Consensus on innovations and future directions of community first responder schemes in United Kingdom: a national nominal group technique study.

AIM: We aimed to achieve consensus among NHS and community stakeholders to identify and prioritise innovations in Community First Responder (CFR) schemes. METHODS: We conducted a mixed-methods study, adopting a modified nominal group technique with participants from ambulance services, CFR schemes and community stakeholders. The 1-day consensus workshop consisted of four sessions: introduction of innovations derived from primary research; round-robin discussions to generate new ideas; discussion and ranking of innovations; feedback of ranking, re-ranking and concluding statements. Innovations were ranked on a 5-point Likert scale and descriptive statistics of median and interquartile range calculated. Discussions were recorded, transcribed, and analysed thematically. RESULTS: The innovations found were classified into two categories: process innovations and technological innovations. The process innovations included six types of innovations: roles, governance, training, policies and protocols, recruitment, and awareness. The technological innovations included three aspects: information and communication; transport; and health technology. The descriptive statistics revealed that innovations such as counselling and support for CFRs (median: 5 IQR 5,5), peer support [5 (4,5)], and enhanced communication with control room [5 (4,5)] were essential priorities. Contrastingly, innovations such as the provision of dual CFR crew [1.5 (1,3)], CFR responsibilities in patient transport to hospital [1 (1,2)], and CFR access to emergency blue light [1 (1,1.5)] were deemed non-priorities. CONCLUSIONS: This article established consensus on innovations in the CFR schemes and their ranking for improving the provision of care delivered by CFRs in communities. The consensus-building process also informed policy- and decision-makers on the potential future change agenda for CFR schemes.

Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis: The KETO Trial.

Background: Increases in low-density lipoprotein cholesterol (LDL-C) can occur on carbohydrate restricted ketogenic diets. Lean metabolically healthy individuals with a low triglyceride-to-high-density lipoprotein cholesterol ratio appear particularly susceptible, giving rise to the novel "lean mass hyper-responder" (LMHR) phenotype. Objectives: The purpose of the study was to assess coronary plaque burden in LMHR and near-LMHR individuals with LDL-C ≥190 mg/dL (ketogenic diet [KETO]) compared to matched controls with lower LDL-C from the Miami Heart (MiHeart) cohort. Methods: There were 80 KETO individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL, high-density lipoprotein cholesterol ≥60 mg/dL, and triglyceride levels ≤80 mg/dL, without familial hypercholesterolemia, matched 1:1 with MiHeart subjects for age, gender, race, hyperlipidemia, hypertension, and smoking status. Coronary artery calcium and coronary computed tomography angiography (CCTA) were used to compare coronary plaque between groups and correlate LDL-C to plaque levels. Results: The matched mean age was 55.5 years, with a mean LDL-C of 272 (maximum LDL-C of 591) mg/dl and a mean 4.7-year duration on a KETO. There was no significant difference in coronary plaque burden in the KETO group as compared to MiHeart controls (mean LDL 123 mg/dL): coronary artery calcium score (median 0 [IQR: 0-56]) vs (1 [IQR: 0-49]) (P = 0.520) CCTA total plaque score (0 [IQR: 0-2] vs [IQR: 0-4]) (P = 0.357). There was also no correlation between LDL-C level and CCTA coronary plaque. Conclusions: Coronary plaque in metabolically healthy individuals with carbohydrate restriction-induced LDL-C ≥190 mg/dL on KETO for a mean of 4.7 years is not greater than a matched cohort with 149 mg/dL lower average LDL-C. There is no association between LDL-C and plaque burden in either cohort. (Diet-induced Elevations in LDL-C and Progression of Atherosclerosis [Keto-CTA]; NCT057333255).

Cardiac resynchronization therapy guided by interventricular conduction delay: How to choose between biventricular pacing or conduction system pacing.

