Brainstem processing of cough sensory inputs in chronic cough hypersensitivity.

BACKGROUND: Chronic cough is a prevalent and difficult to treat condition often accompanied by cough hypersensitivity, characterised by cough triggered from exposure to low level sensory stimuli. The mechanisms underlying cough hypersensitivity may involve alterations in airway sensory nerve responsivity to tussive stimuli which would be accompanied by alterations in stimulus-induced brainstem activation, measurable with functional magnetic resonance imaging (fMRI). METHODS: We investigated brainstem responses during inhalation of capsaicin and adenosine triphosphate (ATP) in 29 participants with chronic cough and 29 age- and sex-matched controls. Psychophysical testing was performed to evaluate individual sensitivities to inhaled stimuli and fMRI was used to compare neural activation in participants with cough and control participants while inhaling stimulus concentrations that evoked equivalent levels of urge-to-cough sensation. FINDINGS: Participants with chronic cough were significantly more sensitive to inhaled capsaicin and ATP and showed a change in relationship between urge-to-cough perception and cough induction. When urge-to-cough levels were matched, participants with chronic cough displayed significantly less neural activation in medullary regions known to integrate airway sensory inputs. By contrast, neural activations did not differ significantly between the two groups in cortical brain regions known to encode cough sensations whereas activation in a midbrain region of participants with chronic cough was significantly increased compared to controls. INTERPRETATION: Cough hypersensitivity in some patients may occur in brain circuits above the level of the medulla, perhaps involving midbrain regions that amplify ascending sensory signals or change the efficacy of central inhibitory control systems that ordinarily serve to filter sensory inputs. FUNDING: Supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Pty Ltd. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme (Australia) Pty Ltd.

SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma.

Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR tyrosine kinase inhibitor (EGFR-TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO ) sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long-term in situ resistance assay, most osimertinib-resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2KO cultures that became osimertinib resistant primarily underwent non-RTK-dependent epithelial-mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib-resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR-mutated LUAD.

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.

KRAS is the most commonly mutated oncogene. Targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance. Survival of drug-tolerant persister cells within the heterogeneous tumor population and/or acquired mutations that reactivate receptor tyrosine kinase (RTK)/RAS signaling can lead to outgrowth of tumor-initiating cells (TICs) and drive therapeutic resistance. Here, we show that targeting the key RTK/RAS pathway signaling intermediates SOS1 (Son of Sevenless 1) or KSR1 (Kinase Suppressor of RAS 1) both enhances the efficacy of, and prevents resistance to, the MEK inhibitor trametinib in KRAS-mutated lung (LUAD) and colorectal (COAD) adenocarcinoma cell lines depending on the specific mutational landscape. The SOS1 inhibitor BI-3406 enhanced the efficacy of trametinib and prevented trametinib resistance by targeting spheroid-initiating cells in KRASG12/G13-mutated LUAD and COAD cell lines that lacked PIK3CA comutations. Cell lines with KRASQ61 and/or PIK3CA mutations were insensitive to trametinib and BI-3406 combination therapy. In contrast, deletion of the RAF/MEK/ERK scaffold protein KSR1 prevented drug-induced SIC upregulation and restored trametinib sensitivity across all tested KRAS mutant cell lines in both PIK3CA-mutated and PIK3CA wild-type cancers. Our findings demonstrate that vertical inhibition of RTK/RAS signaling is an effective strategy to prevent therapeutic resistance in KRAS-mutated cancers, but therapeutic efficacy is dependent on both the specific KRAS mutant and underlying comutations. Thus, selection of optimal therapeutic combinations in KRAS-mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations.

Inequities in Epilepsy: A Scoping Review.

Objectives: The objective of this study was to complete a scoping review of current literature surrounding health inequities in epilepsy while providing recommendations for future research. Methods: During July 2022, we searched MEDLINE and Ovid Embase to find published articles pertaining to epilepsy and health inequities. Initially, authors received training. Authors then screened, and data were extracted in a masked duplicate manner. Studies published within the time frame of 2011-2021 in all countries were deemed appropriate. We screened 5,325 studies for titles and abstracts and then 56 studies for full text. We evaluated the inequities of race/ethnicity, sex or gender, income, occupation status, education level, under-resourced/rural population, and LGBTQ+. To summarize the data and descriptive statistics of our study, we used Stata 17.0 (StataCorp, LLC, College Station, TX). Results: We obtained a sample size of 45 studies for study inclusion. The most reported health inequities were income (18/45, 40.0%), under-resourced/rural population (15/45, 33.3%), and race/ethnicity (15/45, 33.3%). The least reported health inequity was LGBTQ+ (0/45, 0.0%). Discussion: The findings of our study suggest that gaps exist in literature concerning epilepsy and inequities. The inequities of income status, under-resourced/rural population, and race/ethnicity were examined the most, while LGBTQ+, occupation status, and sex or gender were examined the least. With the ultimate goal of more equitable and patient-centered care in mind, it is vital that future studies endeavor to fill in these determined gaps.

Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration.

Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M-deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration.

Examining infants' visual paired comparison performance in the US and rural Malawi.

Measures of attention and memory were evaluated in 6- to 9-month-old infants from two diverse contexts. One sample consisted of African infants residing in rural Malawi (N = 228, 118 girls, 110 boys). The other sample consisted of racially diverse infants residing in suburban California (N = 48, 24 girls, 24 boys). Infants were tested in an eye-tracking version of the visual paired comparison procedure and were shown racially familiar faces. The eye tracking data were parsed into individual looks, revealing that both groups of infants showed significant memory performance. However, how a look was operationally defined impacted some-but not other-measures of infant VPC performance. RESEARCH HIGHLIGHTS: In both the US and Malawi, 6- to 9-month-old infants showed evidence of memory for faces they had previously viewed during a familiarization period. Infant age was associated with peak look duration and memory performance in both contexts. Different operational definitions of a look yielded consistent findings for peak look duration and novelty preference scores-but not shift rate. Operationalization of look-defined measures is an important consideration for studies of infants in different cultural contexts.

SOS2 regulates the threshold of mutant EGFR-dependent oncogenesis.

Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance assay, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting SOS2 has the potential to eliminate the majority of osimertinib resistance.

Pharmacological, non-invasive brain stimulation and psychological interventions, and their combination, for treating depression after stroke.

BACKGROUND: Depression is an important morbidity associated with stroke that impacts on recovery, yet is often undetected or inadequately treated. OBJECTIVES: To evaluate the benefits and harms of pharmacological intervention, non-invasive brain stimulation, psychological therapy, or combinations of these to treat depression after stroke. SEARCH METHODS: This is a living systematic review. We search for new evidence every two months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. We searched the Specialised Registers of Cochrane Stroke, and Cochrane Depression Anxiety and Neurosis, CENTRAL, MEDLINE, Embase, five other databases, two clinical trials registers, reference lists and conference proceedings (February 2022). We contacted study authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing: 1) pharmacological interventions with placebo; 2) non-invasive brain stimulation with sham stimulation or usual care; 3) psychological therapy with usual care or attention control; 4) pharmacological intervention and psychological therapy with pharmacological intervention and usual care or attention control; 5) pharmacological intervention and non-invasive brain stimulation with pharmacological intervention and sham stimulation or usual care; 6) non-invasive brain stimulation and psychological therapy versus sham brain stimulation or usual care and psychological therapy; 7) pharmacological intervention and psychological therapy with placebo and psychological therapy; 8) pharmacological intervention and non-invasive brain stimulation with placebo and non-invasive brain stimulation; and 9) non-invasive brain stimulation and psychological therapy versus non-invasive brain stimulation and usual care or attention control, with the intention of treating depression after stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data from included studies. We calculated mean difference (MD) or standardised mean difference (SMD) for continuous data, and risk ratio (RR) for dichotomous data, with 95% confidence intervals (CIs). We assessed heterogeneity using the I² statistic and certainty of the evidence according to GRADE. MAIN RESULTS: We included 65 trials (72 comparisons) with 5831 participants. Data were available for: 1) 20 comparisons; 2) nine comparisons; 3) 25 comparisons; 4) three comparisons; 5) 14 comparisons; and 6) one comparison. We found no trials for comparisons 7 to 9. Comparison 1: Pharmacological interventions Very low-certainty evidence from eight trials suggests pharmacological interventions decreased the number of people meeting the study criteria for depression (RR 0.70, 95% CI 0.55 to 0.88; P = 0.002; 8 RCTs; 1025 participants) at end of treatment and very low-certainty evidence from six trials suggests that pharmacological interventions decreased the number of people with inadequate response to treatment (RR 0.47, 95% CI 0.32 to 0.70; P = 0.0002; 6 RCTs; 511 participants) compared to placebo. More adverse events related to the central nervous system (CNS) (RR 1.55, 95% CI 1.12 to 2.15; P = 0.008; 5 RCTs; 488 participants; very low-certainty evidence) and gastrointestinal system (RR 1.62, 95% CI 1.19 to 2.19; P = 0.002; 4 RCTs; 473 participants; very low-certainty evidence) were noted in the pharmacological intervention than in the placebo group. Comparison 2: Non-invasive brain stimulation Very low-certainty evidence from two trials show that non-invasive brain stimulation had little to no effect on the number of people meeting the study criteria for depression (RR 0.67, 95% CI 0.39 to 1.14; P = 0.14; 2 RCTs; 130 participants) and the number of people with inadequate response to treatment (RR 0.84, 95% CI 0.52, 1.37; P = 0.49; 2 RCTs; 130 participants) compared to sham stimulation. Non-invasive brain stimulation resulted in no deaths. Comparison 3: Psychological therapy Very low-certainty evidence from six trials suggests that psychological therapy decreased the number of people meeting the study criteria for depression at end of treatment (RR 0.77, 95% CI 0.62 to 0.95; P = 0.01; 521 participants) compared to usual care/attention control. No trials of psychological therapy reported on the outcome inadequate response to treatment. No differences in the number of deaths or adverse events were found in the psychological therapy group compared to the usual care/attention control group. Comparison 4: Pharmacological interventions with psychological therapy No trials of this combination reported on the primary outcomes. Combination therapy resulted in no deaths. Comparison 5: Pharmacological interventions with non-invasive brain stimulation Non-invasive brain stimulation with pharmacological intervention reduced the number of people meeting study criteria for depression at end of treatment (RR 0.77, 95% CI 0.64 to 0.91; P = 0.002; 3 RCTs; 392 participants; low-certainty evidence) but not the number of people with inadequate response to treatment (RR 0.95, 95% CI 0.69 to 1.30; P = 0.75; 3 RCTs; 392 participants; very low-certainty evidence) compared to pharmacological therapy alone. Very low-certainty evidence from five trials suggest no difference in deaths between this combination therapy (RR 1.06, 95% CI 0.27 to 4.16; P = 0.93; 487 participants) compared to pharmacological therapy intervention and sham stimulation or usual care. Comparison 6: Non-invasive brain stimulation with psychological therapy No trials of this combination reported on the primary outcomes. AUTHORS' CONCLUSIONS: Very low-certainty evidence suggests that pharmacological, psychological and combination therapies can reduce the prevalence of depression while non-invasive brain stimulation had little to no effect on the prevalence of depression. Pharmacological intervention was associated with adverse events related to the CNS and the gastrointestinal tract. More research is required before recommendations can be made about the routine use of such treatments.

