Structure of the Hepatitis B virus capsid quasi-6-fold with a trapped C-terminal domain reveals capsid movements associated with domain exit.

Many viruses undergo transient conformational change to surveil their environments for receptors and host factors. In Hepatitis B virus (HBV) infection, after the virus enters the cell, it is transported to the nucleus by interaction of the HBV capsid with an importin α/ß complex. The interaction between virus and importins is mediated by nuclear localization signals on the capsid protein's C-terminal domain (CTD). However, CTDs are located inside the capsid. In this study, we asked where does a CTD exit the capsid, are all quasi-equivalent CTDs created equal, and does the capsid structure deform to facilitate CTD egress from the capsid? Here, we used Impß as a tool to trap transiently exposed CTDs and examined this complex by cryo-electron microscopy. We examined an asymmetric reconstruction of a T = 4 icosahedral capsid and a focused reconstruction of a quasi-6-fold vertex (3.8 and 4.0 Å resolution, respectively). Both approaches showed that a subset of CTDs extended through a pore in the center of the quasi-6-fold complex. CTD egress was accompanied by enlargement of the pore and subtle changes in quaternary and tertiary structure of the quasi-6-fold. When compared to molecular dynamics simulations, structural changes were within the normal range of capsid flexibility. Although pore diameter was enlarged in the Impß-bound reconstruction, simulations indicate that CTD egress does not exclusively depend on enlarged pores. In summary, we find that HBV surveillance of its environment by transient exposure of its CTD requires only modest conformational change of the capsid.

COVID-19 Vaccination Site Accessibility, United States, December 11, 2020-March 29, 2022.

During December 11, 2020-March 29, 2022, the US government delivered ≈700 million doses of COVID-19 vaccine to vaccination sites, resulting in vaccination of ≈75% of US adults during that period. We evaluated accessibility of vaccination sites. Sites were accessible by walking within 15 minutes by 46.6% of persons, 30 minutes by 74.8%, 45 minutes by 82.8%, and 60 minutes by 86.7%. When limited to populations in counties with high social vulnerability, accessibility by walking was 55.3%, 81.1%, 86.7%, and 89.4%, respectively. By driving, lowest accessibility was 96.5% at 15 minutes. For urban/rural categories, the 15-minute walking accessibility between noncore and large central metropolitan areas ranged from 27.2% to 65.1%; driving accessibility was 79.9% to 99.5%. By 30 minutes driving accessibility for all urban/rural categories was >95.9%. Walking time variations across jurisdictions and between urban/rural areas indicate that potential gains could have been made by improving walkability or making transportation more readily available.

A Narrative Review on the Administration of Inhaled Prostaglandins in Critically Ill Adult Patients With Acute Respiratory Distress Syndrome.

OBJECTIVE: To describe the effect of inhaled prostaglandins on both oxygenation and mortality in critically ill patients with acute respiratory distress syndrome (ARDS), with a focus on safety and efficacy in coronavirus disease 2019 (COVID-19)-associated ARDS and non-COVID-19 ARDS. DATA SOURCES: A literature search of MEDLINE was performed using the following search terms: inhaled prostaglandins, inhaled epoprostenol, inhaled nitric oxide, ARDS, critically ill. All abstracts were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language reports and studies conducted in humans between 1980 and June 2023 were considered. DATA SYNTHESIS: Data regarding inhaled prostaglandins and their effect on oxygenation are limited but show a benefit in patients who respond to therapy, and data pertaining to their effect on mortality is scarce. Concerns exist regarding the formulation of inhaled epoprostenol (iEPO) utilized in addition to modes of medication delivery; however, the limited data surrounding their use have shown a reasonable safety profile. Other avenues and beneficial effects may exist with inhaled prostaglandins, such as use in COVID-19-associated ARDS or non-COVID-19 ARDS patients undergoing noninvasive mechanical ventilation or during patient transport. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The use of inhaled prostaglandins can be considered in critically ill patients with COVID-19-associated ARDS or non-COVID-19 ARDS who are experiencing difficulties with oxygenation refractory to nonpharmacologic strategies. CONCLUSIONS: The use of iEPO and other inhaled prostaglandins requires further investigation to fully elucidate their effects on clinical outcomes, but it appears these medications may have a potential benefit in COVID-19-associated ARDS and non-COVID-19 ARDS patients with refractory hypoxemia but with little effect on mortality.

