Heterologous cAd3-Ebola and MVA-EbolaZ vaccines are safe and immunogenic in US and Uganda phase 1/1b trials.

Ebola virus disease (EVD) is a filoviral infection caused by virus species of the Ebolavirus genus including Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). We investigated the safety and immunogenicity of a heterologous prime-boost regimen involving a chimpanzee adenovirus 3 vectored Ebola vaccine [either monovalent (cAd3-EBOZ) or bivalent (cAd3-EBO)] prime followed by a recombinant modified vaccinia virus Ankara EBOV vaccine (MVA-EbolaZ) boost in two phase 1/1b randomized open-label clinical trials in healthy adults in the United States (US) and Uganda (UG). Trial US (NCT02408913) enrolled 140 participants, including 26 EVD vaccine-naïve and 114 cAd3-Ebola-experienced participants (April-November 2015). Trial UG (NCT02354404) enrolled 90 participants, including 60 EVD vaccine-naïve and 30 DNA Ebola vaccine-experienced participants (February-April 2015). All tested vaccines and regimens were safe and well tolerated with no serious adverse events reported related to study products. Solicited local and systemic reactogenicity was mostly mild to moderate in severity. The heterologous prime-boost regimen was immunogenic, including induction of durable antibody responses which peaked as early as two weeks and persisted up to one year after each vaccination. Different prime-boost intervals impacted the magnitude of humoral and cellular immune responses. The results from these studies demonstrate promising implications for use of these vaccines in both prophylactic and outbreak settings.

Benzophenone-3 alters expression of genes encoding vascularization and epithelial-mesenchymal transition functions during Trp53-null mammary tumorigenesis.

Benzophenone-3 (also referred to as oxybenzone) is a putative endocrine disrupting chemical and common ingredient in sunscreens and other personal care products. We previously showed that benzophenone-3 was promotional for epithelial tumorigenesis in mice fed adult high-fat diet, while protective against the incidence of more aggressive spindle cell tumors in the same treatment group. In this study, we show that benzophenone-3 reduces epithelial to mesenchymal transition in the epithelial tumors of these mice. This reduction in epithelial to mesenchymal transition is associated with altered expression of several genes involved in regulation of angiogenesis and epithelial to mesenchymal transition. Among the genes altered in expression, Timp1 is of particular interest because benzophenone-3 suppressed both migration and Timp1 expression in a mammary tumor cell line that displays epithelial to mesenchymal transition characteristics. These alterations in gene expression plausibly stabilize the vasculature of epithelial carcinomas and contribute to benzophenone-3 promotion of epithelial tumors, while at the same time suppress epithelial to mesenchymal transition and suppress incidence of spindle cell tumors.

Development of the internal family systems model: Honoring contributions from family systems therapies.

We describe Richard Schwartz's development of the Internal Family Systems model (IFS) from his position as a Structural/Strategic family therapist. Four decades ago, Schwartz struggled to help clients who exhibited serious risk of harm to self and others. Through a process of inquiry, he began to work with the positive intentions behind his most challenging clients' harmful thoughts and behaviors. He applied foundational ideas from family systems thinking to patterns of internal experiences. As he experimented with ways of applying these ideas, he created an approach to healing. We summarize the IFS model delineating ways a range of family systems theory and practice inform its development and contribute to its best practice. Our purposes are to inform IFS practitioners who are not trained in foundational family systems models as well as to acknowledge the significant contributions family therapy theories made in the development and best practice of the IFS model.

Benzophenone-3 exposure alters composition of tumor infiltrating immune cells and increases lung seeding of 4T1 breast cancer cells.