BACKGROUND: Biventricular pacing (BIV) is the gold standard for cardiac resynchronization therapy (CRT). Thirty percent of patients do not respond to CRT. Conduction system pacing (CSP) represents a viable alternative. Interventricular conduction delay (IVCD), as electrical desynchrony marker, is a CRT response predictor. The aim of this study was to determine the incidence of CRT responders by selecting the best approach between BIV and CPS based on intraoperative IVCD measurement in patients with HFrEF and LBBB. METHODS: Ninety-six patients were randomly assigned in a 1:1 ratio to either a standard BIV group(control group, CG) or a group where the CRT approach was determined based on IVCD evaluation(study group, SG). If the right ventricular sensed electrogram (RVs)-left ventricular sensed electrogram (LVs) interval was ≥100 ms, the lead was left in its original position; otherwise, the LV lead was removed, and CSP was performed instead. Clinical, EKG, and echocardiographic features have been assessed pre- and 6 months post-implant. Echocardiographic and clinical responder were evaluated. RESULTS: Thirty-seven percent of patients in the SG underwent CSP, as the operative algorithm. The incidence of CRT responders was significantly higher in the SG (echocardiographic criterion: 92.5% vs. 69.8%, p:.009; clinical criterion 87.5% vs. 62.8%, p:.014). The SG showed a significantly greater difference in EF between pre- and post-implant as well as reduced end-diastolic and systolic volumes. Univariate and multivariate regression analysis indicated that enrollment in the SG was the only factor associated with CRT response. CONCLUSION: Intraoperative assessment of IVCD could help determine the optimal CRT approach between BIV and CSP, leading to a significant improvement in the rate of CRT responders.

Decreases in cT1 and liver fat content reflect treatment-induced histological improvements in MASH.

BACKGROUND & AIMS: MRI biomarkers of liver disease are robust and reproducible alternatives to liver biopsy. Emerging data suggest that absolute reduction in iron corrected T1 (cT1) of ≥ 80 ms and relative reduction in liver fat content of 30% reflect histological improvement. We aimed to validate the associations of changes to these noninvasive biomarkers with histological improvement, specifically the resolution of steatohepatitis. METHODS: A retrospective analysis of participants from three interventional clinical trials who underwent multiparametric MRI to measure liver cT1 and liver fat content (LFC) (LiverMultiScan) alongside biopsies at baseline and end of study. Responders were defined as those achieving resolution of steatohepatitis with no worsening in fibrosis. Differences in the magnitude of change in cT1 and LFC between responders and non-responders was assessed. RESULTS: Individual patient data from 150 participants were included. There was a significant decrease in liver cT1 (-119 ms vs. -49 ms) and liver fat content (-65% vs. -29%) in responders compared to non-responders (P < .001) respectively. The diagnostic accuracy to identify responders was 0.72 (AUC) for both. The Youden's index for cT1 to separate responders from non-responders was -82 ms and for liver fat was a 58% relative reduction. Those achieving a ≥ 80 ms reduction in cT1 were 5-times more likely to achieve histological response (sens 0.68; spec 0.70). Those achieving a 30% relative reduction in liver fat were ∼4 times more likely to achieve a histological response (sens 0.77; spec 0.53). CONCLUSIONS: These results, from three combined drug trials, demonstrate that changes in multiparametric MRI markers of liver health (cT1 and PDFF) can predict histological response for steatohepatitis following therapeutic intervention. IMPACT AND IMPLICATIONS: There is great interest in identifying suitable biomarkers that can be used to replace liver biopsy, or to identify those patients who would benefit from one, in both the clinical management of MASH and in drug development. We investigated the utility of two MRI-derived non-invasive tests, iron corrected T1 mapping (cT1) and liver fat content from proton density fat fraction (PDFF), to predict histological improvement in patients who had undergone experimental treatment for MASH. Using data from 150 people who participated in one of three clinical trials, we observed that a reduction in cT1 by over 80 ms and a relative reduction in PDFF of over 58% were the optimal thresholds for change that predicted resolution of steatohepatitis. PDFF as a marker of liver fat, and cT1 as a specific measure of liver disease activity, are both effective at identifying those who are likely responding to drug interventions and experiencing improvements in overall liver health. CLINICAL TRIAL NUMBER(S): NCT02443116, NCT03976401, NCT03551522.