Evaluation of Goal Phenytoin Levels After an Initial Intravenous Loading Dose at an Academic Medical Center.

BACKGROUND: Phenytoin intravenous loading doses are administered in status epilepticus to rapidly achieve therapeutic levels. Accurately assessing phenytoin levels after the initial load can be challenging because of its complex pharmacokinetic profile and nonstandardized weight-based loading doses. OBJECTIVES: The objectives of this analysis were to determine the incidence of patients achieving goal phenytoin levels after the initial loading dose and characterize factors that contribute to achieving the goal level. METHODS: This single-center, retrospective cohort analysis was approved by our institutional review board and included adult patients who received a phenytoin load from May 2016 to March 2021. Patients were excluded if no total phenytoin level was drawn within 24 hours of the load, if the maintenance dose was given before the first level was drawn, or if the patient was on phenytoin before the load. The major endpoint was the percentage of patients achieving a corrected goal phenytoin level of ≥10 mcg/mL after the initial load. Multivariate regression was used to determine predictors of achieving the goal phenytoin level. RESULTS: Of the 152 patients included, 139 patients (91.4%) achieved a corrected goal level after the first load. Patients at goal received a significantly higher median weight-based loading dose (19.1 mg/kg [15.0-20.0] vs 12.6 mg/kg [10.1-15.0], P < 0.01). The multivariate analysis identified weight-based dosing as a statistically significant predictor of achieving the corrected goal level (odds ratio, 1.30; 95% CI, 1.12-1.53; P < 0.01). CONCLUSION AND RELEVANCE: Most patients achieved a corrected goal phenytoin level after the initial load. A higher median weight-based loading dose was shown to be a predictor of achieving the goal level and should be encouraged for rapid seizure termination. Future studies are warranted to confirm patient-specific factors that affect rapid achievement of the goal phenytoin level.

Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine.

PURPOSE: Guanfacine is an α2A-adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility. METHODS: We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na+ channels were investigated using voltage-clamp electrophysiology. RESULTS: Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant NaV1.7 encoded by SCN9A, as well as other NaV channel subtypes to a varying degree. CONCLUSION: Our study provides further evidence for a possible pathophysiological role of NaV1.7 in anxiety and dysautonomia. Combined with off-target effects on NaV channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize NaV channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of NaV1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms.

Long-term cognition and speech recognition outcomes after cochlear implantation in the elderly.

OBJECTIVE: The purpose of this study is to investigate how cognition, as measured using the Self-Administered Gerocognitive Examination Test (SAGE), and age affect speech recognition scores in older adults (age > 65) at one year and two years after cochlear implantation. STUDY DESIGN: This is a prospective study. SETTING: This study was conducted at a single institution. METHODS: Unilateral cochlear implantation was performed by two surgeons on adult patients (>65 years) with postlingual bilateral sensorineural hearing loss. There were 230 patients who underwent cochlear implantation from January 2016 to June 2023. Fifty-five of these patients completed the SAGE questionnaire before implantation, one year after implantation, and 2 years after implantation. Paired t-test analysis was used to evaluate pre- and post-operative speech recognition scores (CNC, AzBio in Quiet). RESULTS: Patients who had normal preoperative cognition on SAGE showed greater improvement in postoperative speech recognition tests at 1 year and 2 years after implantation compared with patients who showed preoperative cognitive impairment. There were no significant differences in postoperative speech outcome between age group 1 (between 65 and 80 years old) and age group 2 (over 80 years old) cochlear implant recipients. There were no changes in cognitive SAGE scores after 2 years implantation. CONCLUSION: Cognitive function, as measured by SAGE, is a more reliable predictor than age in determining speech recognition improvement after cochlear implantation. Cochlear implantation did not improve postoperative cognition.

