The reliability, validity and clinical utility of the Clinical Outcomes in Routine Evaluation - ten-item version (CORE-10) in post-acute patients with stroke.

OBJECTIVE: To explore the validity, reliability, and clinical utility of the Clinical Outcomes in Routine Evaluation - ten-item version (CORE-10: a ten-item questionnaire designed to measure psychological distress) in a stroke inpatient sample and calculate reliable and clinically significant change scores. SETTING: A post-acute stroke rehabilitation ward in the East of England. PARTICIPANTS: A total of 53 patients with stroke, capable of completing the CORE-10 as part of their routine clinical assessment. Exclusion criteria included moderate to severe aphasia and/or alexia. MAIN MEASURES: Alongside the CORE-10, the Patient Health Questionnaire - 9, the Hospital Anxiety and Depression Scale, the Centre for Epidemiological Studies-Depression Scale, and the Beck Depression Inventory Second Edition were used as concurrent measures. RESULTS: To assess reliability, the internal consistency and test-retest reliability of the CORE-10 were calculated. The average number of days between CORE-10 test-retest administrations was 2.84 (SD = 3.12, Mdn = 1). Concurrent validity was assessed by examining correlations between the CORE-10 and comparable measures, and clinical utility was assessed using the criteria of Burton and Tyson (2015). The internal consistency (Cronbach's alpha) for the CORE-10 was .80, and test-retest reliability interclass correlation coefficient was .81. Total score correlations between the CORE-10 and concurrent measures ranged from r = .49 to r = .89. The CORE-10 achieved the maximum score (i.e. 6/6) on criteria for clinical utility. Calculations demonstrated a reliable change index of nine points and a clinically significant change cut point of 12 on the CORE-10. Percentiles for CORE-10 total scores are reported. CONCLUSIONS: This study provides preliminary support for the CORE-10 as a valid and reliable measure that has clinical utility for screening distress in inpatients with stroke.

Post-stroke emotionalism: Diagnosis, pathophysiology, and treatment.

BACKGROUND: Post-stroke emotionalism affects one in five stroke sufferers 6 months after their stroke, but despite its frequency remains a poorly understood stroke symptom. The literature is limited, especially compared to other frequently observed neurological conditions such as aphasia and visual neglect. AIM AND METHODS: This narrative review presents a summary of the post-stroke emotionalism literature, to inform clinical practice and future research. We cover discussion of definitions, prevalence, neurobiology, predisposing and precipitating factors, and treatment. RESULTS: Increasing evidence suggests that damage to specific areas functionally linked to emotion expression or regulation processes, disruption to structural pathways and those related to serotonin production and modulation individually or in concert give rise to emotionalism-type presentations. A range of emotionalism measurement tools have been used in research contexts making between study comparisons difficult. Testing for Emotionalism after Recent Stroke-Questionnaire (TEARS-Q) has recently been developed to allow standardized assessment. Treatment options are limited, and there have been few adequately powered treatment trials. Antidepressants may reduce severity, but more trial data are required. There have been no randomized-controlled trials of non-pharmacological interventions. CONCLUSIONS: More research is needed to improve recognition and treatment of this common and disabling symptom. We conclude with research priorities and recommendations for the field.

SARS-CoV-2, influenza A/B and respiratory syncytial virus positivity and association with influenza-like illness and self-reported symptoms, over the 2022/23 winter season in the UK: a longitudinal surveillance cohort.

BACKGROUND: Syndromic surveillance often relies on patients presenting to healthcare. Community cohorts, although more challenging to recruit, could provide additional population-wide insights, particularly with SARS-CoV-2 co-circulating with other respiratory viruses. METHODS: We estimated the positivity and incidence of SARS-CoV-2, influenza A/B, and RSV, and trends in self-reported symptoms including influenza-like illness (ILI), over the 2022/23 winter season in a broadly representative UK community cohort (COVID-19 Infection Survey), using negative-binomial generalised additive models. We estimated associations between test positivity and each of the symptoms and influenza vaccination, using adjusted logistic and multinomial models. RESULTS: Swabs taken at 32,937/1,352,979 (2.4%) assessments tested positive for SARS-CoV-2, 181/14,939 (1.2%) for RSV and 130/14,939 (0.9%) for influenza A/B, varying by age over time. Positivity and incidence peaks were earliest for RSV, then influenza A/B, then SARS-CoV-2, and were highest for RSV in the youngest and for SARS-CoV-2 in the oldest age groups. Many test positives did not report key symptoms: middle-aged participants were generally more symptomatic than older or younger participants, but still, only ~ 25% reported ILI-WHO and ~ 60% ILI-ECDC. Most symptomatic participants did not test positive for any of the three viruses. Influenza A/B-positivity was lower in participants reporting influenza vaccination in the current and previous seasons (odds ratio = 0.55 (95% CI 0.32, 0.95)) versus neither season. CONCLUSIONS: Symptom profiles varied little by aetiology, making distinguishing SARS-CoV-2, influenza and RSV using symptoms challenging. Most symptoms were not explained by these viruses, indicating the importance of other pathogens in syndromic surveillance. Influenza vaccination was associated with lower rates of community influenza test positivity.