One-Year Real-World Outcomes of Intravitreal Faricimab for Previously Treated Neovascular Age-Related Macular Degeneration.

INTRODUCTION: This study assessed the efficacy, durability, and safety of faricimab in patients with neovascular age-related macular degeneration (nAMD), previously treated with aflibercept or ranibizumab with unsatisfactory results. METHODS: This was a single-center, prospective cohort study of all consecutive patients with nAMD switched to intravitreally administered faricimab from traditional anti-vascular endothelial growth factor (anti-VEGF) treatments between September 2022 and April 2023 because of unsatisfactory response (maximal fluid-free interval ≤ 8 weeks). Faricimab was administered with a loading dose of four 4-weekly injections, followed by a treat-and-extend regimen. The primary outcome measures were maximum fluid-free interval after the switch and last assigned treatment interval. Secondary outcome measures included best-corrected visual acuity (BCVA) and structural optical coherence tomography parameters. RESULTS: Thirty-three eyes of 33 patients were included. Patients were followed for a median of 72 weeks [interquartile range 61, 76]. Median maximum fluid-free treatment interval after switch to faricimab and the last assigned interval were significantly longer than before the switch (7 vs. 4 weeks, p < 0.001 and 8 vs. 5 weeks, p < 0.001, respectively). Significant improvements in central subfield thickness (353 vs. 281 µm), macular volume (2.46 vs. 2.16 mm3), and pigment epithelial detachment height (198 vs. 150 µm) were observed (all p < 0.001). BCVA remained stable at 0.4 versus 0.3 logMAR before switch (p = 0.190). One eye (3%) developed intraocular inflammation and one eye (3%) developed a retinal pigment epithelium tear. CONCLUSIONS: Faricimab improved anatomical outcomes and allowed longer treatment intervals in patients with nAMD previously treated with other anti-VEGF therapies with unsatisfactory response, reducing treatment burden. A favorable safety profile was observed.

Latent profile analysis of transdiagnostic emotional distress, suicidality, and resilience in first responders.

BACKGROUND: First responders (i.e., law enforcement officers, firefighters, and emergency medical technicians/paramedics), experience significantly higher occupational trauma exposure than U.S. adult workers outside these fields, leading to increased risks of comorbid mental health disorders. Repeated and intense trauma exposure may combine with personal factors to place them at higher risk for suicide. Conversely, first responders may show higher levels of psychological resilience in the face of occupational trauma experiences. Some research exists on resilience, though little is known about suicide resilience in first responder populations. METHODS: We used latent profile analysis (LPA) on a treatment-seeking sample of first responders (N = 340) with measures of posttraumatic stress disorder (PTSD), generalized anxiety, depression, suicidality, and resilience. RESULTS: We determined the best fit was a five-class solution, including the following emotional distress categories: minimal (19 %), mild (33 %), moderate (8 %), moderately severe (27 %), and severe (13 %) emotional distress. In this study, all multivariate analyses of variance (MANOVAs) were statistically significant and had large effect sizes ranging from the lowest (resilience) to the largest (depression). LIMITATIONS: We used self-report assessments and not a clinical interview. Also, we did not have data on measures of substance use, emotional dysregulation (e.g., attachment), or trauma exposure. CONCLUSIONS: This study underscores the critical need for developing and implementing transdiagnostic interventions that not only address the spectrum of emotional distress and suicidality but also actively enhance resilience among treatment-seeking first responders.

Refractory anti-viral resistant CMV retinitis in an immunological nonresponder person living with HIV.