ANTECEDENTES: La depresión tiene una morbilidad importante asociada con el accidente cerebrovascular que repercute en la recuperación, pero que a menudo no se detecta o se trata de manera inadecuada. OBJETIVOS: Evaluar los efectos beneficiosos y perjudiciales de las intervenciones farmacológicas, la estimulación cerebral no invasiva, la terapia psicológica o las combinaciones de éstas para tratar la depresión después del accidente cerebrovascular. MÉTODOS DE BÚSQUEDA: Esta es una revisión sistemática continua. Cada dos meses se busca nueva evidencia y la revisión se actualiza cuando se identifica evidencia nueva relevante. Consultar el estado actual de esta revisión en la Base de Datos Cochrane de Revisiones Sistemáticas (Cochrane Database of Systematic Reviews). Se realizaron búsquedas en los Registros especializados del Grupo Cochrane de Accidentes cerebrovasculares (Cochrane Stroke) y del Grupo Cochrane de Depresión, ansiedad y neurosis (Cochrane Depression, Anxiety and Neurosis), en CENTRAL, MEDLINE, Embase, otras cinco bases de datos, dos registros de ensayos clínicos, listas de referencias y resúmenes de congresos (febrero de 2022). Se estableció contacto con autores de estudios. CRITERIOS DE SELECCIÓN: Ensayos controlados aleatorizados (ECA) que compararan: 1) intervenciones farmacológicas con placebo; 2) estimulación cerebral no invasiva con estimulación simulada o atención habitual; 3) terapia psicológica con atención habitual o control de atención; 4) intervención farmacológica y terapia psicológica con intervención farmacológica y atención habitual o control de atención; 5) intervención farmacológica y estimulación cerebral no invasiva con intervención farmacológica y estimulación simulada o atención habitual; 6) estimulación cerebral no invasiva y terapia psicológica versus estimulación cerebral simulada o atención habitual y terapia psicológica; 7) intervención farmacológica y terapia psicológica con placebo y terapia psicológica; 8) intervención farmacológica y estimulación cerebral no invasiva con placebo y estimulación cerebral no invasiva; y 9) estimulación cerebral no invasiva y terapia psicológica versus estimulación cerebral no invasiva y atención habitual o control de atención, con la intención de tratar la depresión después del accidente cerebrovascular. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, seleccionaron los estudios, evaluaron el riesgo de sesgo y extrajeron los datos de los estudios incluidos. Se calculó la diferencia de medias (DM) o la diferencia de medias estandarizada (DME) para los datos continuos, y la razón de riesgos (RR) para los datos dicotómicos, con intervalos de confianza (IC) del 95%. La heterogeneidad se evaluó mediante la estadística I² y la certeza de la evidencia según GRADE. RESULTADOS PRINCIPALES: Se incluyeron 65 ensayos (72 comparaciones) con 5831 participantes. Se dispuso de datos para: 1) 20 comparaciones; 2) nueve comparaciones; 3) 25 comparaciones; 4) tres comparaciones; 5) 14 comparaciones; y 6) una comparación. No se encontraron ensayos para las comparaciones 7 a 9. Comparación 1: Intervenciones farmacológicas Evidencia de certeza muy baja de ocho ensayos indica que las intervenciones farmacológicas disminuyeron el número de personas que cumplían los criterios del estudio para la depresión (RR 0,70; IC del 95%: 0,55 a 0,88; p = 0,002; ocho ECA; 1025 participantes) al final del tratamiento y evidencia de certeza muy baja de seis ensayos indica que las intervenciones farmacológicas disminuyeron el número de