Treatment patterns of galcanezumab versus standard of care preventive migraine medications over 24 months: a US retrospective claims study.

OBJECTIVE: To describe long-term (24-month) treatment patterns of patients initiating galcanezumab versus standard of care (SOC) preventive migraine treatments including anticonvulsants, beta-blockers, antidepressants, and onabotulinumtoxinA using administrative claims data. METHODS: This retrospective cohort study, which used Optum de-identified Market Clarity data, included adults with migraine with ≥1 claim for galcanezumab or SOC preventive migraine therapy (September 1, 2018 - March 31, 2020) and continuous database enrollment for 12 months before (baseline) and 24 months after (follow-up) the index date (date of first claim). Baseline patient demographics, clinical characteristics, and treatment patterns were analyzed after 24-month follow-up, including adherence (measured as the proportion of days covered [PDC]), persistence, discontinuation (≥60-day gap), restart, and treatment switch. Propensity score matching (1:1) was used to balance the galcanezumab and SOC cohorts. RESULTS: The study included 2307 matched patient pairs with 24-month follow-up. The mean age across cohorts was 44.5 years (females: ∼87%). Patients in the galcanezumab versus SOC cohort demonstrated greater treatment adherence (PDC: 48% vs. 38%), with more patients considered adherent (PDC ≥80%: 26.6% vs. 20.7%) and persistent (322.1 vs. 236.4 d) (all p < .001). After 24-month follow-up, fewer galcanezumab-treated patients had discontinued compared with SOC-treated patients (80.1% vs. 84.7%; p < .001), of which 41.3% and 39.6% switched to a non-index medication, respectively. The most prevalent medication patients switched to in both cohorts was erenumab. Significantly greater proportions of patients who initiated galcanezumab versus SOC medications switched to fremanezumab (p < .001) and onabotulinumtoxinA (p = .016). CONCLUSION: Patients who initiated galcanezumab for migraine prevention had higher treatment adherence and persistence compared with those who initiated SOC medications after 24-month follow-up.

Only few patients (3 − 13%) with migraine, who qualify for preventive treatment, are using them. Conventional preventive treatments have not been developed specifically for migraine treatment, and more than half of the patients stop using them prematurely. Calcitonin gene-related peptide monoclonal antibodies such as galcanezumab, fremanezumab, and erenumab are newer treatments that provide migraine-specific preventive treatment. Prior studies have compared 6- to 12-month migraine medication use by patients starting galcanezumab versus those starting traditional standard of care (SOC) migraine preventive medications. We compared long-term (24-month) migraine medication use in patients starting galcanezumab versus those starting SOC migraine preventive medications to confirm if the results are sustained over a longer period. Over 24 months, patients who used galcanezumab followed the prescribed treatment regimen to a greater extent compared with those who used SOC medications (48% vs. 38%, respectively). Additionally, patients using galcanezumab continued treatment for a longer time compared with those using SOC. Over 24 months, about 85% of patients stopped taking SOC medications, while around 80% of patients stopped taking galcanezumab. Our findings indicate that patients with migraine are more likely to continue using galcanezumab as a preventive treatment for a longer period compared with SOC medications. This study helps identify gaps in the preventive treatment of migraine and provides insights on how they are not being used enough.

The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions.

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome.

Factors influencing the successful implementation of a novel digital health application to streamline multidisciplinary communication across multiple organisations for emergency care.