Cytomegalovirus (CMV) retinitis caused by drug-resistant viruses poses a major challenge in immunocompromised patients. We present the case of a patient living with HIV with persistently low CD4+ T cells count despite effective antiretroviral therapy, who experienced multiple episodes of CMV retinitis associated with iterative acquisition of resistance. The failure of ganciclovir and foscarnet treatments led us to implement a combined therapy of intravenous cidofovir, high-dose ganciclovir, and anti-CMV immunoglobulin as well as intravitreal injections of ganciclovir. This triple therapy was successful but resulted in significant myelotoxicity. Furthermore, the relapse of CMV retinitis and/or CMV viremia with each therapeutic de-escalation reflects the high level of immunodeficiency in our patient, despite sustained control of HIV viremia for several months. This case report highlights the need for a particular management of CMV infection in patients living with HIV who are immunological nonresponders.

'I've got no PPE to protect my mind': understanding the needs and experiences of first responders exposed to trauma in the workplace.

ABSTRACTBackground: First responders (FRs) are at high risk of being exposed to traumatic events in their occupational roles. Responding to critical incidents often involves exposure to life-threatening circumstances, dealing with fatalities and encountering highly stressful situations that may trigger traumatic responses. These experiences can lead to poor physical and mental health (MH) outcomes including post-traumatic stress disorder, co-morbid conditions such as depression, anxiety, substance abuse, insomnia, and suicidality. Little research has explored the perspectives and experiences of FRs in dealing with occupational trauma(s) and how best to meet their health needs.Objective: This study aimed to explore FRs' experiences of exposure to occupational trauma and its impact on their mental wellbeing. The wider objective was to investigate how FRs can be supported to access appropriate and relevant help, addressing barriers like stigma.Method: A qualitative research design using in-depth semi-structured interviews with FRs (n = 54) was adopted. Interviews were audio-recorded, transcribed and analysed using an inductive thematic approach.Results: Themes developed were: (1) the pervasive, cumulative and salient impact of occupational trauma on MH (micro-traumas, nightmares, flashbacks and reliving experiences); (2) the demands of the job exacerbating the adverse effects of trauma (self and others); (3) insufficient support and unhelpful ways of coping following exposure to trauma (lack of psychological safety); (4) stigma and fear of judgement as barriers to MH help-seeking; and (5) need for specific, accessible and credible trauma-focused interventions and workplace support.Conclusions: The implications of these findings are discussed at the individual, service provider and organisational level, emphasising the importance of implementing a strengths-based, non-pathologising and de-stigmatising approach to trauma in the workplace as experienced by FRs. Emphasis is placed on the importance of overcoming barriers to accessing MH support and improving access to evidence-based, trauma-focused psychological interventions and workplace support.

First responders regularly experience traumatic events in their workplace which can bring about traumatic stress, which is further exacerbated by the demands and pressures of their jobs.First responders' coping needs are not being met to a sufficient extent, especially in terms of psychological/MH input.There is need for evidenced-based, easily accessible, occupation-specific trauma-focused interventions to support first responders with their MH needs from occupational trauma-related stressors.

Characterization of Super-Responder Profile in Chronic Plaque Psoriatic Patients under Guselkumab Treatment: A Long-Term Real-Life Experience.

Background: The term "super responder" identifies a group of patients who exhibit a rapid and optimal response to biological treatment compared to the overall treated population. The primary objective of our study is to characterize this subgroup of patients to enable the early identification of those who will respond most effectively to the proposed treatment while also evaluating clinical efficacy. Methods: This retrospective study evaluated 232 patients treated with guselkumab in monotherapy for at least 20 weeks between November 2018 and November 2023. Patients were divided into two groups: those who achieved complete clear skin (PASI = 0) during the first 20 weeks of treatment were defined as super responders (SRe) and non-super responders (nSRe) were the remaining patients. PASI was assessed at weeks 0, 4, and subsequently every eight weeks. Predictors of the SRe status were evaluated by univariate and multivariate logistic regression analyses. Results: The univariate analyses showed that patients with psoriatic arthritis at the baseline, bio-naïve patients, or those who had not received an interleukin (IL) 17 inhibitor as their last therapy before guselkumab administration were more likely to be super responders to the proposed treatment. Multivariate logistic analysis models suggested that the combination of psoriatic arthritis at the baseline and the bio-naïve condition was the strongest predictive model for the SRe status. At week 204, the main difference between the two groups concerned the achievement of PASI100, maintained by 86.8 of SRe compared to 62.8% of nSRe. Conclusions: The efficacy and safety of guselkumab are confirmed in our real-life experience. Identifying the SRe status will undoubtedly play a role in clinical practice and the therapeutic decision-making algorithm.