Environmental chemicals are a persistent and pervasive part of everyday life. A subset of environmental chemicals are xenoestrogens, compounds that bind to the estrogen receptor (ER) and drive estrogen-related processes. One such chemical, benzophenone-3 (BP3), is a common chemical in sunscreen. It is a potent UV protectant but also is quickly absorbed through the skin. While it has been approved by the FDA, there is a renewed interest in the safety of BP3, particularly in relation to breast cancer. The focus of this study was to examine the impact that BP3 has on triple negative breast cancer (TNBC) through alterations to cells in the immune microenvironment. In this study, we exposed female mice to one of two doses of BP3 before injecting them with a TNBC cell line. Several immune endpoints were examined both in the primary tissues and from in vitro studies of T cell behavior. Our studies revealed that in the lung tumor microenvironment, exposure to BP3 not only increased the number of metastases, but also the total area of tumor coverage. We also found that BP3 caused alterations in immune populations in a tissue-dependent manner, particularly in T cells. Taken together, our data suggest that while BP3 may not directly affect the proliferation of TNBC, growth and metastasis of TNBC-derived tumors can be altered by BP3 exposures via the alterations in the immune populations of the tumor microenvironment.

Are prosodic effects on sentence comprehension dependent on age?

PURPOSE: to investigate prosodic boundary effects on the comprehension of attachment ambiguities in Brazilian Portuguese and to test two hypotheses relying on the notion of boundary strength: the absolute boundary hypothesis (ABH) and the relative boundary hypothesis (RBH). Manipulations of prosodic structure influence how listeners interpret syntactically ambiguous sentences. However, the role of prosody in spoken language comprehension of sentences has received limited attention in languages other than English, particularly from a developmental perspective. METHODS: Twenty-three adults and 15 children participated in a computerized sentence comprehension task involving syntactically ambiguous sentences. Each sentence was recorded in eight different prosodic forms with acoustic manipulations of F0, duration and pause varying the boundary size to reflect predictions of the ABH and RBH. RESULTS: Children and adults differed in how prosody influenced their syntactic processing and children were significantly slower than adults. Results indicated that interpretation of sentences varied according to their prosodic forms. CONCLUSION: Neither the ABH or the RBH explained how children and adults who speak Brazilian Portuguese use prosodic boundaries to disambiguate sentences. There is evidence that the way prosodic boundaries influence disambiguation varies cross-linguistically.

The effect of sentence length on question comprehension in children with cochlear implants.

OBJECTIVES: The present study investigated the comprehension of subject and object who and which questions in children with cochlear implants (CI). METHODS: Growth Curve Analysis (GCA) was used to compare eye gaze fixations and gaze patterns to the appropriate subject or object nouns within a four-picture array between 16 children with CI and 31 children with typical hearing (aged 7;0-12;0) on wh-questions with and without added adjectives to increase length. Offline accuracy was also compared. RESULTS: Findings indicated children with typical hearing exhibited more fixations to the target noun across all conditions, supporting higher comprehension accuracy. Both groups of children demonstrated more fixations to the target noun in object questions and questions without added length. Patterns of eye movement were significantly different between groups, suggesting different patterns of eye gaze across the array before fixation on the target noun. Children with CI exhibited fewer fixations, slower speed to fixation, and differences in gaze patterns that may imply the presence of processing limitations. Error analyses also suggested that children with CI frequently fixated on a picture similar to the target noun. CONCLUSIONS: Results indicate children with CI comprehend questions more slowly than their hearing peers, which may be related to limitations in working memory.

Are prosodic effects on sentence comprehension dependent on age? / Os efeitos prosódicos na compreensão de frases variam de acordo com a idade?

