying variants in TNFRSF13B and PIK3R1 in a family. We describe immune features of both NFκB1 haploinsufficiency and APDS2, and the inhibition of excessive PI3K signalling by rapamycin in vitro., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Months after the declaration of the coronavirus disease of 2019 (COVID-19) national emergency, visits among children remained suppressed for unclear reasons, which we sought to understand by examining child visit rates., Methods: Using de-identified claims data for children <18 years old from OptumLabs® Data Warehouse, a large commercial claims database, we compared monthly primary care visit and vaccination rates from January-October 2020 to January-October 2018 and 2019. Visit rates were analyzed by visit reason and by the month after (eg, month +1) the COVID-19 public health emergency declaration using a series of child-level Poisson regression models., Results: There were 3.4, 3.4, and 3.1 million children in 2018, 2019, and 2020 cohorts, respectively. Compared to the same months in prior years, primary care visits in 2020 were 60% lower in month +1 (incidence rate ratio [IRR] 0.40, 99% confidence interval [CI] 0.40-0.40) and 17% lower in month +7 (IRR 0.83, 99% CI 0.83-0.83). Preventive visit rates were 53% lower in month +1 (IRR 0.47, 99% CI 0.47-0.47), but 8% higher than prior years in month +7 (IRR 1.08, 99% CI 1.08-1.08). Monthly rates of vaccine administration followed a similar pattern. Problem-focused visits remained 31% lower in month +7 (IRR 0.69, 99% CI 0.68-0.69), with notably fewer infection-related visits (acute respiratory tract infections IRR 0.37, 99% CI 0.36-0.37; gastroenteritis IRR 0.20, 99% CI 0.20-0.20)., Conclusion: Seven months after the COVID-19 emergency declaration, receipt of pediatric care remained suppressed due to fewer problem-focused visits, with notably fewer infection-related visits. By October 2020, rates of preventive visits and vaccination exceeded rates in prior years., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: See Disclosures at the end of the article.

Purpose: Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients., Methods: Germline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls., Results: Targeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis., Conclusion: These data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity., (© 2021. The Author(s).)

Anemia occurs in a significant group of patients with bladder cancer before radical cystectomy. Iron deficiency is a readily identifiable cause of anemia, which can be treated before surgery. The proportion of patients with bladder cancer with iron deficiency anemia is unknown. Laboratory and clinical outcomes were collected on 47 consecutive patients presenting for radical cystectomy. Iron studies found 30% of patients had iron deficiency anemia. These findings present an opportunity to treat anemia before surgery, to reduce blood transfusions during radical cystectomy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Background: Epidural anesthesia has been associated with a decrease in cardiopulmonary complications and a decrease in blood loss in orthopedic procedures. Its influence on the outcomes of patients receiving radical cystectomies is unknown. We aim to use the large national database from the National Surgical Quality Improvement Project (NSQIP) to examine whether postoperative complications may be affected by the use of epidural anesthesia during radical cystectomy., Methods: Data were collected from the 2014-2016 participant user files of the NSQIP database. Patients receiving radical cystectomy were identified by CPT code and further stratified by anesthesia type. Demographics, length of stay, and 30-day complications including death were collected and analyzed using univariable and multivariable analysis., Results: A total of 6448 patients met the inclusion criteria for analysis. Between 2014 and 2016, 5064 patients received general anesthesia only (GA) and 1384 patients received general and epidural anesthesia (GEA). Statistical analysis showed an overall increase in major complications (17.8% vs 18.5%) in the GEA group (p = 0.0046). Subgroup analysis showed major complications to be more likely in patients older than 75 years receiving GEA instead of GA (p = 0.0301)., Conclusions: Elderly patients (age > 75) undergoing radical cystectomy may experience more major complications with the use of epidural anesthesia. This may be due to end-organ effects from the hemodynamic changes of epidural anesthesia which are poorly tolerated in the elderly population. Further single intervention epidural studies need to be performed to isolate the effects of epidural anesthesia on individual surgical procedures.

Coronavirus disease 2019 (COVID-19) spurred a rapid rise in telemedicine, but it is unclear how use has varied by clinical and patient factors during the pandemic. We examined the variation in total outpatient visits and telemedicine use across patient demographics, specialties, and conditions in a database of 16.7 million commercially insured and Medicare Advantage enrollees from January to June 2020. During the pandemic, 30.1 percent of all visits were provided via telemedicine, and the weekly number of visits increased twenty-three-fold compared with the prepandemic period. Telemedicine use was lower in communities with higher rates of poverty (31.9 percent versus 27.9 percent for the lowest and highest quartiles of poverty rate, respectively). Across specialties, the use of any telemedicine during the pandemic ranged from 68 percent of endocrinologists to 9 percent of ophthalmologists. Across common conditions, the percentage of visits provided during the pandemic via telemedicine ranged from 53 percent for depression to 3 percent for glaucoma. Higher rates of telemedicine use for common conditions were associated with smaller decreases in total weekly visits during the pandemic.