Long-term results of induction chemotherapy for non-operable esophageal squamous cell carcinoma followed by concurrent chemoradiotherapy: a single-centre experience.

BACKGROUND: This study aimed to investigate the long-term clinical outcomes and toxicities of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) vs. CCRT alone in patients with non-operable esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Between 2008 and 2022, 271 ESCC patients who received definitive CCRT based on intensity modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) were enrolled. Through a propensity score-matched (PSM) method, 71 patients receiving IC and CCRT were matched 1:1 to patients who received CCRT alone. The Kaplan-Meier method and Cox proportional hazards model were applied to analyze survival and prognosis. RESULTS: The IC + CCRT group had no improvement in 5-year overall survival (OS) rate, recurrence-free survival (RFS) rate, and distant metastasis-free survival (DMFS) rate (all p > 0.05) compared with the CCRT group. The 5-year OS rate (65.6% vs. 17.6% vs. 29.3%, p < 0.001), RFS rate (65.6% vs. 17.6% vs. 26.9%, p < 0.001), and DMFS rate (62.5% vs. 10.3% vs. 27.2%, p < 0.001) of the IC good responders were significantly higher than that of the IC poor responders and CCRT group. Multivariate analysis revealed that total radiotherapy time (≥ 49 days) and stage III/IV were independent predictive factors of OS, RFS, and DMFS. No significant differences were observed in the rates of grade 3-4 toxicities between both groups. CONCLUSIONS: Our results showed the addition of IC to CCRT was not superior to CCRT in unselected ESCC patients, while IC responders could benefit from this regime without an increase in toxicities.

Cost-per-responder analysis of patients with lenalidomide-refractory multiple myeloma receiving ciltacabtagene autoleucel in CARTITUDE-4.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.

Predictive Factors for Long-Term High Responders to Upadacitinib Treatment in Patients with Atopic Dermatitis.

Background: Upadacitinib, a Janus kinase 1 inhibitor, is an effective medicine for moderate-to-severe atopic dermatitis (AD). Identifying long-term responders to upadacitinib is crucial for optimal treatment strategies in real-world clinical practice. To identify predictive factors for long-term high responders to upadacitinib 15 mg or 30 mg, defined as achievers of investigator's global assessment (IGA) 0/1 with ≥2-point improvement from baseline IGA at week 48. Methods: A retrospective study was conducted from August 2021 to September 2023 on 63 AD patients treated with upadacitinib 15 mg and 31 patients with 30 mg. Patients of each group were categorized into long-term high responders (achievers of IGA 0/1 at week 48) and low responders (non-achievers). We compared baseline values of clinical indexes and laboratory parameters between long-term responders and nonresponders. Results: In 15 mg group, long-term high responders showed lower rate of bronchial asthma (BA), lower values of baseline eczema area and severity index (EASI) of head and neck, IgE, and systemic inflammatory response index (SIRI) compared with low responders. In 30 mg group, long-term high responders showed lower baseline levels of IgE compared with low responders. Conclusion: Patients with lower baseline EASI of head and neck, IgE, or SIRI or without BA and those with lower baseline IgE may have a higher potential to become long-term high responders to upadacitinib 15 mg and 30 mg treatment, respectively.