An evaluation of an open group for depressed mood on a stroke rehabilitation ward: three years of clinical data.

PURPOSE: An open group intervention for stroke inpatients, based on Acceptance and Commitment Therapy, is evaluated using retrospective clinical service data. MATERIALS AND METHODS: Participants were included unless severely unwell or unable to provide informed consent. 117 participants attended at least two sessions in a non-controlled, repeated measures design. Two session protocols were delivered on alternating weeks by an Assistant Psychologist and Trainee Psychologist, covering values, committed action, and acceptance. Participants rated their mood each session using the Depression Intensity Scale Circles (DISCs). RESULTS: Attended sessions ranged from 1 to 11 (Md: 2). Significant reductions in DISCs scores with medium effect sizes were found among those scoring above the cut-off for depression at baseline, Χ2(3) = 20.87, p < .001. The likelihood of scoring below the cut-off for depression did not change between participants' first and last sessions, X2(1, N = 117) = 1.36, p = .24. The number of sessions attended did not predict outcome, rs(117) = .09, p = .33. CONCLUSIONS: Design limitations prevented inferences of clinical effectiveness, but the group met several clinical utility criteria by providing a flexible intervention on a rehabilitation ward with competing demands. We highlight the importance of contrasting findings of clinical trials with data from clinical services.

In an uncontrolled, within-subjects analysis, we found that attendance of an open-group Acceptance and Commitment Therapy (ACT) based intervention was associated with reduced depressive symptoms in stroke rehabilitation inpatientsOpen-group psychological interventions may be an accessible and low-cost option for stroke clinicians on inpatient wards where flexibility is important.

Trajectories of Quality of Life After Pelvic Exenteration: A Latent Class Growth Analysis.