RATIONALE: Delivering optimal patient health care requires interdisciplinary clinician communication. A single communication tool across multiple pre-hospital and hospital settings, and between hospital departments is a novel solution to current systems. Fit-for-purpose, secure smartphone applications allow clinical information to be shared quickly between health providers. Little is known as to what underpins their successful implementation in an emergency care context. AIMS: To identify (a) whether implementing a single, digital health communication application across multiple health care organisations and hospital departments is feasible; (b) the barriers and facilitators to implementation; and (c) which factors are associated with clinicians' intentions to use the technology. METHODS: We used a multimethod design, evaluating the implementation of a secure, digital communication application (Pulsara™). The technology was trialled in two Australian regional hospitals and 25 Ambulance Victoria branches (AV). Post-training, clinicians involved in treating patients with suspected stroke or cardiac events were administered surveys measuring perceived organisational readiness (Organisational Readiness for Implementing Change), clinicians' intentions (Unified Theory of Acceptance and Use of Technology) and internal motivations (Self-Determination Theory) to use Pulsara™, and the perceived benefits and barriers of use. Quantitative data were descriptively summarised with multivariable associations between factors and intentions to use Pulsara™ examined with linear regression. Qualitative data responses were subjected to directed content analysis (two coders). RESULTS: Participants were paramedics (n = 82, median 44 years) or hospital-based clinicians (n = 90, median 37 years), with organisations perceived to be similarly ready. Regression results (F(11, 136) = 21.28, p = <0.001, Adj R2 = 0.60) indicated Habit, Effort Expectancy, Perceived Organisational Readiness, Performance Expectancy and Organisation membership (AV) as predictors of intending to use Pulsara™. Themes relating to benefits (95% coder agreement) included improved communication, procedural efficiencies and faster patient care. Barriers (92% coder agreement) included network accessibility and remembering passwords. PulsaraTM was initiated 562 times. CONCLUSION: Implementing multiorganisational, digital health communication applications is feasible, and facilitated when organisations are change-ready for an easy-to-use, effective solution. Developing habitual use is key, supported through implementation strategies (e.g., hands-on training). Benefits should be emphasised (e.g., during education sessions), including streamlining communication and patient flow, and barriers addressed (e.g., identify champions and local technical support) at project commencement.

Fertility care for all: impact of New York State's Medicaid expansion on infertility care.

PURPOSE: To assess whether the New York State (NYS) mandate expanding Medicaid coverage of fertility diagnostic testing and treatment is successfully increasing patient access to and utilization of fertility care. METHODS: A retrospective chart review was performed of NYS Medicaid patients who presented for fertility services to a large academic reproductive endocrinology and infertility (REI) clinic. Information on patient demographics, medical history, diagnostic testing, treatments, and outcomes was collected. Patients presenting to the clinic in the 1 year prior to the mandate (October 1, 2018-September 30, 2019) were compared to patients presenting in the 1 year after the mandate (October 1, 2019-September 30, 2020). Primary outcomes of the study were differences in presentation to the clinic between the two cohorts and differences in utilization of infertility diagnostic testing and treatment. Secondary outcomes were differences in treatment outcomes. RESULTS: A significantly larger percentage of Medicaid patients presented to the clinic for fertility assessment post-mandate (22%) as compared to pre-mandate (9%, p < 0.05). There were no demographic differences between the pre- and post-mandate patient groups. A similar percentage of patients completed diagnostic testing pre- vs. post-mandate. Post-mandate patients underwent more treatment cycles with ovulation induction medications compared to natural treatment cycles. There was no significant difference in pregnancy rates pre- vs. post-mandate. CONCLUSION: The NYS Medicaid mandate allowed a significantly larger percentage of Medicaid patients to present for fertility evaluation. The patients in the post-mandate cohort underwent more treatment cycles with ovulation induction medications compared to natural cycles.

SARS-CoV-2 hijacks fragile X mental retardation proteins for efficient infection.

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1 and FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and have delayed disease onset in vivo. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins for efficient infection and provides molecular insight to the possible underlying molecular defects in fragile X syndrome.

Identifying barriers individuals face in accessing fertility care after a gynecologic cancer diagnosis.

Objective: To (1) identify the major barriers premenopausal individuals face in accessing fertility care at the time of gynecologic cancer diagnosis and (2) to assess patient experiences pertaining to fertility. Methods: We distributed an online survey about cancer diagnosis and fertility goals to patients ages 18-40 who had been treated for ovarian, endometrial, or cervical cancer at a single, large academic hospital. Descriptive statistics were used to analyze survey results. Patients who completed the survey were given the option to participate in a follow-up virtual interview. We conducted semi-structured interviews to discuss their fertility goals and barriers to these. Grounded theory was used to qualitatively analyze the interviews. Results: Fifty-five patients completed the survey, and 20 patients participated in the interview. The median age at diagnosis was 32 years old. Seventy-three percent of patients recalled that at the time of their diagnosis they were considering future childbearing, and 32% underwent fertility preservation. Patients reported the emotional response to their diagnosis as a barrier to receiving fertility care, with patients reporting lack of control (80%), shock (55%), and confusion (45%). Patients also identified inadequate counseling (60.0%), lack of time (60.0%), economic constraints (55.0%) and prioritization of cancer treatment (55.0%) as barriers. Nearly all patients had a positive interview experience and expressed desire to help patients in similar situations. Conclusion: Many premenopausal patients diagnosed with gynecologic malignancies are considering future childbearing at the time of diagnosis. Both logistical and emotional barriers prevent them from undergoing fertility preservation before initiating oncologic treatment.