ABSTRACT Purpose to investigate prosodic boundary effects on the comprehension of attachment ambiguities in Brazilian Portuguese and to test two hypotheses relying on the notion of boundary strength: the absolute boundary hypothesis (ABH) and the relative boundary hypothesis (RBH). Manipulations of prosodic structure influence how listeners interpret syntactically ambiguous sentences. However, the role of prosody in spoken language comprehension of sentences has received limited attention in languages other than English, particularly from a developmental perspective. Methods Twenty-three adults and 15 children participated in a computerized sentence comprehension task involving syntactically ambiguous sentences. Each sentence was recorded in eight different prosodic forms with acoustic manipulations of F0, duration and pause varying the boundary size to reflect predictions of the ABH and RBH. Results Children and adults differed in how prosody influenced their syntactic processing and children were significantly slower than adults. Results indicated that interpretation of sentences varied according to their prosodic forms. Conclusion Neither the ABH or the RBH explained how children and adults who speak Brazilian Portuguese use prosodic boundaries to disambiguate sentences. There is evidence that the way prosodic boundaries influence disambiguation varies cross-linguistically.

RESUMO Objetivo investigar os efeitos de fronteiras prosódicas na compreensão de ambiguidades sintáticas no português brasileiro além de testar duas hipóteses baseadas na noção de intensidade de fronteira: a hipótese de fronteira absoluta (ABH) e a hipótese de fronteira relativa (RBH). Manipulações da estrutura prosódica influenciam como os ouvintes interpretam frases sintaticamente ambíguas. No entanto, o papel da prosódia na compreensão da linguagem oral tem recebido atenção limitada em línguas além do inglês, particularmente do ponto de vista do desenvolvimento. Método Vinte e três adultos e 15 crianças participaram de uma tarefa computadorizada de compreensão de frases envolvendo frases sintaticamente ambíguas. Cada frase foi gravada em oito formas prosódicas diferentes com manipulações acústicas de F0, duração, e pausa, variando o tamanho da fronteira prosódica de modo a transparecer as previsões da ABH e RBH. Resultados Crianças e adultos diferiram em como a prosódia influenciou o processamento sintático; as crianças foram significativamente mais lentas que os adultos. Os resultados indicaram que a interpretação das frases variou de acordo com suas formas prosódicas. Conclusão Nenhuma das hipóteses (ABH ou RBH) explica como crianças e adultos falantes do Português brasileiro utilizam as fronteiras prosódicas para desambiguar frases. Há evidências de que a maneira com a qual os limites prosódicos influenciam a desambiguação de frases varia entre os idiomas.

Comparison of Low-Value Services Among Medicare Advantage and Traditional Medicare Beneficiaries.

Importance: Low-value care in the Medicare program is prevalent, costly, potentially harmful, and persistent. Although Medicare Advantage (MA) plans can use managed care strategies not available in traditional Medicare (TM), it is not clear whether this flexibility is associated with lower rates of low-value care. Objectives: To compare rates of low-value services between MA and TM beneficiaries and explore how elements of insurance design present in MA are associated with the delivery of low-value care. Design, Setting, and Participants: This cross-sectional study analyzed beneficiaries enrolled in MA and TM using claims data from a large, national MA insurer and a random 5% sample of TM beneficiaries. The study period was January 1, 2017, through December 31, 2019. All analyses were conducted from July 2021 to March 2022. Exposures: Enrollment in MA vs TM. Main Outcomes and Measures: Low-value care was assessed using 26 claims-based measures. Regression models were used to estimate the association between MA enrollment and rates of low-value services while controlling for beneficiary characteristics. Stratified analyses explored whether network design, product design, value-based payment, or utilization management moderated differences in low-value care between MA and TM beneficiaries and among MA beneficiaries. Results: Among a study population of 2 470 199 Medicare beneficiaries (mean [SD] age, 75.6 [7.0] years; 1 346 777 [54.5%] female; 229 107 [9.3%] Black and 2 126 353 [86.1%] White individuals), 1 527 763 (61.8%) were enrolled in MA and 942 436 (38.2%) were enrolled in TM. Beneficiaries enrolled in MA received 9.2% (95% CI, 8.5%-9.8%) fewer low-value services in 2019 than TM beneficiaries (23.1 vs 25.4 total low-value services per 100 beneficiaries). Although MA beneficiaries enrolled in health management organization and preferred provider organization products received fewer low-value services than TM beneficiaries, the difference was largest for those enrolled in health management organization products (2.6 fewer [95% CI, 2.4-2.8] vs 2.1 fewer [95% CI, 1.9-2.3] services per 100 beneficiaries, respectively). Across primary care payment arrangements, MA beneficiaries received fewer low-value services than TM beneficiaries, with the largest difference observed for MA beneficiaries whose primary care physicians were reimbursed within 2-sided risk arrangements. Conclusions and Relevance: In this cross-sectional study of Medicare beneficiaries, those enrolled in MA had lower rates of low-value care than those enrolled in TM; elements of insurance design present in the MA program and absent in TM were associated with reduction in low-value care.