personas con respuesta inadecuada al tratamiento (RR 0,47; IC del 95%: 0,32 a 0,70; p = 0,0002; seis ECA; 511 participantes) en comparación con placebo. Se observaron más eventos adversos relacionados con el sistema nervioso central (SNC) (RR 1,55; IC del 95%: 1,12 a 2,15; p = 0,008; cinco ECA; 488 participantes; evidencia de certeza muy baja) y el sistema gastrointestinal (RR 1,62; IC del 95%: 1,19 a 2,19; p = 0,002; cuatro ECA; 473 participantes; evidencia de certeza muy baja) en el grupo de intervención farmacológica que en el grupo placebo. Comparación 2: Estimulación cerebral no invasiva Evidencia de certeza muy baja de dos ensayos muestra que la estimulación cerebral no invasiva tuvo poco o ningún efecto sobre el número de personas que cumplían los criterios del estudio para la depresión (RR 0,67; IC del 95%: 0,39 a 1,14; p = 0,14; dos ECA; 130 participantes) y el número de personas con respuesta inadecuada al tratamiento (RR 0,84; IC del 95%: 0,52 a 1,37; p = 0,49; dos ECA; 130 participantes) en comparación con la estimulación simulada. La estimulación cerebral no invasiva no provocó muertes. Comparación 3: Terapia psicológica Evidencia de certeza muy baja de seis ensayos indica que la terapia psicológica disminuyó el número de personas que cumplían los criterios del estudio para la depresión al final del tratamiento (RR 0,77; IC del 95%: 0,62 a 0,95; p = 0,01; 521 participantes) en comparación con atención habitual/control de atención. Ningún ensayo de terapia psicológica informó sobre el desenlace respuesta inadecuada al tratamiento. No se encontraron diferencias en el número de muertes o eventos adversos en el grupo de terapia psicológica en comparación con el grupo de control de atención/atención habitual. Comparación 4: Intervenciones farmacológicas con terapia psicológica Ningún ensayo de esta combinación informó sobre los desenlaces principales. El tratamiento combinado no provocó muertes. Comparación 5: Intervenciones farmacológicas con estimulación cerebral no invasiva La estimulación cerebral no invasiva con intervención farmacológica redujo el número de personas que cumplían los criterios del estudio para la depresión al final del tratamiento (RR 0,77; IC del 95%: 0,64 a 0,91; p = 0,002; tres ECA; 392 participantes; evidencia de certeza baja), pero no el número de personas con respuesta inadecuada al tratamiento (RR 0,95; IC del 95%: 0,69 a 1,30; p = 0,75; tres ECA; 392 participantes; evidencia de certeza muy baja) en comparación con el tratamiento farmacológico solo. Evidencia de certeza muy baja de cinco ensayos no indica diferencias en las muertes entre este tratamiento combinado (RR 1,06; IC del 95%: 0,27 a 4,16; p = 0,93; 487 participantes) en comparación con la intervención de tratamiento farmacológico y la estimulación simulada o la atención habitual. Comparación 6: Estimulación cerebral no invasiva con terapia psicológica Ningún ensayo de esta combinación informó sobre los desenlaces principales. CONCLUSIONES DE LOS AUTORES: Evidencia de certeza muy baja indica que los tratamientos farmacológicos, las terapias psicológicas y los tratamientos combinados pueden reducir la prevalencia de la depresión, mientras que la estimulación cerebral no invasiva tuvo poco o ningún efecto sobre la prevalencia de la depresión. Las intervenciones farmacológicas se asociaron con eventos adversos relacionados con el SNC y el sistema gastrointestinal. Se necesitan más estudios de investigación antes de poder hacer recomendaciones sobre el uso habitual de dichos tratamientos.