Loss-of-function mutation in Omicron variants reduces spike protein expression and attenuates SARS-CoV-2 infection.

SARS-CoV-2 Omicron variants emerged in 2022 with >30 novel amino acid mutations in the spike protein alone. While most studies focus on receptor binding domain changes, mutations in the C-terminus of S1 (CTS1), adjacent to the furin cleavage site, have largely been ignored. In this study, we examined three Omicron mutations in CTS1: H655Y, N679K, and P681H. Generating a SARS-CoV-2 triple mutant (YKH), we found that the mutant increased spike processing, consistent with prior reports for H655Y and P681H individually. Next, we generated a single N679K mutant, finding reduced viral replication in vitro and less disease in vivo. Mechanistically, the N679K mutant had reduced spike protein in purified virions compared to wild-type; spike protein decreases were further exacerbated in infected cell lysates. Importantly, exogenous spike expression also revealed that N679K reduced overall spike protein yield independent of infection. Although a loss-of-function mutation, transmission competition demonstrated that N679K had a replication advantage in the upper airway over wild-type SARS-CoV-2 in hamsters, potentially impacting transmissibility. Together, the data show that N679K reduces overall spike protein levels during Omicron infection, which has important implications for infection, immunity, and transmission.

Comparison of hospitalization costs for the same adverse reaction associated with different medications.

PURPOSE: Costs of hospitalization due to severe adverse drug reactions (ADRs) were previously estimated within the Veterans Health Administration (VHA), but additional analyses are needed to infer potential interventions to mitigate these negative outcomes. The objective of this study was to compare specific adverse reaction-related hospitalization costs between medications with similar indications. METHODS: Mean hospitalization costs associated with the same ADR symptom were compared for different drugs with similar indications using adjusted generalized linear models with a Bonferroni correction for multiple comparisons as well as a gamma distribution. RESULTS: Overall, hospitalization costs between medications with similar indications were not significantly different for specific adverse reactions. However, gastrointestinal hemorrhage-associated costs were higher for warfarin versus nonsteroidal anti-inflammatory drugs (model estimate of mean cost, $18,114 [range of lower and upper model estimates, $12,522-$26,202] vs $14,255 [estimate range, $9,710-$20,929]). Similarly, the estimated mean hospitalization cost associated with angioedema was higher for losartan versus lisinopril or lisinopril/hydrochlorothiazide: $14,591 (range, $9467-$22,488) versus $8,935 (range, $6,301-$12,669) and $8,022 (range, $5,424-$11,865), respectively. CONCLUSION: Although we found few differences in the cost of hospitalization when comparing drugs with similar indications and the same adverse reaction, there were specific drug-ADR pairs that merit attention and consideration of interventions to improve safe and appropriate medication use. Evaluation of the effect of those interventions on the incidence of ADRs is an area for future study.

Comparison of surgery rates in biologic-naïve patients with Crohn's disease treated with vedolizumab or ustekinumab: findings from SOJOURN.