Comparison of Health Care Utilization by Medicare Advantage and Traditional Medicare Beneficiaries With Complex Care Needs.

Importance: Medicare beneficiaries with co-occurring chronic conditions and complex care needs experience high rates of acute care utilization and poor outcomes. These patterns are well described among traditional Medicare (TM) beneficiaries, but less is known about outcomes among Medicare Advantage (MA) beneficiaries. Compared with TM, MA plans have additional levers to potentially address beneficiary needs, such as network design, care management, supplemental benefits, and value-based contracting. Objective: To compare health care utilization for MA and TM beneficiaries with complex care needs. Design, Setting, and Participants: This cross-sectional study analyzed beneficiaries enrolled in MA and TM using claims data from a large, national MA insurer and a random 5% sample of TM beneficiaries. Beneficiaries were segmented into the following cohorts: frail elderly, major complex chronic, and minor complex chronic. Regression models estimated the association between MA enrollment and health care utilization in 2018, using inverse probability of treatment weighting to balance the MA and TM cohorts on observable characteristics. The study period was January 1, 2017, through December 31, 2018. All analyses were conducted from December 2020 to August 2022. Exposures: Enrollment in MA vs TM. Main Outcomes and Measures: Hospital stays (inpatient admissions and observation stays), emergency department (ED) visits, and 30-day readmissions. Results: Among a study population of 1 844 326 Medicare beneficiaries (mean [SD] age, 75.6 [7.1] years; 1 021 479 [55.4%] women; 1 524 458 [82.7%] White; 223 377 [12.1%] with Medicare-Medicaid dual eligibility), 1 177 896 (63.9%) were enrolled in MA and 666 430 (36.1%) in TM. Beneficiary distribution across cohorts was as follows: frail elderly, 116 047 with MA (10.0% of the MA sample) and 104 036 with TM (15.6% of the TM sample); major complex chronic, 320 954 (27.2%) and 158 811 (23.8%), respectively; and minor complex chronic, 740 895 (62.9%) and 403 583 (60.6%), respectively. Beneficiaries enrolled in MA had lower rates of hospital stays, ED visits, and 30-day readmissions. The largest relative differences were observed for hospital stays, which ranged from -9.3% (95% CI, -10.9% to -7.7%) for the frail elderly cohort to -11.9% (95% CI, -13.2% to -10.7%) for the major complex chronic cohort. Conclusions and Relevance: In this cross-sectional study of Medicare beneficiaries with complex care needs, those enrolled in MA had lower rates of hospital stays, ED visits, and 30-day readmissions than similar beneficiaries enrolled in TM, suggesting that managed care activities in MA may influence the nature and quality of care provided to these beneficiaries.

RNF185 regulates proteostasis in Ebolavirus infection by crosstalk between the calnexin cycle, ERAD, and reticulophagy.