Open-source Tools for Training Resources - OTTR.

Data science and informatics tools are developing at a blistering rate, but their users often lack the educational background or resources to efficiently apply the methods to their research. Training resources and vignettes that accompany these tools often deprecate because their maintenance is not prioritized by funding, giving teams little time to devote to such endeavors. Our group has developed Open-source Tools for Training Resources (OTTR) to offer greater efficiency and flexibility for creating and maintaining these training resources. OTTR empowers creators to customize their work and allows for a simple workflow to publish using multiple platforms. OTTR allows content creators to publish training material to multiple massive online learner communities using familiar rendering mechanics. OTTR allows the incorporation of pedagogical practices like formative and summative assessments in the form of multiple choice questions and fill in the blank problems that are automatically graded. No local installation of any software is required to begin creating content with OTTR. Thus far, 15 training courses have been created with OTTR repository template. By using the OTTR system, the maintenance workload for updating these courses across platforms has been drastically reduced. For more information about OTTR and how to get started, go to ottrproject.org.

Augmenting project ECHO for opioid use disorder with data-informed quality improvement.

BACKGROUND: National opioid-related overdose fatalities totaled 650,000 from 1999 to 2021. Some of the highest rates occurred in New Hampshire, where 40% of the population lives rurally. Medications for opioid use disorder (MOUD; methadone, buprenorphine, and naltrexone) have demonstrated effectiveness in reducing opioid overdose and mortality. Methadone access barriers disproportionally impact rural areas and naltrexone uptake has been limited. Buprenorphine availability has increased and relaxed regulations reduces barriers in general medical settings common in rural areas. Barriers to prescribing buprenorphine include lack of confidence, inadequate training, and lack of access to experts. To address these barriers, learning collaboratives have trained clinics on best-practice performance data collection to inform quality improvement (QI). This project sought to explore the feasibility of training clinics to collect performance data and initiate QI alongside clinics' participation in a Project ECHO virtual collaborative for buprenorphine providers. METHODS: Eighteen New Hampshire clinics participating in a Project ECHO were offered a supplemental project exploring the feasibility of performance data collection to inform QI targeting increased alignment with best practice. Feasibility was assessed descriptively, through each clinic's participation in training sessions, data collection, and QI initiatives. An end-of-project survey was conducted to understand clinic staff perceptions of how useful and acceptable they found the program. RESULTS: Five of the eighteen health care clinics that participated in the Project ECHO joined the training project, four of which served rural communities in New Hampshire. All five clinics met the criteria for engagement, as each clinic attended at least one training session, submitted at least one month of performance data, and completed at least one QI initiative. Survey results showed that while clinic staff perceived the training and data collection to be useful, there were several barriers to collecting the data, including lack of staff time, and difficulty standardizing documentation within the clinic electronic health record. CONCLUSIONS: Results suggest that training clinics to monitor their performance and base QI initiatives on data has potential to impact clinical best practice. While data collection was inconsistent, clinics completed several data-informed QI initiatives, indicating that smaller scale data collection might be more attainable.

Assessing the Reporting of Harms in Systematic Reviews Focused on the Therapeutic and Cosmetic Uses of Botulinum Toxin.