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory bowel disease characterized by relapsing and remitting inflammation that leads to progressive bowel damage. Despite advances in medical treatment for CD, many patients require surgical intervention. Most studies of surgery rates are from patients treated with anti-tumor necrosis factor alpha (anti-TNFα) treatments, with comparatively little data on the surgery rates of patients treated with vedolizumab and ustekinumab. SOJOURN aimed to estimate the hazard rate and incidence of the first CD-related surgery following initiation of treatment with vedolizumab or ustekinumab in biologic-naïve patients with CD. METHODS: SOJOURN was a retrospective, observational cohort study examining administrative claims data from the Optum® Research Database between July 1, 2017 and March 31, 2020. Included participants were adults with a diagnosis of CD and a claim for vedolizumab or ustekinumab (defined as the index treatment) between January 1, 2018 and December 31, 2019, with no claims for a biologic in the 6 months before initiation of this treatment. The variable follow-up started on the day after the index date and continued until whichever came first of discontinuation of the index treatment, surgery event, switching of the index treatment, initiation of combination biologic treatment, disenrollment, or March 31, 2020. The time to the first CD-related surgery on biologic treatment was estimated by Kaplan-Meier analysis. The hazard ratio and incidence rate ratio of CD-related surgery for each treatment cohort was compared using a Cox proportional hazards model and a Poisson regression model, respectively. RESULTS: Of the 1,122 included patients, 578 received vedolizumab and 544 received ustekinumab. After 1 year of the variable follow-up, 7.7% of patients receiving vedolizumab and 11.6% of patients receiving ustekinumab had undergone a CD-related surgery. Vedolizumab was associated with a 34.2% lower hazard rate of surgery (hazard ratio 0.658, 95% confidence interval [CI] 0.436-0.994, p = 0.047) and a 34.5% lower incidence of surgery (rate ratio 0.655, 95% CI 0.434-0.988, p = 0.044) than ustekinumab. CONCLUSIONS: This real-world analysis of biologic-naïve patients with CD suggests that vedolizumab is associated with greater effectiveness in reducing the rate of CD-related surgery than ustekinumab.

Increased delay from initial concern to diagnosis of autism spectrum disorder and associated health care resource utilization and cost among children aged younger than 6 years in the United States.

BACKGROUND: Prolonged delays between first caregiver concern and autism spectrum disorder (ASD) diagnosis have been reported, but associations between length of time to diagnosis (TTD) and health care resource utilization (HCRU) and costs have not been studied in a large sample of children with ASD. OBJECTIVE: To address these informational gaps in the ASD diagnostic pathway. METHODS: This retrospective, observational, single cohort analysis of Optum's administrative claims data from January 1, 2011, to December 31, 2020, included commercially insured children who had 2 or more claims for an ASD diagnosis (earliest diagnosis designated as the index date), were between the ages of older than 1.5 years and 6 years or younger at index date, and were continuously enrolled for up to 48 months before and for 12 months after the index date. Two cohorts (between the ages of older than 1.5 years and 3 years or younger and between the ages of older than 3 years and 6 years or younger at ASD diagnosis) were divided into shorter (less than median) and longer (greater than or equal to median) TTD around each cohort median TTD calculated from the first documented ASD-related concern to the earliest ASD diagnosis, because TTD may vary by age at diagnosis. This exploratory analysis compared all-cause and ASD-related HCRU and costs during a 12-month period preceding ASD diagnosis among children with shorter vs longer TTD. RESULTS: 8,954 children met selection criteria: 4,205 aged 3 years or younger and 4,749 aged older than 3 years at diagnosis, with median TTD of 9.5 and 22.1 months, respectively. In the year preceding ASD diagnosis, children with longer TTD in both age cohorts experienced a greater number of all-cause and ASD-related health care visits compared with those with shorter TTD (mean and median number of office or home visits were approximately 1.5- and 2-fold greater in longer vs shorter TTD groups; P < 0.0001). The mean all-cause medical cost per child in the year preceding ASD diagnosis was approximately 2-fold higher for those with longer vs shorter TTD ($5,268 vs $2,525 in the younger and $5,570 vs $2,265 in the older cohort; P < 0.0001 for both). Mean ASD-related costs were also higher across age cohorts for those with longer vs shorter TTD ($2,355 vs $859 in the younger and $2,351 vs $1,144 in the older cohort; P < 0.0001 for both). CONCLUSIONS: In the year prior to diagnosis, children with longer TTD experienced more frequent health care visits and greater cost burden in their diagnostic journey compared with children with shorter TTD. Novel diagnostic approaches that could accelerate TTD may reduce costs and HCRU for commercially insured children. DISCLOSURES: This study was funded by Cognoa, Inc. Optum received funding from Cognoa to conduct this study. Dr Salomon is an employee and holds stock options of Cognoa, Inc. Dr Campbell was an employee of Cognoa, Inc., at the time this study was conducted. Dr Duhig was an employee of Cognoa, Inc., at the time the study was conducted and holds stock options. Dr Vu, Ms Kruse, Mr Gaur, and Ms Gupta are employees and/or stockholders of Optum. Dr Tibrewal was an employee of Optum at the time the research for this study was conducted. Dr Taraman is an employee and holds stock options of Cognoa, Inc., receives consulting fees from Cognito Therapeutics, volunteers as a board member of the American Academy of Pediatrics California and Orange County Chapter, is a paid advisor for MI10 LLC, and owns stock options of NTX, Inc., and HandzIn.