Temporal summation does not predict the acupuncture response in patients with chronic non-specific low back pain.

Introduction: Previously, we had observed that immediate pain reduction after one acupuncture treatment was associated with high temporal summation of pain (TS) at a pain free control site and younger age in a mixed population of chronic pain patients. The aim of the present study was to verify these results in chronic non-specific low back pain (LBP) and to collect pilot data on the association between TS and the response to an acupuncture series. Methods: TS at a pain free control site (back of dominant hand) and at the pain site was quantified by the pin-prick induced wind-up ratio (WUR) in 60 LBP patients aged 50 years or younger. Response to one acupuncture treatment was assessed by change in pain intensity and pressure pain threshold (PPT) at the pain site. The primary hypothesis was that a high TS (WUR > 2.5) would be associated with a clinically relevant reduction in pain intensity of at least 30%. In study part two, 26 patients received nine additional treatments. Response to the acupuncture series was assessed by the pain intensity during the last week, the PPT and the Hannover functional ability questionnaire (FFbH-R). Results: An immediate reduction in pain intensity of at least 30% was frequent irrespective of TS at the control site (low vs. high TS 58% vs. 72%, p = 0.266). High TS at the pain site was also not significantly associated with a clinically relevant immediate reduction in pain intensity (low vs. high TS 46% vs. 73%, p = 0.064). The PPT was not changed after one acupuncture treatment. Study part two did not reveal a consistent association between TS at the control site and any of the outcome measures but also a trend toward a higher chance for a clinically relevant response along with low TS at the pain site. Conclusion: Our results do not suggest an important role of TS for predicting a clinically important acupuncture effect or the response to a series of 10 acupuncture treatments in patients with chronic non-specific LBP. Overall high response rates imply that acupuncture is a suitable treatment option for LBP patients irrespective of their TS.

The zero responder: a definition and report of current literature.

The term 'zero responder' was initially devised in 2010 to describe those passing by or unharmed in a mass casualty incident, who provide life-saving care for injured persons before qualified professionals arrive. This review aims to determine how the literature defines the role of the zero responder and to explore how they can be better integrated into the emergency response. Current definitions of the zero responder in a medical setting were found through a literature search of several databases and online libraries using defined search terms. Additionally, a manual search of citations in included articles was performed to yield more results. In total, 16 papers defining the zero responder were included. These definitions were evaluated, and a revised definition was suggested to clarify the role in a medical setting relating to mass casualty incidents. The role of the zero responder can be facilitated through authority recognition and adequate equipment provision. Familiarisation with the term and role of zero responders among ambulance services is essential for effective collaboration. Further research and clarity on the integration of these two groups is necessary to facilitate effective and safe working between them.

Strategic placement of volunteer responder system defibrillators.

Volunteer responder systems (VRS) alert and guide nearby lay rescuers towards the location of an emergency. An application of such a system is to out-of-hospital cardiac arrests, where early cardiopulmonary resuscitation (CPR) and defibrillation with an automated external defibrillator (AED) are crucial for improving survival rates. However, many AEDs remain underutilized due to poor location choices, while other areas lack adequate AED coverage. In this paper, we present a comprehensive data-driven algorithmic approach to optimize deployment of (additional) public-access AEDs to be used in a VRS. Alongside a binary integer programming (BIP) formulation, we consider two heuristic methods, namely Greedy and Greedy Randomized Adaptive Search Procedure (GRASP), to solve the gradual Maximal Covering Location (MCLP) problem with partial coverage for AED deployment. We develop realistic gradually decreasing coverage functions for volunteers going on foot, by bike, or by car. A spatial probability distribution of cardiac arrest is estimated using kernel density estimation to be used as input for the models and to evaluate the solutions. We apply our approach to 29 real-world instances (municipalities) in the Netherlands. We show that GRASP can obtain near-optimal solutions for large problem instances in significantly less time than the exact method. The results indicate that relocating existing AEDs improves the weighted average coverage from 36% to 49% across all municipalities, with relative improvements ranging from 1% to 175%. For most municipalities, strategically placing 5 to 10 additional AEDs can already provide substantial improvements.