Virus infection affects cellular proteostasis and provides an opportunity to study this cellular process under perturbation. The proteostasis network in the endoplasmic reticulum (ER) is composed of the calnexin cycle, and the two protein degradation pathways ER-associated protein degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD/ER-phagy/reticulophagy). Here we show that calnexin and calreticulin trigger Zaire Ebolavirus (EBOV) glycoprotein GP1,2 misfolding. Misfolded EBOV-GP1,2 is targeted by ERAD machinery, but this results in lysosomal instead of proteasomal degradation. Moreover, the ER Ub ligase RNF185, usually associated with ERAD, polyubiquitinates EBOV-GP1,2 on lysine 673 via ubiquitin K27-linkage. Polyubiquinated GP1,2 is subsequently recruited into autophagosomes by the soluble autophagy receptor sequestosome 1 (SQSTM1/p62), in an ATG3- and ATG5-dependent manner. We conclude that EBOV hijacks all three proteostasis mechanisms in the ER to downregulate GP1,2 via polyubiquitination and show that this increases viral fitness. This study identifies linkages among proteostasis network components previously thought to function independently.

Rapid initiation of nasal saline irrigation to reduce severity in high-risk COVID+ outpatients.

OBJECTIVE: To determine whether initiating saline nasal irrigation after COVID-19 diagnosis reduces hospitalization and death in high-risk outpatients compared with observational controls, and if irrigant composition impacts severity. METHODS: Participants 55 and older were enrolled within 24 hours of a + PCR COVID-19 test between September 24 and December 21, 2020. Among 826 screened, 79 participants were enrolled and randomly assigned to add 2.5 mL povidone-iodine 10% or 2.5 mL sodium bicarbonate to 240 mL of isotonic nasal irrigation twice daily for 14 days. The primary outcome was hospitalization or death from COVID-19 within 28 days of enrollment by daily self-report confirmed with phone calls and hospital records, compared to the CDC Surveillance Dataset covering the same time. Secondary outcomes compared symptom resolution by irrigant additive. RESULTS: Seventy-nine high-risk participants were enrolled (mean [SD] age, 64 [8] years; 36 [46%] women; 71% Non-Hispanic White), with mean BMI 30.3. Analyzed by intention-to-treat, by day 28, COVID-19 symptoms resulted in one ED visit and no hospitalizations in 42 irrigating with alkalinization, one hospitalization of 37 in the povidone-iodine group, (1.27%) and no deaths. Of nearly three million CDC cases, 9.47% were known to be hospitalized, with an additional 1.5% mortality in those without hospitalization data. Age, sex, and percentage with pre-existing conditions did not significantly differ by exact binomial test from the CDC dataset, while reported race and hospitalization rate did. The total risk of hospitalization or death (11%) was 8.57 times that of enrolled nasal irrigation participants (SE = 2.74; P = .006). Sixty-two participants completed daily surveys (78%), averaging 1.8 irrigations/day. Eleven reported irrigation-related complaints and four discontinued use. Symptom resolution was more likely for those reporting twice daily irrigation (X2 = 8.728, P = .0031) regardless of additive. CONCLUSION: SARS-CoV-2+ participants initiating nasal irrigation were over 8 times less likely to be hospitalized than the national rate.

Toward a digital analysis of environmental impacts on rodent mammary gland density during critical developmental windows.

While mammographic breast density is associated with breast cancer risk in humans, there is no comparable surrogate risk measure in mouse and rat mammary glands following various environmental exposures. In the current study, mammary glands from mice and rats subjected to reproductive factors and exposures to environmental chemicals that have been shown to influence mammary gland development and/or susceptibility to mammary tumors were evaluated for histologic density by manual and automated digital methods. Digital histological density detected changes due to hormonal stimuli/reproductive factors (parity), dietary fat, and exposure to environmental chemicals, such as benzophenone-3 and a combination of perfluorooctanoic acid and zeranol. Thus, digital analysis of mammary gland density offers a high throughput method that can provide a highly reproducible means of comparing a measure of histological density across independent experiments, experimental systems, and laboratories. This methodology holds promise for the detection of environmental impacts on mammary gland structure in mice and rats that may be comparable to human breast density, thus potentially allowing comparisons between rodent models and human breast cancer studies.

Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.

Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRC07 (AAV8-VRC07) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial ( NCT03374202 ). AAV8-VRC07 was given at doses of 5 × 1010, 5 × 1011 and 2.5 × 1012 vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRC07; to determine the pharmacokinetics and immunogenicity of in vivo VRC07 production; and to describe the immune response directed against AAV8-VRC07 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRC07 on CD4 T cell count and VL and to assess the persistence of VRC07 produced in participants. In this cohort, IM injection of AAV8-VRC07 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1-3 years of follow-up reported here. In participants who received AAV8-VRC07, concentrations of VRC07 were increased 6 weeks (P = 0.008) and 52 weeks (P = 0.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRC07, with maximal VRC07 concentrations >1 µg ml-1 in three individuals. In four individuals, VRC07 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRC07 was similar to that of in vitro produced VRC07. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRC07. This ADA response appeared to decrease the production of serum VRC07 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases.

Developmental Language Disorder as Syntactic Prediction Impairment.

We provide evidence that children with Developmental Language Disorder (DLD) are impaired in predictive syntactic processing. In the current study, children listened passively to auditorily-presented sentences, where the critical condition included an unexpected "filled gap" in the direct object position of the relative clause verb. A filled gap is illustrated by the underlined phrase in "The zebra that the hippo kissed the camel on the nose…", rather than the expected "the zebra that the hippo kissed [e] on the nose", where [e] denotes the gap. Brain responses to the filled gap were compared to a control condition using adverb-relative clauses with identical substrings: "The weekend that the hippo kissed the camel on the nose [e]…". Here, the same noun phrase is not unexpected because the adverb gap occurs later in the structure. We hypothesized that a filled gap would elicit a prediction error brain signal in the form of an early anterior negativity, as we have previously observed in adults. We found an early (bilateral) anterior negativity to the filled gap in a control group of children with Typical Development (TD), but the children with DLD exhibited no brain response to the filled gap during the same early time window. This suggests that children with DLD fail to predict that a relativized object should correspond to an empty position after the relative clause verb, suggesting an impairment in predictive processing. We discuss how this lack of a prediction error signal can interact with language acquisition and result in DLD.

Protein disulfide isomerases (PDIs) negatively regulate ebolavirus structural glycoprotein expression in the endoplasmic reticulum (ER) via the autophagy-lysosomal pathway.