BACKGROUND AND OBJECTIVE: The expanding use of botulinum toxin (BoNT) in medical practice demonstrates the need to highlight whether there is adequate information regarding its safety profile. The aim of our study was to identify completeness of harms reporting for BoNT treatment within systematic reviews (SRs), assess quality of SRs using the AMSTAR-2 tool, and determine the degree of overlap among primary studies within each SR. METHODS: On May 31, 2022, we searched Embase, Epistemonikos, MEDLINE, and the Cochrane Database of Systematic Reviews for SRs on BoNT therapy. Screening and data extraction were performed in a masked, duplicate fashion. AMSTAR-2 was used to evaluate the methodological quality of included SRs. Corrected covered area (CCA) was calculated for SR dyads. RESULTS: Of the 90 included SRs, we found that 70 completed less than 50% of harms items. The most reported items were BoNT as a favorable intervention (73/90, 81.1%) and harms as a primary outcome (72/90, 80.0%). The least reported items were grades and severity scales used to classify harms (8/90, 8.9%) and number of treatment discontinuations in each arm (10/90, 11.1%). Eighty-three SRs were rated "critically low" (83/90, 92.2%), while 5 SRs were rated "high" (5/90, 5.6%) via AMSTAR-2 tool. Significant associations were found between completion of harms reporting and: (1) a "critically low" appraisal on AMSTAR-2 tool (p = 0.0060) and (2) whether harms was reported as a primary outcome (p = 0.0001). The total CCA overlap was determined to be 0.8%. CONCLUSION: Our results demonstrate that harms are underreported within BoNT SRs. Because healthcare professionals often refer to SRs to guide clinical decision making, it is important to continue to explore shortcomings among BoNT literature in future studies.

The Effect of Patient Positioning on Intraoperative Neuromonitoring During Thyroid and Parathyroid Surgery.

BACKGROUND: Intraoperative neuromonitoring (IONM) has been accepted as a routine adjunct among surgeons who perform thyroid and parathyroid surgeries. Thyroid and parathyroid surgeries use various patient positioning strategies that have poorly understood effects on IONM. The aim of this study was to compare IONM signals between the transaxillary and transcervical approaches. METHODS: In this retrospective cohort study, we evaluated 463 adult patients who underwent a total of 502 procedures. The procedures performed included total thyroidectomy, right or left hemithyroidectomy, and parathyroidectomy. Vagus nerve and recurrent laryngeal nerve (RLN) latency and amplitude measurements were analyzed intra-operatively. The distances between the vagus nerve and the trachea were measured via ultrasound during transaxillary procedures. RESULTS: Compared to the transcervical approach, the right vagus nerve latency was significantly decreased in the transaxillary approach. Transaxillary surgery was not associated with increased latency or decreased amplitude on IONM. The distance between the vagus nerve and trachea was significantly decreased post-positioning during transaxillary approaches. DISCUSSION: Despite differences in patient positioning, a transaxillary approach was not associated with increased stress on the vagus nerve or RLN, according to IONM data. The decreased right vagus nerve latency associated with a transaxillary approach highlights the importance of considering patient positioning and laterality while interpreting IONM data.

Effects of alcohol hangover on attentional resources during a verbal memory/psychomotor tracking dual attention task.

BACKGROUND: Alcohol hangover (AH) is associated with impaired attention and memory performance. However, whether this effect is related to reduced attentional resources remains unclear. AIMS: A dual-attention paradigm was employed to assess the effects of AH on attentional resources, delayed memory recognition, and the interaction between attentional load and AH. Mental effort and perceived performance during AH and control conditions were also assessed. METHODS: A seminaturalistic, crossover design was used. In total, 25 healthy social drinkers aged 18-35 years, visited the laboratory following a typical night out drinking (Hangover condition) and after alcohol abstinence (control) between 8:30 am and 12:30 pm, with conditions counterbalanced. Attentional load was manipulated via the presence (dual attention) or absence of psychomotor tracking during verbal memory encoding. Perceived mental effort and performance were measured using the NASA-TLX. Participants' recollected alcohol consumption was used to compute estimated blood alcohol level (eBAC). RESULTS: Compared with the control visit, AH was associated with reduced recognition accuracy (particularly more false negatives), higher "tracking costs" (poorer accuracy) in the dual attention condition, increased ratings of "mental demand," "effort," and "frustration," and lower ratings of task performance. There was also a significant main effect of attentional load with poorer recognition accuracy and response time in the dual attention condition. There were no significant interaction effects between hangover and attentional load. CONCLUSION: These findings suggest that reduced attentional resources contribute to the cognitive deficits associated with AH including impaired memory consolidation. They further suggest that while hungover, participants are aware of these deficits but are unable to compensate.

Facilitators and barriers of life jacket use for drowning prevention: Qualitative evidence synthesis.