BACKGROUND: Information on the course of quality of life after surgery for advanced cancers within the pelvis is important to guide patient decision-making; however, the current evidence is limited. OBJECTIVE: To identify quality-of-life trajectory classes and their predictors after pelvic exenteration. DESIGN: Prospective cohort study. SETTINGS: Highly specialized quaternary pelvic exenteration referral center. PATIENTS: Patients undergoing pelvic exenteration due to advanced/recurrent cancers within the pelvis between July 2008 and July 2022. MAIN OUTCOME MEASURES: Quality-of-life data included the 36-item Short-Form Survey (physical and mental component scores) and the Functional Assessment of Cancer Therapy-Colorectal instruments, which were collected at 11 distinct points from baseline to 5 years postoperatively. Predictors included patient characteristics and surgical outcomes. Latent class analysis was used to identify the likelihood of a better quality-of-life class, and logistic regression models were used to identify predictors of the identified classes. RESULTS: The study included 565 participants. Two distinct quality-of-life trajectory classes were identified for the Physical Component Score (class 1: high stable and class 2: high decreasing). Three distinct classes were identified for the Mental Component Score (class 1: high increasing, class 2: moderate stable, and class 3: moderate decreasing) and for Functional Assessment of Cancer Therapy-Colorectal total score (class 1: high increasing, class 2: high decreasing, and class 3: low decreasing). Across the 3 quality-of-life domains, overall survival probabilities were also higher in class 1 ( p < 0.0001). Age, repeat exenteration, neoadjuvant therapy, surgical margin, length of operation, and hospital stay were significant predictors of quality-of-life classes. LIMITATIONS: This study was conducted at a single highly specialized quaternary pelvic exenteration referral center, and findings may not apply to other centers. CONCLUSIONS: This study demonstrates that quality of life after pelvic exenteration diverges into distinct trajectories, with most patients reporting an optimal course. See Video Abstract . TRAYECTORIAS EN LA CALIDAD DE VIDA DESPUS DE EXENTERACIN PLVICA ANLISIS DE CRECIMIENTO DE CLASES LATENTES: ANTECEDENTES:La información sobre la evolución en la calidad de vida después de cirugía en cánceres avanzados situados en la pelvis es importante para guiar la toma de decisiones sobre el paciente; sin embargo, la evidencia actual es muy limitada.OBJETIVO:Identificar las clases de trayectorias en la calidad de vida y sus factores pronóstico después de la exenteración pélvica.DISEÑO:Estudio de cohortes prospectivo.AJUSTES:Centro de referencia altamente especializado en la exenteración pélvica cuaternaria.PACIENTES:Todos aquellos sometidos a exenteración pélvica por cáncer avanzados/recurrentes situados en la pelvis entre Julio de 2008 y Julio de 2022.PRINCIPALES MEDIDAS DE RESULTADO:Los datos sobre la calidad de vida incluyeron el Cuestionario de Salud SF-36 (puntuaciones de componentes físicos y mentales) y la evaluación funcional entre la terapia del cáncer/-herramientas colorrectales, recopilados en 11 puntos distintos desde el diagnóstico hasta los 5 años después de la operación.Los predictores incluyeron las características de los pacientes y los resultados quirúrgicos. Se utilizó el análisis de clases latentes para identificar la probabilidad de una mejor calidad de vida y se utilizaron modelos de regresión logística para identificar predictores de las clases identificadas.RESULTADOS:El estudio incluyó a 565 participantes. Se identificaron dos clases distintas de trayectorias de calidad de vida para la puntuación del componente físico (clase 1: alta estable y clase 2: alta decreciente), se identificaron tres clases distintas para la puntuación del componente mental (clase 1: alta creciente; clase 2: moderadamente estable; y clase 3: moderada disminución) y para la evaluación funcional de la terapia contra el cáncer-puntuación total colorrectal (clase 1: aumento alto; clase 2: disminución alta; y clase 3: disminución baja). En los tres dominios de calidad de vida, las probabilidades de supervivencia general también fueron mayores en las clases 1 (p <0,0001). La edad, las exenteraciones pélvicas repetidas, la terapia neoadyuvante, el margen quirúrgico, la duración de la operación y la estadía hospitalaria fueron predictores significativos en las clases de calidad de vida.LIMITACIONES:El presente estudio fué realizado en un único centro de referencia altamente especializado en exenteración pélvica cuaternaria y es posible que los hallazgos no se apliquen a otros centros.CONCLUSIONES:Demostramos con nuestro estudio que la calidad de vida después de la exenteración pélvica diverge en trayectorias distintas, y que la mayoría de los pacientes nos reportaron de una évolución óptima. (Traducción-Dr. Xavier Delgadillo ).

Challenges in estimation, uncertainty quantification and elicitation for pandemic modelling.

The estimation of parameters and model structure for informing infectious disease response has become a focal point of the recent pandemic. However, it has also highlighted a plethora of challenges remaining in the fast and robust extraction of information using data and models to help inform policy. In this paper, we identify and discuss four broad challenges in the estimation paradigm relating to infectious disease modelling, namely the Uncertainty Quantification framework, data challenges in estimation, model-based inference and prediction, and expert judgement. We also postulate priorities in estimation methodology to facilitate preparation for future pandemics.

Estimation of reproduction numbers in real time: Conceptual and statistical challenges.

The reproduction number R has been a central metric of the COVID-19 pandemic response, published weekly by the UK government and regularly reported in the media. Here, we provide a formal definition and discuss the advantages and most common misconceptions around this quantity. We consider the intuition behind different formulations of R , the complexities in its estimation (including the unavoidable lags involved), and its value compared to other indicators (e.g. the growth rate) that can be directly observed from aggregate surveillance data and react more promptly to changes in epidemic trend. As models become more sophisticated, with age and/or spatial structure, formulating R becomes increasingly complicated and inevitably model-dependent. We present some models currently used in the UK pandemic response as examples. Ultimately, limitations in the available data streams, data quality and time constraints force pragmatic choices to be made on a quantity that is an average across time, space, social structure and settings. Effectively communicating these challenges is important but often difficult in an emergency.

Real-time nowcasting and forecasting of COVID-19 dynamics in England: the first wave.