Benefits of unilateral cochlear implantation in adults with asymmetric hearing loss: Audiologic and patient-related outcome measures.

PURPOSE: To investigate the benefits of cochlear implantation in adults with single-sided deafness (SSD) and asymmetric hearing loss (AHL). STUDY DESIGN: Prospective within-subjects repeated-measures. SETTING: Two tertiary cochlear implant centers. PATIENTS: Fourteen adults with severe-to-profound sensorineural hearing loss in the worse hearing ear and up to moderate SNHL in the better hearing ear. INTERVENTION: Cochlear implantation in the worse hearing ear. MAIN OUTCOME MEASURES: Consonant-nucleus-consonant (CNC) test, AzBio sentence test in noise, and lateralization testing were conducted preoperatively and at 3-, 6-, and 12-months post-activation. Patient-related outcomes were measured using the Speech, Spatial, and Qualities of Hearing Scale and Glasgow Benefit Inventory. Tinnitus Handicap Inventory was administered to subjects with tinnitus. RESULTS: Mean length of hearing loss in the worse hearing ear was 3.5 years. The mean CNC change scores from baseline were 54.8, 55.9, and 58.9 percentage points at 3-, 6-, and 12-months (p < 0.001). AzBio sentence test in noise demonstrated improved scores in all spatial configurations, although statistically significant in S0N0 (speech front, noise front) only. Lateralization testing showed significant improvement of 22.9, 24.5, and 24.0 percentage points at 3-, 6-, and 12 months post-activation (p = 0.002). All patient-related outcome measures revealed significant improvement. CONCLUSION: This study demonstrates improved speech perception in noise, sound lateralization, quality of life, and reduction in tinnitus perception in adults with SSD/AHL who undergo cochlear implantation. Our results add to the growing body of evidence that cochlear implant should be offered to this population.

N1-acetylspermidine is a determinant of hair follicle stem cell fate.

Stem cell differentiation is accompanied by increased mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine and spermine, which are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translational control remains obscure. Here, we investigate the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. Compared to progenitor cells, HFSCs showed lower translation rates, correlating with reduced polyamine levels. Surprisingly, overall polyamine depletion decreased translation but did not affect cell fate. In contrast, specific depletion of natural polyamines mediated by spermidine/spermine N1-acetyltransferase (SSAT; also known as SAT1) activation did not reduce translation but enhanced stemness. These results suggest a translation-independent role of polyamines in cell fate regulation. Indeed, we identified N1-acetylspermidine as a determinant of cell fate that acted through increasing self-renewal, and observed elevated N1-acetylspermidine levels upon depilation-mediated HFSC proliferation and differentiation in vivo. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions. This article has an associated First Person interview with the first author of the paper.

Immunotherapy May Improve Tumor Sensitivity to Palliative Chemotherapy in Platinum Resistant Ovarian Cancer.

Ovarian cancer is the second most common gynecologic cancer in the US and ranks among the top 10 causes of female cancer-related deaths. Platinum-resistant disease carries a particularly poor prognosis and leaves patients with limited remaining therapeutic options. Patients with platinum-resistant disease have significantly lower response rates to additional chemotherapy, with estimates as low as 10%-25%. We hypothesize that in patients with platinum-resistant ovarian cancer, treatment with immunotherapy followed by cytotoxic chemotherapy with antiangiogenic therapy results in prolonged survival without compromising quality of life. Our experience of 3 patients with recurrent, metastatic platinum-resistant ovarian cancer treated with immunotherapy followed by anti-angiogenic treatment plus chemotherapy resulted in progression-free survival durations significantly above previously published averages. Further studies evaluating the role of immunotherapy followed by chemotherapy in combination with drugs targeting angiogenesis are needed and may provide a long-sought after breakthrough for advancing survival in platinum-resistant ovarian cancer.