Background: High-frequency ultrasound (HFUS) is a mobile, radiation-free imaging tool for the diagnosis of musculoskeletal disorders. We aim to demonstrate the diagnostic value of dynamic HFUS for undiagnosed lower chest, upper abdomen, and loin pain with this case series., Case Series: A cricketer presented with long-standing left-sided dull ache lower chest and upper abdominal pain, aggravated on exertion and leaning forward. His previous laboratory and previous imaging tests were unrevealing. Dynamic HFUS of his left ribs during hooking maneuver demonstrated slipping of the eighth rib over the seventh rib associated with clicking. He also reported tenderness over this region. He was diagnosed with slipping rib syndrome (SRS), and was treated with the eighth nerve block under the HFUS guidance. The second and third cases presented with chronic undiagnosed waxing and waning loin pain despite extensive laboratory and radiological workup. Both patients demonstrated twelfth rib HFUS probe tenderness in a sitting position with a specific movement that reproduced the pain during the dynamic HFUS study. The diagnosis of twelfth rib syndrome (TRS) was confirmed and treated successfully with a local intercostal nerve block., Review of the Literature: HFUS is the most underutilized imaging tool for the diagnosis of unexplained upper abdominal and lower chest pain syndromes. We identified only a few such reported cases managed with the help of HFUS., Conclusion: The dynamic HFUS is a valuable imaging modality for the undiagnosed lower chest, upper abdominal, or loin pain., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Interstitial lung disease (ILD) is an important non-infectious complication in several primary immune deficiencies. In common variable immune deficiency (CVID) it is associated with complex clinical phenotypes and adverse outcomes. The histology of ILD in CVID is heterogeneous and mixed patterns are frequently observed within a single biopsy, including non-necrotising granulomatous inflammation, lymphoid interstitial pneumonitis, lymphoid hyperplasia, follicular bronchiolitis, organizing pneumonia, and interstitial fibrosis; ILD has to be differentiated from lymphoma. The term granulomatous-lymphocytic interstitial lung disease (GLILD), coined to describe the histopathological findings within the lungs of patients with CVID with or without multisystem granulomata, is somewhat controversial as pulmonary granulomata are not always present on histology and the nature of infiltrating lymphocytes is variable. In this mini review we summarize the literature on the histology of CVID-related ILD and discuss some of the factors that may contribute to the inter- and intra- patient variability in the histological patterns reported. Finally, we highlight areas for future development. In particular, there is a need for standardization of histological assessments and reporting, together with a better understanding of the immunopathogenesis of CVID-related ILD to resolve the apparent heterogeneity of ILD in this setting and guide the selection of rational targeted therapies in different patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past collaboration with one of the authors, SP., (Copyright © 2020 Dhalla, Lochlainn, Chapel and Patel.)

Objectives. To examine whether growing use of telemental health (TMH) has reduced the rural-urban gap in specialty mental health care use in the United States. Methods. Using 2010-2017 Medicare data, we analyzed trends in the rural-urban difference in rates of specialty visits (in-person and TMH). Results. Among rural beneficiaries diagnosed with schizophrenia or bipolar disorder, TMH use grew by 425% over the 8 years and, in higher-use rural areas, accounted for one quarter of all specialty mental health visits in 2017. Among patients with schizophrenia or bipolar disorder, TMH visits differentially grew in rural areas by 0.14 visits from 2010 to 2017. This growth partially offset the 0.42-visit differential decline in in-person visits in rural areas. In net, the gap between rural and urban patients in specialty visits was larger by 2017. Conclusions. TMH has improved access to specialty care in rural areas, particularly for individuals diagnosed with schizophrenia or bipolar disorder. While growth in TMH use has been insufficient to eliminate the overall rural-urban difference in specialty care use, this difference may have been larger if not for TMH. Public Health Implications. Targeted policy to extend TMH to underserved areas may help offset declines in in-person specialty care.

Gynecologic brachytherapy procedures require targeted procedural and anesthetic needs including optimization of intra- and post-procedure analgesia, low rate of complications, and appropriate and timely transitions of care. It is uncertain whether neuraxial or general anesthesia is superior for these and other anesthetic outcomes. After a targeted search of the recent literature for anesthesia and analgesia studies for gynecologic brachytherapy, twenty studies were identified and appraised for potential review. Meta-analysis showed a decreased frequency in rescue analgesic administration in patients who underwent neuraxial anesthesia compared with general anesthesia for the procedure and literature review showed a comparable rate of anesthesia-related complications. Neuraxial anesthesia may be considered for gynecologic brachytherapy because of improved pain control, decreased opioid consumption, and similar rate of anesthesia complications., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Anemia is common in the perioperative period and is associated with poor patient outcomes. Remarkably, anemia is frequently ignored until hemoglobin levels drop low enough to warrant a red blood cell transfusion. This simplified transfusion-based approach has unfortunately shifted clinical focus away from strategies to adequately prevent, diagnose, and treat anemia through direct management of the underlying cause(s). While recommendations have been published for the treatment of anemia before elective surgery, information regarding the design and implementation of evidence-based anemia management strategies is sparse. Moreover, anemia is not solely a concern of the preoperative encounter. Rather, anemia must be actively addressed throughout the perioperative spectrum of patient care. This article provides practical information regarding the implementation of anemia management strategies in surgical patients throughout the perioperative period. This includes evidence-based recommendations for the prevention, diagnosis, and treatment of anemia, including the utility of iron supplementation and erythropoiesis-stimulating agents (ESAs).