BACKGROUND: Drowning is a public health problem globally. Despite substantial evidence on the effectiveness of life jackets, their use for drowning prevention has remained low. This study aims to understand the barriers and facilitators of life jacket use. METHODS: We searched four major electronic databases, contacted experts, hand-searched conference abstracts and screened reference lists to identify primary qualitative studies. We used the Critical Appraisal Skills Programme Checklist for quality appraisal and the PROGRESS Plus framework to understand equity issues. Thematic analysis was conducted. RESULTS: We retrieved 1153 records and finally included ten studies that met eligibility criteria. All except two studies were from high-income countries. Four key themes were identified. Firstly, life jacket use was shaped through complex interactions between lived experience and cultural norms which influenced the risk-perception of life jacket utility in preventing deaths. Secondly, the high cost of life jackets was almost always a barrier for its usage. Thirdly, adoption of laws and its subsequent enforcement was perceived to be an important facilitator for life jacket use. Lastly, design issues around comfort, fashion-sense, and shelf life influenced usage. CONCLUSION: The results of this qualitative evidence synthesis should be considered for health promotion, legal and policy interventions to promote the uptake of life jackets. There is a need for better understanding of perceptions and their role in the uptake of safety behaviours in different countries including the role of equity issues on the use of life jackets.

Recent developments of neuroprotective agents for degenerative retinal disorders.

Retinal degeneration is a debilitating ocular complication characterized by the progressive loss of photoreceptors and other retinal neurons, which are caused by a group of retinal diseases affecting various age groups, and increasingly prevalent in the elderly. Age-related macular degeneration, diabetic retinopathy and glaucoma are among the most common complex degenerative retinal disorders, posing significant public health problems worldwide largely due to the aging society and the lack of effective therapeutics. Whilst pathoetiologies vary, if left untreated, loss of retinal neurons can result in an acquired degeneration and ultimately severe visual impairment. Irrespective of underlined etiology, loss of neurons and supporting cells including retinal pigment epithelium, microvascular endothelium, and glia, converges as the common endpoint of retinal degeneration and therefore discovery or repurposing of therapies to protect retinal neurons directly or indirectly are under intensive investigation. This review overviews recent developments of potential neuroprotectants including neuropeptides, exosomes, mitochondrial-derived peptides, complement inhibitors, senolytics, autophagy enhancers and antioxidants either still experimentally or in clinical trials. Effective treatments that possess direct or indirect neuroprotective properties would significantly lift the burden of visual handicap.

Deciphering excess healthcare burden in head and neck cancer patients with cardiovascular comorbidity.

BACKGROUND: This study aimed to determine the perioperative surgical outcomes for head and neck cancer patients with cardiovascular diseases (CVDs). METHODS: A cross-sectional analysis was performed using data from the Nationwide Readmissions Database between 2010 and 2014. Logistic regression analysis by enter and backward stepwise methods were used. RESULTS: A total of 8346 patients met the inclusion criteria. Patients with concomitant CVD had a higher frequency of complications (57.6%) compared with those without (47.4%) (odds ratio [OR] = 1.35, 95% confidence interval [CI] = 1.23-1.48, p < 0.001). Patients with CVD comorbidities were prone to experience in-patient mortality at both admission (OR = 2.4, 95% CI = 1.42-4.05) and readmission (OR = 2.55, 95% CI = 1.10-5.87). CVD patients have prolonged hospital admission (OR = 1.14, 95% CI = 1.02-1.27, p = 0.020) and higher cost (OR = 1.28, 95% CI = 1.15-1.43, p < 0.001). Patients with congestive heart failure were prone to 30 days readmission (OR = 1.67, 95% CI = 1.10-2.53, p = 0.019) and 90 days (OR = 1.65, 95% CI = 1.14-2.39, p = 0.010). CONCLUSION: This is the first study identifying factors predicting higher risk of perioperative complications of surgical management of head and neck cancer. Those with CVD had higher risk of adverse events.

Evaluating the Public's Interest in Testicle Tanning: Observational Study.