Zaire ebolavirus (EBOV) causes a severe hemorrhagic fever in humans and non-human primates with high morbidity and mortality. EBOV infection is dependent on its structural glycoprotein (GP), but high levels of GP expression also trigger cell rounding, detachment, and downregulation of many surface molecules that is thought to contribute to its high pathogenicity. Thus, EBOV has evolved an RNA editing mechanism to reduce its GP expression and increase its fitness. We now report that the GP expression is also suppressed at the protein level in cells by protein disulfide isomerases (PDIs). Although PDIs promote oxidative protein folding by catalyzing correct disulfide formation in the endoplasmic reticulum (ER), PDIA3/ERp57 adversely triggered the GP misfolding by targeting GP cysteine residues and activated the unfolded protein response (UPR). Abnormally folded GP was targeted by ER-associated protein degradation (ERAD) machinery and, unexpectedly, was degraded via the macroautophagy/autophagy-lysosomal pathway, but not the proteasomal pathway. PDIA3 also decreased the GP expression from other ebolavirus species but increased the GP expression from Marburg virus (MARV), which is consistent with the observation that MARV-GP does not cause cell rounding and detachment, and MARV does not regulate its GP expression via RNA editing during infection. Furthermore, five other PDIs also had a similar inhibitory activity to EBOV-GP. Thus, PDIs negatively regulate ebolavirus glycoprotein expression, which balances the viral life cycle by maximizing their infection but minimizing their cellular effect. We suggest that ebolaviruses hijack the host protein folding and ERAD machinery to increase their fitness via reticulophagy during infection.Abbreviations: 3-MA: 3-methyladenine; 4-PBA: 4-phenylbutyrate; ACTB: ß-actin; ATF: activating transcription factor; ATG: autophagy-related; BafA1: bafilomycin A1; BDBV: Bundibugyo ebolavirus; CALR: calreticulin; CANX: calnexin; CHX: cycloheximide; CMA: chaperone-mediated autophagy; ConA: concanamycin A; CRISPR: clusters of regularly interspaced short palindromic repeats; Cas9: CRISPR-associated protein 9; dsRNA: double-stranded RNA; EBOV: Zaire ebolavirus; EDEM: ER degradation enhancing alpha-mannosidase like protein; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; Env: envelope glycoprotein; ER: endoplasmic reticulum; ERAD: ER-associated protein degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GP: glycoprotein; HA: hemagglutinin; HDAC6: histone deacetylase 6; HMM: high-molecular-mass; HIV-1: human immunodeficiency virus type 1; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IAV: influenza A virus; IP: immunoprecipitation; KIF: kifenesine; Lac: lactacystin; LAMP: lysosomal associated membrane protein; MAN1B1/ERManI: mannosidase alpha class 1B member 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MARV: Marburg virus; MLD: mucin-like domain; NHK/SERPINA1: alpha1-antitrypsin variant null (Hong Kong); NTZ: nitazoxanide; PDI: protein disulfide isomerase; RAVV: Ravn virus; RESTV: Reston ebolavirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SBOV: Sudan ebolavirus; sGP: soluble GP; SQSTM1/p62: sequestosome 1; ssGP: small soluble GP; TAFV: Taï Forest ebolavirus; TIZ: tizoxanide; TGN: thapsigargin; TLD: TXN (thioredoxin)-like domain; Ub: ubiquitin; UPR: unfolded protein response; VLP: virus-like particle; VSV: vesicular stomatitis virus; WB: Western blotting; WT: wild-type; XBP1: X-box binding protein 1.

Initial Single-Center ST-Segment Elevation Myocardial Infarction Experience in New York Before and During the COVID-19 Pandemic.

BACKGROUND/PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a highly contagious and lethal virus, devastating healthcare systems throughout the world. Following a period of stability, the coronavirus disease 2019 (COVID-19) pandemic appears to be re-intensifying globally. As the virus continues to evolve, so does our understanding of its implications on ST-segment elevation myocardial infarction (STEMI). We sought to describe a single center STEMI experience at one of the epicenters during the COVID-19 pandemic. METHODS/MATERIALS: We conducted a retrospective, observational study comparing STEMI patients during the pandemic period (March 1 to August 31, 2020) to those with STEMI during the pre-pandemic period (March 1 to August 31, 2019) at NYU Langone Hospital - Long Island, a tertiary-care center in Nassau County, New York. Additionally, we describe our subset of COVID-19 patients with STEMI during the pandemic. RESULTS: The acute myocardial infarction (AMI) team was activated for 183 patients during both periods. There were a similar number of AMI team activations during the pandemic period (n = 93) compared to the pre-pandemic period (n = 90). Baseline characteristics did not differ during both periods; however, infection control measures and additional investigation were required to clarify the diagnosis during the pandemic, resulting in a signal toward longer door-to-balloon times (95.9 min vs. 74.4 min, p = 0.0587). We observed similar inpatient length of stay (LOS) (3.6 days vs. 5.0 days, p = 0.0901) and mortality (13.2% vs. 9.2%, p = 0.5876). There were 6 COVID-19-positive patients who presented with STEMI, of whom 4 were emergently taken to the cardiac catheterization laboratory with successful percutaneous coronary intervention (PCI) performed in 3 patients. The 2 patients who were not offered primary PCI expired, as both were treated medically, one with thrombolytics. CONCLUSIONS: Our single-center study, in New York, at one of the epicenters of the pandemic, demonstrated a similar number of AMI team activations, mimicking the seasonal variability seen in 2019, but with a signal toward longer door-to-balloon time. Despite this, inpatient LOS and mortality remained similar.