SARS-CoV-2 Uses Nonstructural Protein 16 To Evade Restriction by IFIT1 and IFIT3.

Understanding the molecular basis of innate immune evasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important consideration for designing the next wave of therapeutics. Here, we investigate the role of the nonstructural protein 16 (NSP16) of SARS-CoV-2 in infection and pathogenesis. NSP16, a ribonucleoside 2'-O-methyltransferase (MTase), catalyzes the transfer of a methyl group to mRNA as part of the capping process. Based on observations with other CoVs, we hypothesized that NSP16 2'-O-MTase function protects SARS-CoV-2 from cap-sensing host restriction. Therefore, we engineered SARS-CoV-2 with a mutation that disrupts a conserved residue in the active site of NSP16. We subsequently show that this mutant is attenuated both in vitro and in vivo, using a hamster model of SARS-CoV-2 infection. Mechanistically, we confirm that the NSP16 mutant is more sensitive than wild-type SARS-CoV-2 to type I interferon (IFN-I) in vitro. Furthermore, silencing IFIT1 or IFIT3, IFN-stimulated genes that sense a lack of 2'-O-methylation, partially restores fitness to the NSP16 mutant. Finally, we demonstrate that sinefungin, an MTase inhibitor that binds the catalytic site of NSP16, sensitizes wild-type SARS-CoV-2 to IFN-I treatment and attenuates viral replication. Overall, our findings highlight the importance of SARS-CoV-2 NSP16 in evading host innate immunity and suggest a target for future antiviral therapies. IMPORTANCE Similar to other coronaviruses, disruption of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP16 function attenuates viral replication in a type I interferon-dependent manner. In vivo, our results show reduced disease and viral replication at late times in the hamster lung, but an earlier titer deficit for the NSP16 mutant (dNSP16) in the upper airway. In addition, our results confirm a role for IFIT1 but also demonstrate the necessity of IFIT3 in mediating dNSP16 attenuation. Finally, we show that targeting NSP16 activity with a 2'-O-methyltransferase inhibitor in combination with type I interferon offers a novel avenue for antiviral development.

Positive-strand RNA viruses-a Keystone Symposia report.

Positive-strand RNA viruses have been the cause of several recent outbreaks and epidemics, including the Zika virus epidemic in 2015, the SARS outbreak in 2003, and the ongoing SARS-CoV-2 pandemic. On June 18-22, 2022, researchers focusing on positive-strand RNA viruses met for the Keystone Symposium "Positive-Strand RNA Viruses" to share the latest research in molecular and cell biology, virology, immunology, vaccinology, and antiviral drug development. This report presents concise summaries of the scientific discussions at the symposium.

A deep learning platform to assess drug proarrhythmia risk.

Drug safety initiatives have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an in vitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of in vitro arrhythmia predict actual clinical risk has been much debated. Here, we trained a convolutional neural network classifier (CNN) to learn features of in vitro action potential recordings of hiPSC-CMs that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia in people. The risk profile of the test drugs was similar across hiPSC-CMs derived from different healthy donors. In contrast, pathogenic mutations that cause arrhythmogenic cardiomyopathies in patients significantly increased the proarrhythmic propensity to certain intermediate and high-risk drugs in the hiPSC-CMs. Thus, deep learning can identify in vitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of patient genetics on the risk of drug-induced arrhythmia.

Enterovirus-Cardiomyocyte Interactions: Impact of Terminally Deleted Genomic RNAs on Viral and Host Functions.