Core Protein-Directed Antivirals and Importin ß Can Synergistically Disrupt Hepatitis B Virus Capsids.

Viral structural proteins can have multiple activities. Antivirals that target structural proteins have potential to exhibit multiple antiviral mechanisms. Hepatitis B virus (HBV) core protein (Cp) is involved in most stages of the viral life cycle; it assembles into capsids, packages viral RNA, is a metabolic compartment for reverse transcription, interacts with nuclear trafficking machinery, and disassembles to release the viral genome into the nucleus. During nuclear localization, HBV capsids bind to host importins (e.g., Impß) via Cp's C-terminal domain (CTD); the CTD is localized to the interior of the capsid and is transiently exposed on the exterior. We used HAP12 as a representative Cp allosteric modulator (CpAM), a class of antivirals that inappropriately stimulates and misdirects HBV assembly and deforms capsids. CpAM impact on other aspects of the HBV life cycle is poorly understood. We investigate how HAP12 influences the interactions between empty or RNA-filled capsids with Impß and trypsin in vitro. We show that HAP12 can modulate CTD accessibility and capsid stability, depending on the saturation of HAP12-binding sites. We demonstrate that Impß synergistically contributes to capsid disruption at high levels of HAP12 saturation, using electron microscopy to visualize the disruption and rearrangement of Cp dimers into aberrant complexes. However, RNA-filled capsids resist the destabilizing effects of HAP12 and Impß. In summary, we show host protein-induced catalysis of capsid disruption, an unexpected additional mechanism of action for CpAMs. Potentially, untimely capsid disassembly can hamper the HBV life cycle and also cause the virus to become vulnerable to host innate immune responses. IMPORTANCE The HBV core, an icosahedral complex of 120 copies of the homodimeric core (capsid) protein with or without packaged nucleic acid, is transported to the host nucleus by its interaction with host importin proteins. Importin-core interaction requires the core protein C-terminal domain, which is inside the capsid, to "flip" to the capsid exterior. Core protein-directed drugs that affect capsid assembly and stability have been developed recently. We show that these molecules can, synergistically with importins, disrupt capsids. This mechanism of action, synergism with host protein, has the potential to disrupt the virus life cycle and activate the innate immune system.

Two Models for Increasing the Scope and Activities of Human Immunodeficiency Virus Partner Services Programs: Preliminary Findings From the Fast Track Project.

BACKGROUND: We sought to develop a novel strategy for expanding an existing human immunodeficiency virus (HIV) partner services (PS) model to provide comprehensive sexual health services, including sexually transmitted infection testing, a virtual telemedicine visit, and access to immediate start medication (antiretroviral treatment, preexposure or postexposure prophylaxis). Fast Track was a National Institutes of Health-funded implementation science trial in New York City to pilot and refine the new strategy, and examine its feasibility, acceptability, and impact. METHODS: Over the course of 1 year, health department staff collaborated with the academic research team to develop Fast Track protocols and workflows, create a cloud-based database to interview and track patients, and train disease intervention specialists to deliver the new program. The initial field-based program (Fast Track 1.0) was piloted March to December 2019. A modified telephone-based program (Fast Track 2.0) was developed in response to COVID-19 pandemic constraints and was piloted August 2020 to March 2021. RESULTS: These 2 pilots demonstrate the feasibility and acceptability of integrating comprehensive sexual health services into HIV PS programs. Disease intervention specialists were successfully trained to conduct comprehensive sexual health visits, and clients reported that the availability of comprehensive sexual health services made them more willing to engage with PS. Key lessons for scale-up include managing collaboration with a licensed provider, navigating technical and technological issues, and challenges in client engagement and retention. CONCLUSIONS: The success of this integrated strategy suggests that telehealth visits may be a critical gateway to care engagement for PS clients. This model is an innovative strategy for increasing engagement with HIV testing, prevention, and treatment for underserved populations.