BACKGROUND: A new and potentially dangerous health trend, testicle tanning, received extensive media attention following a popular television program where a health and fitness influencer touted that testicular tanning increases testosterone levels. It has been shown that the public has a particular interest in tanning wellness trends; thus, given the vague nomenclature of the practice, the abundance of misleading information and support for using UV light by other health influencers may lead to an increase in men exposing themselves to UV radiation and developing associated complications. OBJECTIVE: The aim of this paper is to evaluate the public's interest in testicle tanning. METHODS: Relative search interest was collected from Google Trends, and daily tweet volume was collected using Twitter via Sprout Social. The search was filtered to observe internet activity between February 1, 2022, and August 18, 2022. Autoregressive integrated moving average models were applied to forecast the predicted values through April 30 to compare to the actual observed values immediately following the airing of the show. RESULTS: We found that the relative search interest for testicle tanning peaked (100) on April 19, 2022, following a discussion of the topic on a television program. Compared to the forecasted relative search interest of 1.36 (95% CI -3.29 to 6.01), had the topic not been discussed, it showed a 7252% increase in relative search interest. A similar spike was observed in the volume of tweets peaking on April 18 with 42,736. The expected number of tweets from the autoregressive integrated moving average model was 122 (95% CI -154 to 397), representing a 35,053% increase. CONCLUSIONS: Our results show that the promotion of testicle tanning generated significant public interest in an evidence-lacking and potentially dangerous health trend. Dermatologists and other health care professionals should be aware of these new viral health trends to best counsel patients and combat health misinformation.

Media coverage of COVID-19 health information in India: a content analysis.

Effective response to the COVID-19 pandemic is dependent on individual understanding of the disease and compliance to prevention measures. Early media depiction of health information about COVID-19 may influence public perceptions and behaviour. Media should ensure coverage is relevant, timely and actionable to encourage individuals to respond appropriately. India has been particularly affected by a large COVID-19 caseload. We analysed online reporting in India to assess how well the media represented health information about COVID-19 as per the World Health Organization's Strategic Risk Communications guidelines. This included media coverage of symptoms, transmission and prevention. We found that limited articles (18.8%) provided actionable suggestions to readers, including urging people to stay at home and social distance. Most articles were relevant as per WHO COVID-19 updates, accurately covering symptoms, risk factors for severe symptoms, transmission and prevention. However, 40% of media coverage of treatments options provided misleading information, such as suggesting plasma therapy or chloroquine, were effective. In addition, only 1.9% of articles included discussion of equity issues, where many prevention activities such as distancing are less applicable in lower-income households. Sixty-seven per cent of articles quoting sources of information quoted credible sources such as public health agencies and researchers. Media coverage also did not appear to reflect WHO updates in a timely manner, with most of the coverage preceding these updates. The findings show that Indian media should focus on actionable and relevant reporting that provides guidance for individual response. Media should also endeavour to report on evidence-based prevention and treatment options to avert the spread of misinformation.

The way media represents health information about COVID-19 may influence public understanding of the virus and behaviours they take to contain its spread. Therefore, media coverage should be accurate, timely and provide specific actions. India has been particularly affected by COVID-19. Based on the World Health Organization's Strategic Risk Communications guidelines, we analysed online reporting in India to assess how well the media represented COVID-19 health information. This included media coverage of symptoms, transmission and prevention. We found that very few articles provided direct suggestions to readers on prevention behaviours, such as staying at home. Most articles accurately covered symptoms, risk factors for severe symptoms, transmission and prevention. However, there was limited coverage of equity issues that affect low-income households, such as their ability to social distance or hand wash. In addition, treatment options not known to be effective received high coverage, such as plasma therapy. Only some articles included credible sources of information such as quoting public health agencies and researchers. Media coverage also usually preceding official updates from WHO, rather than waiting and responding to validated information. The Media should report on evidence-based prevention and treatment options to avert the spread of misinformation and encourage appropriate behaviours.

Interplay between state anxiety, heart rate variability, and cognition: An ex-Gaussian analysis of response times.

The present study employed an ex-Gaussian model of response times (RTs) to elucidate the cognitive processes related to experimentally induced state anxiety (SA) and vagally mediated heart rate variability (vmHRV), an indicator of adaptive responses in both cognitive and affective domains. Participants (n = 110) completed a dual task composed of (i) a flanker attention and (2) working memory load task, while SA was induced by threat of noise. Electrocardiography was measured during the dual task and during four baseline periods in order to calculate vmHRV. RTs on the flanker task were fit to an ex-Gaussian distribution, which estimated three RT parameters: mu (Gaussian mean), sigma (Gaussian SD), and tau (combination of exponential mean and SD). First, findings indicate that threat of noise was associated with reductions in mu and tau, suggesting that SA might improve attention and motor responding. Second, higher resting vmHRV was associated with lower tau (averaged across conditions) and stronger threat-related decreases in tau. Third, intra-individual decreases in vmHRV were accompanied by concomitant decreases in tau. These findings support roles for trait and state vagal control in guiding adaptive anxiety-related (and anxiety-unrelated) attentional responses. Findings are consistent with extant theories that emphasize functional interrelations among emotion, cognition, and vagal function.