Group B enteroviruses, including coxsackievirus B3 (CVB3), can persistently infect cardiac tissue and cause dilated cardiomyopathy. Persistence is linked to 5' terminal deletions of viral genomic RNAs that have been detected together with minor populations of full-length genomes in human infections. In this study, we explored the functions and interactions of the different viral RNA forms found in persistently infected patients and their putative role(s) in pathogenesis. Since enterovirus cardiac pathogenesis is linked to the viral proteinase 2A, we investigated the effect of different terminal genomic RNA deletions on 2A activity. We discovered that 5' terminal deletions in CVB3 genomic RNAs decreased the levels of 2A proteinase activity but could not abrogate it. Using newly generated viral reporters encoding nano-luciferase, we found that 5' terminal deletions resulted in decreased levels of viral protein and RNA synthesis in singly transfected cardiomyocyte cultures. Unexpectedly, when full-length and terminally deleted forms were cotransfected into cardiomyocytes, a cooperative interaction was observed, leading to increased viral RNA and protein production. However, when viral infections were carried out in cells harboring 5' terminally deleted CVB3 RNAs, a decrease in infectious particle production was observed. Our results provide a possible explanation for the necessity of full-length viral genomes during persistent infection, as they would stimulate efficient viral replication compared to that of the deleted genomes alone. To avoid high levels of viral particle production that would trigger cellular immune activation and host cell death, the terminally deleted RNA forms act to limit the production of viral particles, possibly as trans-dominant inhibitors. IMPORTANCE Enteroviruses like coxsackievirus B3 are able to initiate acute infections of cardiac tissue and, in some cases, to establish a long-term persistent infection that can lead to serious disease sequelae, including dilated cardiomyopathy. Previous studies have demonstrated the presence of 5' terminally deleted forms of enterovirus RNAs in heart tissues derived from patients with dilated cardiomyopathy. These deleted RNAs are found in association with very low levels of full-length enterovirus genomic RNAs, an interaction that may facilitate continued persistence while limiting virus particle production. Even in the absence of detectable infectious virus particle production, these deleted viral RNA forms express viral proteinases at levels capable of causing viral pathology. Our studies provide mechanistic insights into how full-length and deleted forms of enterovirus RNA cooperate to stimulate viral protein and RNA synthesis without stimulating infectious viral particle production. They also highlight the importance of targeting enteroviral proteinases to inhibit viral replication while at the same time limiting the long-term pathologies they trigger.

Outpatient treatment and clinical outcomes of bacteriuria in veterans: A retrospective cohort analysis.

Objective: To conduct a contemporary detailed assessment of outpatient antibiotic prescribing and outcomes for positive urine cultures in a mixed-sex cohort. Design: Multicenter retrospective cohort review. Setting: The study was conducted using data from 31 Veterans' Affairs medical centers. Patients: Outpatient adults with positive urine cultures. Methods: From 2016 to 2019, data were extracted through a nationwide database and manual chart review. Positive urine cultures were reviewed at the chart, clinician, and aggregate levels. Cases were classified as cystitis, pyelonephritis, or asymptomatic bacteriuria (ASB) based upon documented signs and symptoms. Preferred therapy definitions were applied for subdiagnoses: ASB (no antibiotics), cystitis (trimethoprim-sulfamethoxazole, nitrofurantoin, ß-lactams), and pyelonephritis (trimethoprim-sulfamethoxazole, fluoroquinolone). Outcomes included 30-day clinical failure or hospitalization. Odds ratios for outcomes between treatments were estimated using logistic regression. Results: Of 3,255 cases reviewed, ASB was identified in 1,628 cases (50%), cystitis was identified in 1,156 cases (36%), and pyelonephritis was identified in 471 cases (15%). Of all 2,831 cases, 1,298 (46%) received preferred therapy selection and duration for cases where it could be defined. The most common antibiotic class prescribed was a fluoroquinolone (34%). Patients prescribed preferred therapy had lower odds of clinical failure: preferred (8%) versus nonpreferred (10%) (unadjusted OR, 0.74; 95% confidence interval [CI], 0.58-0.95; P = .018). They also had lower odds of 30-day hospitalization: preferred therapy (3%) versus nonpreferred therapy (5%) (unadjusted OR, 0.55; 95% CI, 0.37-0.81; P = .002). Odds of clinical treatment failure or hospitalization was higher for ß-lactams relative to ciprofloxacin (unadjusted OR, 1.89; 95% CI, 1.23-2.90; P = .002). Conclusions: Clinicians prescribed preferred therapy 46% of the time. Those prescribed preferred therapy had lower odds of clinical failure and of being hospitalized.