Low alanine aminotransferase activity gene variant in a Siberian Husky with copper-associated hepatopathy.

BACKGROUND: Alanine aminotransferase (ALT) is commonly used as a marker of hepatocellular injury. Increased serum ALT activity due to hepatocyte injury occurs in copper-associated hepatopathy (CuCH) and other necroinflammatory liver conditions. Blood ALT concentrations are frequently used to monitor therapy in cases of CuCH. Low serum ALT activities have been associated with an allele at a CFA13 locus. CASE PRESENTATION: A 9-year-old female spayed Siberian Husky was diagnosed with CuCH (hepatic copper dry weight 2680 µg/g [normal, 120-400 µg/g; toxic, > 1500 µg/g]) and a normal ALT (78 U/L; reference range, 10-125 U/L). Mild hepatocellular necrosis was evident histologically. Genetic testing (Embark) revealed that the dog was heterozygous for the low ALT activity gene allele. CONCLUSIONS: This case report illustrates the clinical implications for diagnosing and managing necroinflammatory liver disease such as CuCH in dogs with a low ALT activity genotype.

Perceptions of service providers, service recipients and female community health volunteers on a rural obstetric ultrasound program in rural Nepal: a qualitative study.

BACKGROUND: In rural Nepal, where women face financial and geographic barriers in accessing ultrasound scans, the government initiated a Rural Obstetric Ultrasound Program (ROUSG) to train skilled birth attendants (SBAs) in rural birthing centers and expand access to routine ultrasound scans for local pregnant women. This study explores the perceived benefits and limitations of the training and implementation of this program. METHODS: A qualitative study was conducted in 15 primary care facilities in Bhojpur and Dhading, two rural districts of Nepal. The research team conducted in-depth interviews with 15 trained SBAs and focus group discussions with 48 service recipients and 30 FCHVs to gain insight into their perceptions. All interviews and focus group discussions were recorded, reviewed, and manually coded into MS Excel. RESULTS: Overall, our findings indicated that the ROUSG program was very well received among all our study participants, though critical gaps were identified, mostly during the training of the SBAs. These included insufficient guidance or practice opportunities during training and the challenges of implementing the mobile obstetric ultrasound service. Most importantly, though, our results suggest that the implementation of the ROUSG program increased access to prenatal care, earlier identification and referrals for abnormal scans, as well as reduced pregnancy-related stress. There was also a notable anecdotal increase in antenatal care utilization and institutional deliveries, as well as high satisfaction in both service providers and recipients. CONCLUSION: Our findings highlighted that while the training component could use some strengthening with increased opportunities for supervised practice sessions and periodic refresher training after the initial 21-days, the program itself had the potential to fill crucial gaps in maternal and newborn care in rural Nepal, by expanding access not only to ROUSG services but also to other MNH services such as ANC and institutional deliveries. Our findings also support the use of ultrasound in areas with limited resources as a solution to identify potential complications at earlier stages of pregnancy and improve timely referrals, indicating the potential for reducing maternal and neonatal morbidities. This initial study supports further research into the role ROUSG can play in expanding critical MNH services in underserved areas and improving broader health outcomes through earlier identification of potential obstetric complications.

Federal Housing Assistance and Chronic Disease Among US Adults, 2005-2018.