"When I hold my daughter, she quiets, no need [for]any verbal conversation": A qualitative understanding of responsive caregiving in rural, Sindh Pakistan.

Responsive caregiving is associated with secure attachment and positive child developmental outcomes. However, there is some debate on whether responsive caregiving is a universal construct. Few studies have researched responsive caregiving in diverse cultural settings, particularly in low- and middle-income countries. In this study, we explore if and how responsive caregiving is conceptualized among mothers of children under 3-years-old in rural, Sindh Pakistan. A phenomenological qualitative study was implemented in Naushahro Feroze through in-depth interviews with twenty mothers. Mothers were asked about their aspirations for their children and how they would respond in a variety of different scenarios. Data were analyzed using thematic content analysis with an inductive-deductive coding scheme. There was substantial variation in mothers' described responsive behaviors and beliefs. Almost all mothers described using some form of responsive parenting. Responding to children's demands while the mother was preoccupied, using verbal responses to console children, and if mothers believed that children should be praised, lacked consensus. Most mothers described using breastfeeding for consolation and highlighted the importance of immediately consoling their crying child. The results suggest that there is a need for a more nuanced approach to understand caregiver behaviors across contexts.

Una sensible prestación de cuidado se asocia con una afectividad segura y con resultados positivos en el desarrollo del niño. Sin embargo, se da un debate sobre si la sensible prestación de cuidado es una estructura universal. Pocos estudios han investigado la sensible prestación de cuidado en diversos escenarios culturales, particularmente en países de bajas y medias entradas económicas. En este estudio, exploramos si la sensible prestación de cuidado está conceptualizada entre las madres de niños menores de 3 años en el área rural de Sindh en Pakistán y cómo lo está. Un estudio fenomenológico cualitativo se implementó usando datos de Naushahro Feroze (ciudad en la provincia de Sindh), por medio de entrevistas profundas con veinte madres. A las madres se les preguntó acerca de sus aspiraciones con respecto a sus niños y cómo ellas responderían en una variedad de diferentes escenarios. Se analizaron los datos usando un análisis de contenido temático con un esquema de codificación inductivo­deductivo. Hubo variación sustancial en las descripciones de las madres acerca de sus conductas y creencias sensibles. Casi todas las madres hicieron las descripciones usando alguna forma de crianza sensible. Faltó el consenso en el caso de responder a las peticiones de los niños mientras la madre estaba preocupada, en el uso de respuestas verbales para consolar a los niños, así como en el caso de si las madres creían que los niños debían ser elogiados. La mayoría de las madres hizo sus descripciones usando el amamantar como manera de consolar y subrayó la importancia de consolar inmediatamente al niño que llora. Los resultados sugieren que hay una necesidad de un acercamiento más matizado para comprender las conductas de prestación de cuidado a través de los contextos.

Trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio in patients with HIV and long-term virological suppression based on Yunnan HIV cohort.

OBJECTIVE: Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression. METHODS: This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization. RESULTS: A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/µL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/µL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization. CONCLUSIONS: Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.

Triptan non-response in a London tertiary headache centre: What can we learn? A retrospective study.