SARS-CoV-2 Uses Nonstructural Protein 16 to Evade Restriction by IFIT1 and IFIT3.

Understanding the molecular basis of innate immune evasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important consideration for designing the next wave of therapeutics. Here, we investigate the role of the nonstructural protein 16 (NSP16) of SARS-CoV-2 in infection and pathogenesis. NSP16, a ribonucleoside 2'- O methyltransferase (MTase), catalyzes the transfer of a methyl group to mRNA as part of the capping process. Based on observations with other CoVs, we hypothesized that NSP16 2'- O MTase function protects SARS-CoV-2 from cap-sensing host restriction. Therefore, we engineered SARS-CoV-2 with a mutation that disrupts a conserved residue in the active site of NSP16. We subsequently show that this mutant is attenuated both in vitro and in vivo , using a hamster model of SARS-CoV-2 infection. Mechanistically, we confirm that the NSP16 mutant is more sensitive to type I interferon (IFN-I) in vitro . Furthermore, silencing IFIT1 or IFIT3, IFN-stimulated genes that sense a lack of 2'- O methylation, partially restores fitness to the NSP16 mutant. Finally, we demonstrate that sinefungin, a methyltransferase inhibitor that binds the catalytic site of NSP16, sensitizes wild-type SARS-CoV-2 to IFN-I treatment. Overall, our findings highlight the importance of SARS-CoV-2 NSP16 in evading host innate immunity and suggest a possible target for future antiviral therapies. Importance: Similar to other coronaviruses, disruption of SARS-CoV-2 NSP16 function attenuates viral replication in a type I interferon-dependent manner. In vivo , our results show reduced disease and viral replication at late times in the hamster lung, but an earlier titer deficit for the NSP16 mutant (dNSP16) in the upper airway. In addition, our results confirm a role for IFIT1, but also demonstrate the necessity of IFIT3 in mediating dNSP16 attenuation. Finally, we show that targeting NSP16 activity with a 2'- O methyltransferase inhibitor in combination with type I interferon offers a novel avenue for antiviral development.

See one, do one, teach one: Reimagining reproductive endocrinology and infertility training programs to expand access to care.

Objective: To provide a review of the current literature surrounding barriers to reproductive medicine and present examples of how resident and fellow education can be used to overcome these barriers. Design: A review of the relevant literature addressing barriers to reproductive medicine, resident and fellow education, and related materials was completed. Setting: Academic medical institutions. Patients: None. Interventions: None. Main Outcome Measures: Health disparities and barriers in access to care. Results: Of barriers in access to care, 3 were reviewed in detail: cost of health care, racial inequities, and marginalization of immigrant communities. The suggested strategies to mitigate these barriers include the following: reducing racial inequities through improved diversity within reproductive medicine and through antiracism training, developing opportunities for trainees to engage in advocacy, strengthening reproductive endocrinology and infertility clinical exposure and educational curricula in training programs, inclusion of residents and fellows in clinical care, and improving the accessibility of fertility care through implementing approaches to optimize the management of infertility in challenging, resource-constrained settings. Conclusions: Infertility is one of the most prevalent reproductive health diseases, yet profound disparities and inequities in access to care exist today in the United States. Lower-income, minority, and immigrant communities are among those most marginalized. Improved access to care begins with broadened obstetrics and gynecology and reproductive endocrinology and infertility trainee education, which acknowledges the barriers these communities face and provides strategies to help overcome these obstacles to care.

Provision of infertility care for the underserved in reproductive endocrinology and infertility practices associated with obstetrics and gynecology residency training programs in the United States.