Introduction: Housing insecurity is associated with poor health outcomes. Characterization of chronic disease outcomes among adults with and without housing assistance would enable housing programs to better understand their population's health care needs. Methods: We used National Health and Nutrition Examination Survey (NHANES) data from 2005 through 2018 linked to US Department of Housing and Urban Development (HUD) administrative records to estimate the prevalence of obesity, diabetes, and hypertension and to assess the independent associations between housing assistance and chronic conditions among adults receiving HUD assistance and HUD-assistance-eligible adults not receiving HUD assistance at the time of their NHANES examination. We estimated propensity scores to adjust for potential confounders among linkage-eligible adults who had an income-to-poverty ratio less than 2 and were not receiving HUD assistance. Sensitivity analysis used 2013-2018 NHANES cycles to account for disability status. Results: Adults not receiving HUD assistance had a significantly lower adjusted prevalence of obesity (42.1%; 95% CI, 40.4%-43.8%) compared with adults receiving HUD assistance (47.5%; 95% CI, 44.8%-50.3%), but we found no differences for diabetes and hypertension. We found significant associations between housing assistance and obesity (adjusted odds ratio = 1.29; 95% CI, 1.12-1.47), but these were not significant in the sensitivity analysis with and without controlling for disability status. We found no significant associations between housing assistance and diabetes or hypertension. Conclusion: Based on data from a cross-sectional survey, we observed a higher prevalence of obesity among adults with HUD assistance compared with HUD-assistance-eligible adults without HUD assistance. Results from this study can help inform research on understanding the prevalence of chronic disease among adults with HUD assistance.

Is lobectomy sufficient for multifocal papillary thyroid microcarcinoma?

IMPORTANCE: Multifocal papillary thyroid microcarcinoma (PTMC) has been associated with a higher incidence of lymph node involvement, bilateral involvement, and extrathyroidal extension compared to unifocal papillary thyroid cancer (PTC). OBJECTIVE: To describe the incidence and determinants of survival for patients with multifocal PTMC using the Surveillance, Epidemiology, and End Result (SEER) database. DESIGN, SETTING, PARTICIPANTS: The SEER registry was utilized to calculate survival trends for patients with PTMC between 2010 and 2015. Patient data was then analyzed with respect to age, sex, race, multifocality, and types of surgery rendered. MAIN OUTCOMES AND MEASURES: Overall Survival (OS) and Disease Specific Survival (DSS). RESULTS: 22,283 cases of papillary thyroid microcarcinoma (T1a N0 M0) were identified. The cohort was composed of 82.6 % females, and about 82 % of patients were of white race. The mean age at diagnosis was 51.9 years. Multifocal PTMC was present in 32.2 % of the tumors (n = 7186). 73.9 % of patients underwent total thyroidectomy and 23.0 % received lobectomy. OS at 2 and 5 years was 98 % and 95 %, respectively. Multivariate analysis revealed that age, sex, and multifocality were determinants of OS. Only age was a determinant of DSS. Kaplan-Meier survival analysis revealed that multifocal PTMC had similar mean OS between lobectomy and total thyroidectomy patients (69.59 months versus 69.82 months). CONCLUSIONS AND RELEVANCE: PTMC has a good prognosis. Our analysis revealed that age was a determinant of OS and DSS; sex and multifocality were also prognosticators for OS. The type of surgery, whether lobectomy or total thyroidectomy, was not a determinant of survival in multifocal PTMC.

Surgeon idiosyncrasy is a key driver of cost in arthroscopic rotator cuff repair: a time-driven activity-based costing analysis.