BACKGROUND: Triptans revolutionized the acute treatment of migraine; however, varied responses to triptans, as a result of poor efficacy and tolerability, are reported. A standardized definition of triptan non-response was recently proposed by the European Headache Federation (EHF). There is currently limited data available on the prevalence of triptan non-response. METHODS: We used clinic letters over a two-year duration to evaluate the triptan response and triptan efficacy or tolerability failure, or both, in a London-based tertiary headache service. RESULTS: In total, 419 adult migraine patients (females: 83.8%, age: 46 ± 18 years, chronic migraine: 88.5%) were included in a service evaluation. In line with the EHF definitions, "triptan non-response" was seen in 63.8% of patients (264/414), whereas 37.7% of patients (156/414) had failed at least two triptans (EHF "triptan resistant") and 4.6% of patients (19/414) had failed at least three triptans, including a subcutaneous formulation (EHF "triptan refractory"). Notably, 21.3% of patients (88/414) had failed at least three triptans inclusive and exclusive of subcutaneous triptan use. Advancing age (p < 0.001) and the presence of medication overuse (p = 0.006) increased the probability of triptan response, whereas an increased number of failed preventives (p < 0.001) and the use of calcitonin gene-related peptide monoclonal antibodies (p = 0.022) increased the probability of triptan non-response. The largest proportion of patients responded to eletriptan (49.5%), followed by nasal zolmitriptan (44.4%) and rizatriptan (35.7%). CONCLUSIONS: Our findings highlight an alarming prevalence of triptan non-response among adult migraineurs receiving treatment in a London-based tertiary headache service. It is imperative for clinicians to explore methods to optimize acute medication efficacy, whether this comprises changing to a triptan with a superior response rate, advocating for early intervention or considering alternative acute medication classes, such as gepants or ditans.

Cost per treatment responder analysis of atogepant compared to rimegepant for the preventive treatment of episodic migraine.

OBJECTIVE: To estimate the number needed to treat and cost per additional responder for atogepant and rimegepant versus placebo for the preventive treatment of episodic migraine (EM) in the United States. BACKGROUND: Migraine has an enormous impact on a person's daily activities and quality of life, and results in significant clinical and economic burden to both individuals and society. It is important to understand the comparative efficacy and economic value of oral calcitonin gene-related peptide receptor antagonists (gepants) for preventive treatment of EM. Currently, atogepant and rimegepant are US Food and Drug Administration approved for preventive treatment of migraine (rimegepant for EM and atogepant for EM and for chronic migraine). In the absence of head-to-head trials, we utilized an indirect treatment comparison on efficacy data from clinical trials conducted for the preventive treatment of EM. We estimated number needed to treat, a valuable metric used in clinical practice to compare treatment efficacy, and cost per additional responder, which can be used to establish the cost effectiveness of a treatment. METHODS: An indirect treatment comparison was conducted to compare the efficacy of atogepant 60 mg once daily and rimegepant 75 mg once every other day as preventive treatments for EM using published data from the registrational trials of atogepant (ADVANCE) and rimegepant (BHV3000-305). The efficacy outcome of interest was ≥50% reduction from baseline in mean monthly migraine/headache days (≥50% responder rate), which was variably defined for a base case and two scenario analyses. Number needed to treat and cost per additional responder versus placebo were calculated and compared between both treatments (weeks 9-12 in the base case analysis; weeks 1-12 and 9-12 for atogepant and during weeks 9-12 for rimegepant in the scenario analyses). RESULTS: In the base case analysis, ≥50% responder rates were 64.9% (95% confidence interval [CI], 53.9-74.5) for atogepant and 51.8% (95% CI, 42.9-60.6) for rimegepant, compared to 44.1% (95% CI, 39.4-49.0) for placebo. The median number needed to treat versus placebo in the base case scenario was 4.8 (95% CI, 3.1-9.0) for atogepant compared to 13.0 (95% CI, 5.9-75.1) for rimegepant. The cost per additional responder versus placebo in the base case scenario was estimated to be $15,823 (95% CI, $11,079-$29,516) for atogepant compared to $73,029 (95% CI, $32,901-$422,104) for rimegepant. Results of the two scenario analyses were consistent with the base case analysis. CONCLUSIONS: Atogepant had substantially lower numbers needed to treat and costs per additional responder versus placebo than rimegepant for the preventive treatment of EM across all evaluated scenarios. These analyses suggest that atogepant may be more cost effective than rimegepant for the preventive treatment of EM. Limitations include differences in inclusion/exclusion criteria and in reporting of the ≥50% responder rates between trials.