Objective: To survey practice patterns designed to increase access to infertility care and evaluate the exposure of obstetrics and gynecology residents to infertility care for the underserved. Design: Cross-sectional. Setting: Reproductive endocrinology and infertility (REI) practices associated with Accreditation Council for Graduate Medical Education-accredited obstetrics and gynecology residency training programs. Patients: None. Interventions: Questionnaire survey. Main Outcome Measures: Presence of clinical programs designed to improve access to REI care, resident involvement in such programs, and perceived barriers to expanding access to care. Results: Clinical initiatives to expand access included discounted infertility services (38%, n = 30), utilization of a low-cost in vitro fertilization (IVF) program (28%, n = 22), and utilization of a resident- and/or fellow-staffed clinic to provide infertility care (39%, n = 31). The most commonly discounted infertility services were IVF (73%, n = 22), clinical consultation (70%, n = 21), and intrauterine insemination (53%, n = 16). The provision of discounted prices was correlated with the increasing practice size (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.23-4.24) and number of assisted reproductive technology cycles performed annually (OR, 3.65; 95% CI, 1.48-9.02). Academic REI practices (OR, 3.6; 95% CI, 0.98-13.25) were more likely to have a low-cost IVF program. Less than half of obstetrics and gynecology residency programs (39%, n = 31) had an associated REI clinic in which obstetrics and gynecology residents provide direct infertility care to the medically underserved. Frequency and services offered in trainee clinics varied. Multiple barriers to expanding access to care were reported. Conclusions: Reproductive endocrinology and infertility practices associated with obstetrics and gynecology residency programs utilize a diverse range of approaches to provide infertility care to the underserved in the backdrop of considerable challenges and barriers, but significant gaps persist.

Asian Americans and infertility: genetic susceptibilities, sociocultural stigma, and access to care.

Infertility affects over 6 million people in the United States and has been shown to disproportionally affect minority patient populations. Asian American infertility is a particularly understudied area of research. This mini review article explores the current state of published research focusing on Asian American infertility trends as well as their barriers to fertility care. A small number of published studies have found that Asian American patients have decreased success with fertility treatments, including lower rates of pregnancy and live birth. These trends may be attributed to a combination of genetic, environmental, and cultural factors, which will be discussed here in further detail. It is crucial to continue building on Asian American fertility research to provide this diverse patient population with comprehensive, compassionate, and culturally sensitive care.

Real-world, feasibility study to investigate the use of a multidisciplinary app (Pulsara) to improve prehospital communication and timelines for acute stroke/STEMI care.

OBJECTIVES: To determine if a digital communication app improves care timelines for patients with suspected acute stroke/ST-elevation myocardial infarction (STEMI). DESIGN: Real-world feasibility study, quasi-experimental design. SETTING: Prehospital (25 Ambulance Victoria branches) and within-hospital (2 hospitals) in regional Victoria, Australia. PARTICIPANTS: Paramedics or emergency department (ED) clinicians identified patients with suspected acute stroke (onset <4.5 hours; n=604) or STEMI (n=247). INTERVENTION: The Pulsara communication app provides secure, two-way, real-time communication. Assessment and treatment times were recorded for 12 months (May 2017-April 2018), with timelines compared between 'Pulsara initiated' (Pulsara) and 'not initiated' (no Pulsara). PRIMARY OUTCOME MEASURE: Door-to-treatment (needle for stroke, balloon for STEMI) Secondary outcome measures: ambulance and hospital processes. RESULTS: Stroke (no Pulsara n=215, Pulsara n=389) and STEMI (no Pulsara n=76, Pulsara n=171) groups were of similar age and sex (stroke: 76 vs 75 years; both groups 50% male; STEMI: 66 vs 63 years; 68% and 72% male). When Pulsara was used, patients were off ambulance stretcher faster for stroke (11(7, 17) vs 19(11, 29); p=0.0001) and STEMI (14(7, 23) vs 19(10, 32); p=0.0014). ED door-to-first medical review was faster (6(2, 14) vs 23(8, 67); p=0.0001) for stroke but only by 1 min for STEMI (3 (0, 7) vs 4 (0, 14); p=0.25). Door-to-CT times were 44 min faster (27(18, 44) vs 71(43, 147); p=0.0001) for stroke, and percutaneous intervention door-to-balloon times improved by 17 min, but non-significant (56 (34, 88) vs 73 (49, 110); p=0.41) for STEMI. There were improvements in the proportions of patients treated within 60 min for stroke (12%-26%, p=0.15) and 90 min for STEMI (50%-78%, p=0.20). CONCLUSIONS: In this Australian-first study, uptake of the digital communication app was strong, patient-centred care timelines improved, although door-to-treatment times remained similar.