Reconstruction of large craniofacial defects requires several factors to be considered before deciding on the best reconstructive option. This article discusses various factors taken into consideration when deciding on which reconstructive option is ideal for a given patient and defect. For large craniofacial defects, reconstruction using tissue transfer is considered preferentially over obturation, although in select defects obturation using a traditional tooth- or implant-borne prosthetic obturator can be considered a viable option., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Traditional chemotherapy agents adversely affect wound healing and need to be held prior to or after surgery. Immune checkpoint inhibitors (ICIs) and targeted agents are now standard of care for the several treatment cancers. We hypothesize that ICI and targeted therapy do not have similar adverse effects on perioperative outcomes., Methods: We performed a review of melanoma patients undergoing surgery at an academic hospital between 2011 and 2019. All patients received ICI or targeted therapy ≤ 60 days prior to surgery, including palliative procedures. Preoperative performance status was assessed using Eastern Cooperative Oncology Group score and American Society of Anesthesiologists Classification System. Thirty-day complications were classified by Clavien-Dindo grade. No statistical comparisons were performed., Results: Of 63 patients included in the analysis, 29 (46%) patients received ICI and 34 (54%) received targeted therapy with median of 14 days (IQR 5-27 days) between the last preoperative dose and day of surgery (ICI, median 18 days [IQR 13-34.5]; targeted therapy, median 7 days [IQR 3-22.25]). There were no perioperative mortalities. Among patients treated with ICI, 22 patients (76%) had no complications. Four patients had wound infections (2 readmitted), 1 had reoperation (hematoma) and 2 readmitted for other reasons (fever; volvulus). Among patients treated with targeted therapy, 25 patients (74%) had no complications. Seven patients had wound infections (none readmitted), 1 had reoperation (flap failure) and 1 had dehiscence (not treated)., Conclusions: Patients undergoing treatment with ICI or targeted therapies can safely undergo surgery without substantially increased risk of serious intraoperative and postoperative complications.

Preoperative carbohydrate loading is a contemporary element of the enhanced recovery after surgery (ERAS) paradigm. In addition to intraoperative surgical and anesthetic modifications and postoperative care practices, preoperative optimization is essential to good postsurgical outcomes. What was long held as dogma, a period of prolonged fasting prior to the administration of anesthesia, was later re-examined and challenged. Along with the proposed physiologic effects of decreasing the surgical stress response and insulin resistance, preoperative carbohydrate loading was also demonstrated to improve patient satisfaction and well-being, without an increase in perioperative complications. The benefits are most strongly observed in abdominal and cardiac surgery patients, but there has also been data which support its use in other specialties and surgeries. Barriers to the adoption of perioperative carbohydrate loading are few, but importantly include overcoming the inertia to modify older and more restrictive fasting guidelines and achieving the multidisciplinary consensus necessary to implement such changes. Despite these challenges, and with an existing body of evidence supporting its benefits, preoperative carbohydrate loading presents a significant contribution to the ERAS programs., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Purpose: To analyze and quantify the characteristics and parameters of the eyelid and adnexa of males and females and correlate these findings to an aesthetically pleasing score., Methods: This is an Institutional Review Board approved study involving healthy male and female volunteers. The margin-to-reflex distance, palpebral fissure, inferior scleral show, tarsal platform show, and brow fat span were measured using Image J digital photographic analysis and the images were scored by 110 non-ophthalmologists. The eyelid parameters were compared between the groups with Student t tests and the total aesthetic score was correlated to the measured parameters with Pearson's correlation coefficients (r). This study was HIPAA-compliant with protection of individually identifiable information., Results: Twenty male and 22 female participants were included and divided into 2 groups based on the aesthetic score. The average aesthetic score was 3.06 for males and 3.36 for females. None of the eyelid parameters were found to be significantly significant between the 2 male groups. In females, both inferior scleral show and tarsal platform show were significantly lower in the more aesthetic group. A greater margin-to-reflex distance correlated with increased aesthetic appeal. The ratio of brow fat span/tarsal platform show was not significantly different between the 2 female groups., Conclusions: Quantifying goals are important for the surgical and nonsurgical management of the eyelid and periorbita. Beauty is considered to be subjective and is comprised of various criteria. However, this study reveals that the female sex may have certain quantifiable goals for eyelid parameters that are considered more aesthetically pleasing.

Despite an abundance of evidence, routine perioperative antifibrinolytics have been avoided in oncology patients due to concern of thrombosis when given to patients with a preexisting hypercoagulable state. We present a retrospective review of 104 patients with an oncologic diagnosis who received intraoperative tranexamic acid during orthopedic surgery. Overall, complication rates were low, including deep vein thrombosis (1.0%), pulmonary embolism (4.8%), stroke (0%), and myocardial infarction (0%). This preliminary evidence shows that antifibrinolytics such as tranexamic acid may be considered perioperatively in oncology patients without increased risk of thromboembolic events; however, further prospective trials are encouraged.