BACKGROUND: Delivering high-value orthopedic care requires optimizing value, defined as health outcomes achieved per dollar spent. Published literature is stippled with inaccurate proxies for cost, including negotiated reimbursement rates, fees paid, or listed prices. Time-driven activity-based costing (TDABC) offers a more robust and accurate approach to calculating cost, including shoulder care. In the present study, we sought to determine the drivers of total cost in arthroscopic rotator cuff repair (aRCR) using TDABC. METHODS: Consecutive patients undergoing aRCR at multiple sites associated with a large urban health care system between January 2019 and September 2021 were identified. Total cost was determined using TDABC methodology. The episode of care was defined by 3 phases: preoperative, intraoperative, and postoperative care. Patient, procedure, rotator cuff tear morphology, and surgeon characteristics were collected. Bivariate analysis was performed across all characteristics between high-cost (top decile) and all other aRCRs. Multivariable linear regression was used to identify the key cost drivers. RESULTS: In total, 625 aRCRs performed by 24 orthopedic surgeons and 572 aRCRs performed by 13 orthopedic surgeons were included in the bivariate and multivariable linear regression analyses, respectively. By TDABC analysis, total aRCR cost varied 6-fold (5.9×) from least to most costly. Intraoperative costs accounted for 91% of average total cost, followed by preoperative costs and postoperative costs (6% and 3%, respectively). Biologic adjuncts (regression coefficient [RC] 0.54, 95% confidence interval [CI] 0.49-0.58, P < .001) and surgeon idiosyncrasy (RC of highest-cost surgeon 0.50, 95% CI 0.26-0.73, P < .001) were the major cost drivers in aRCR. Patient age, comorbidities, number of rotator cuff tendons torn, and revision surgery were not significantly associated with total cost. The amount of tendon retraction (RC 0.0012, 95% CI 0.000020-0.0024, P = .046), average Goutallier grade (RC 0.029, 95% CI 0.0086-0.049, P = .005), and the number of anchors used (RC 0.039, 95% CI 0.032-0.046, P < .001) were also significantly associated with cost, but with far smaller effect sizes. DISCUSSION AND CONCLUSION: Episode of care costs vary nearly 6-fold in aRCR and are almost exclusively dictated by the intraoperative phase. Tear morphology and repair technique contribute to cost, although the largest cost drivers of aRCR are the use of biologic adjuncts and surgeon idiosyncrasy, defined as something a surgeon does or does not do that impacts total cost and is not controlled for in the current analysis. Future work should seek to better delineate what these surgeon idiosyncrasies may represent.

COVID-19 Vaccine Provider Access and Vaccination Coverage Among Children Aged 5-11 Years - United States, November 2021-January 2022.

On October 29, 2021, the Pfizer-BioNTech pediatric COVID-19 vaccine received Emergency Use Authorization for children aged 5-11 years in the United States.† For a successful immunization program, both access to and uptake of the vaccine are needed. Fifteen million doses were initially made available to pediatric providers to ensure the broadest possible access for the estimated 28 million eligible children aged 5-11 years, especially those in high social vulnerability index (SVI)§ communities. Initial supply was strategically distributed to maximize vaccination opportunities for U.S. children aged 5-11 years. COVID-19 vaccination coverage among persons aged 12-17 years has lagged (1), and vaccine confidence has been identified as a concern among parents and caregivers (2). Therefore, COVID-19 provider access and early vaccination coverage among children aged 5-11 years in high and low SVI communities were examined during November 1, 2021-January 18, 2022. As of November 29, 2021 (4 weeks after program launch), 38,732 providers were enrolled, and 92% of U.S. children aged 5-11 years lived within 5 miles of an active provider. As of January 18, 2022 (11 weeks after program launch), 39,786 providers had administered 13.3 million doses. First dose coverage at 4 weeks after launch was 15.0% (10.5% and 17.5% in high and low SVI areas, respectively; rate ratio [RR] = 0.68; 95% CI = 0.60-0.78), and at 11 weeks was 27.7% (21.2% and 29.0% in high and low SVI areas, respectively; RR = 0.76; 95% CI = 0.68-0.84). Overall series completion at 11 weeks after launch was 19.1% (13.7% and 21.7% in high and low SVI areas, respectively; RR = 0.67; 95% CI = 0.58-0.77). Pharmacies administered 46.4% of doses to this age group, including 48.7% of doses in high SVI areas and 44.4% in low SVI areas. Although COVID-19 vaccination coverage rates were low, particularly in high SVI areas, first dose coverage improved over time. Additional outreach is critical, especially in high SVI areas, to improve vaccine confidence and increase coverage rates among children aged 5-11 years.

Correlates of Blood Pressure Awareness, Treatment, and Control Among Adults 50 Years or Older by HIV Status in Northwestern Tanzania.