The Association between Sex Hormones, Pubertal Milestones and Benzophenone-3 Exposure, Measured by Urinary Biomarker or Questionnaire.

Experimental studies have suggested benzophenone-3 (BP-3), a sunscreen ingredient, may have endocrine-disrupting properties. A cohort of girls were recruited at ages 6-7 years and returned semi-annually for pubertal maturation staging, provided blood for serum hormone analyses [estradiol, estrone, testosterone, dehydroepiandrosterone-sulfate (DHEA-S)], and urine to measure BP-3 concentrations. We found a significant negative linear association between amount of reported sunscreen use and testosterone levels at the onset of puberty (N = 157, adjusted ß = -0.0163, 97.5% CI:-0.0300,-0.0026). The 2nd quartile of the BP-3 biomarker had earlier thelarche compared to the 1st quartile (N = 282, adjusted HR = 1.584, 97.5% CI:1.038,2.415). Results suggest that higher report of sunscreen use may be associated with lower testosterone levels at thelarche and a non-linear relationship between the BP-3 urinary biomarker and onset of puberty, although the clinical significance of the finding is limited and may be a random effect. Improved methods of BP-3 exposure characterization are needed.

A Comparison of Home Health Utilization, Outcomes, and Cost Between Medicare Advantage and Traditional Medicare.

BACKGROUND: Home health use is rising rapidly in the United States as the population ages, the prevalence of chronic disease increases, and older Americans express their desire to age at home. Enrollment in Medicare Advantage (MA) plans rather than Traditional Medicare (TM) has grown as well, from 13% of total Medicare enrollment in 2004 to 39% in 2020. Despite these shifts, little is known about outcomes and costs following home health in MA as compared with TM. OBJECTIVE: The objective of this study was to measure the association of MA enrollment with outcomes and costs for patients using home health. DESIGN: This was a retrospective cohort study. PARTICIPANTS: Patients enrolled in plans offered by 1 large, national MA organization and patients enrolled in TM, with at least 1 home health visit between January 1, 2017, and June 30, 2018. EXPOSURE: MA enrollment. MAIN MEASURES: We compared the intensity of home health services and types of care delivered. The main outcome measures were hospitalization, the proportion of days in the home, and total allowed costs during the 180-day period following the first qualifying home health visit during the study period. KEY RESULTS: Among patients who used home health, our models demonstrated enrollment in MA was associated with 14%, and 6% decreased odds of 60- and 180-day hospitalization, respectively, a 12.8% and 14.7% decrease in medical costs exclusive and inclusive of home health costs, respectively, and a 0.27% increase in the proportion of days at home during the 180-day follow-up, equivalent to an additional half-day at home. There were few differences in home health care delivered for MA and TM [mean number of visits in the first episode of care (17.1 vs. 17.3) and mean visits per week (3.2 vs. 3.3)]. The mean number of visits by visit type and percent of patients with each type was similar between MA and TM as well. CONCLUSIONS: Compared with enrollment in TM, enrollment in MA was associated with improved patient-centered outcomes and lower cost and utilization, despite few differences in the way home health was delivered. These findings might be explained by structural components of MA that encourage better care management, but further investigation is needed to clarify the mechanisms by which MA enrollment may lead to higher value home health care.

Femoral Injury Over the Site of Spontaneous Regression of an Osteochondroma in a Teenage Athlete.

ABSTRACT: The spontaneous regression of an osteochondroma is extremely rare. We report a case of medial femoral condyle impaction fracture over the site of spontaneous regression of a pedunculated osteochondroma discovered on advanced imaging after an acute injury in a 16-year-old male American football athlete. Although spontaneous regression of an osteochondroma has been described, the case presented reveals questions regarding resultant architectural changes to the bone after resorption, leaving it prone to injury. This is the first case that describes increased injury risk potential at the site of osteochondral regression.