PURPOSE OF REVIEW: The objective of this study was to describe the increasing incidence and risk of cardiovascular disease among persons living with HIV (PLWH) in Sub-Saharan Africa. We also used data to compare hypertension (a common NCD among PLWH) outcomes between PLWH and HIV-uninfected individuals among older adults in Northwestern Tanzania. RECENT FINDINGS: Hypertension is increasingly common in Sub-Saharan Africa and a leading cause of cardiovascular disease for PLWH. Among those with hypertension, PLWH have a 50% higher risk of incident myocardial infarction compared to the general population. In response to the rising incidence of these non-communicable diseases (NCDs) among PLWH, recently, the Joint United Nations Program on HIV/AIDS supported the integration of NCD care into routine clinical care for HIV. However, data are lacking on levels of awareness of hypertension status, diagnosis, and antihypertensive medication adherence. Given the higher likelihood of elevated blood pressure among PLWH, there is an urgent need to implement interventions to improve blood pressure control in this population. Researchers should evaluate treatment barriers at multiple levels including health system, healthcare providers, and patients' level and tailor evidence-based interventions to increase achievement of blood pressure control for PLWH.

Chronic arsenic increases cell migration in BEAS-2B cells by increasing cell speed, cell persistence, and cell protrusion length.

There is a strong association between arsenic exposure and lung cancer development, however, the mechanism by which arsenic exposure leads to carcinogenesis is not clear. In our previous study, we observed that when BEAS-2B cells are chronically exposed to arsenic, there is an increase in secreted TGFα, as well as an increase in EGFR expression and activity. Further, these changes were broadly accompanied with an increase in cell migration. The overarching goal of this study was to acquire finer resolution of the arsenic-dependent changes in cell migration, as well as to understand the role of increased EGFR expression and activity levels in the underlying mechanisms of cell migration. To do this, we used a combination of biochemical and single cell assays, and observed chronic arsenic treatment enhancing cell migration by increasing cell speed, cell persistence and cell protrusion length. All three parameters were further increased by the addition of TGFα, indicating EGFR activity is sufficient to enhance those aspects of cell migration. In contrast, EGFR activity was necessary for the increase in cell speed, as it was reversed with an EGFR inhibitor, AG1478, but was not necessary to enhance persistence and protrusion length. From these data, we were able to isolate both EGFR-dependent and -independent features of cell migration that were enhanced by chronic arsenic exposure.

Maternal blood metal concentrations are associated with matrix metalloproteinases (MMPs) among pregnant women in Puerto Rico.

BACKGROUND/AIM: Matrix metalloproteinases (MMPs) are important regulators of uterine remodeling, a critical process for healthy pregnancies, and studies have revealed a link between an imbalance in MMPs and adverse birth outcomes. Toxicological studies have indicated that exposure to heavy metals can alter the levels of inflammatory cytokines, including MMPs. Despite growing evidence, the clear association between heavy metal exposure and MMPs has yet to be explored extensively in human populations. To have a better understanding of the association, in this study, we assessed associations between maternal blood metal levels with MMPs among 617 pregnant women in the Puerto Rico PROTECT birth cohort. METHODS: We measured blood concentrations for 11 metals in the first and/or second trimester of pregnancy using ICP-MS. MMPs (MMP1, MMP2, and MMP9) were quantified using a customized Luminex assay. Linear mixed effects models (LMEs) were used to regress MMPs on metals and included random intercepts for study participants to account for correlated repeated outcome measures. Fetal sex effects were estimated using interaction terms between metal exposure variables and fetal sex indicators. RESULTS: We observed significant associations between cesium, manganese, and zinc with all the MMPs that were measured. We also observed differences in metal-MMPs associations by fetal sex. Cobalt was positively associated with MMP1 only in women with male fetuses, and cesium was negatively associated with MMP1 only in women with female fetuses. MMP2 had significant associations with maternal blood metal concentrations only in women with female fetuses. CONCLUSION: Certain metals were significantly associated with MMPs that are responsible for uterine remodeling and healthy pregnancies. Most of these associations differed by fetal sex. This study highlighted significant metal-MMPs associations that may inform research on new avenues for understanding heavy metal-induced adverse birth outcomes and the development of diagnostic tools.