England has been heavily affected by the SARS-CoV-2 pandemic, with severe 'lockdown' mitigation measures now gradually being lifted. The real-time pandemic monitoring presented here has contributed to the evidence informing this pandemic management throughout the first wave. Estimates on the 10 May showed lockdown had reduced transmission by 75%, the reproduction number falling from 2.6 to 0.61. This regionally varying impact was largest in London with a reduction of 81% (95% credible interval: 77-84%). Reproduction numbers have since then slowly increased, and on 19 June the probability of the epidemic growing was greater than 5% in two regions, South West and London. By this date, an estimated 8% of the population had been infected, with a higher proportion in London (17%). The infection-to-fatality ratio is 1.1% (0.9-1.4%) overall but 17% (14-22%) among the over-75s. This ongoing work continues to be key to quantifying any widespread resurgence, should accrued immunity and effective contact tracing be insufficient to preclude a second wave. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.

Outcomes following repeat exenteration for locally advanced pelvic malignancy.

AIM: This study aims to assess surgical outcomes and survival following first, second and third pelvic exenterations for pelvic malignancy. METHOD: Consecutive patients undergoing pelvic exenteration for pelvic malignancy at a quaternary referral centre from January 1994 and December 2017 were included. Demographics and surgical outcomes were compared between patients who underwent first, second and third pelvic exenterations by generalized mixed modelling with repeated measures. Survival was assessed using Cox proportional hazards models and Kaplan-Meier plots. RESULTS: Of the 642 exenterations reviewed, 29 (4.5%) were second and 6 (0.9%) were third exenterations. Patients selected for repeat exenteration were more likely to have asymptomatic local recurrences detected on routine surveillance (P < 0.001). Postoperative wound complications increased with repeat exenteration (6%, 17%, 33%; P = 0.003, respectively). Additionally, postoperative length of stay increased from 27 to 38 and 48 days, respectively (P = 0.004). Median survival from first exenteration was 4.75, 5.30 and 8.14 years respectively amongst first, second and third exenteration cohorts (P = 0.849). Median survival from the most recent exenteration was 4.75 years after a first exenteration, 2.02 years after a second exenteration and 1.45 years after a third exenteration (P = 0.0546). CONCLUSION: This study demonstrates that repeat exenteration for recurrent pelvic malignancy is feasible but is associated with increased complication rates and length of admission and reduced likelihood of attaining R0 margin. Moreover, these data indicate that repeat exenteration does not afford a survival advantage compared with patients having a single exenteration. These data suggest that repeat exenteration for recurrent pelvic malignancy may be of questionable therapeutic value.

Hedgehog-GLI signaling in Foxd1-positive stromal cells promotes murine nephrogenesis via TGFß signaling.

Normal kidney function depends on the proper development of the nephron: the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of hedgehog intracellular effector smoothened (Smo-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-hedgehog-Smo signaling acts through a GLI3 repressor. Whole-kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFß2 signaling in Smo-deficient mutants. We show that neutralization and knockdown of TGFß2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of Tgfbr2 in stromal and nephrogenic cells in vivo results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in Smo-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal hedgehog-TGFß2 signaling axis acts to control nephrogenesis.

Urogenital development in Pallister-Hall syndrome is disrupted in a cell-lineage-specific manner by constitutive expression of GLI3 repressor.

Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.

Renal branching morphogenesis: morphogenetic and signaling mechanisms.

The human kidney is composed of an arborized network of collecting ducts, calyces and urinary pelvis that facilitate urine excretion and regulate urine composition. The renal collecting system is formed in utero, completed by the 34th week of gestation in humans, and dictates final nephron complement. The renal collecting system arises from the ureteric bud, a derivative of the intermediate-mesoderm derived nephric duct that responds to inductive signals from adjacent tissues via a process termed ureteric induction. The ureteric bud subsequently undergoes a series of iterative branching and remodeling events in a process called renal branching morphogenesis. Altered signaling that disrupts patterning of the nephric duct, ureteric induction, or renal branching morphogenesis leads to varied malformations of the renal collecting system collectively known as congenital anomalies of the kidney and urinary tract (CAKUT) and is the most frequently detected congenital renal aberration in infants. Here, we describe critical morphogenetic and cellular events that govern nephric duct specification, ureteric bud induction, renal branching morphogenesis, and cessation of renal branching morphogenesis. We also highlight salient molecular signaling pathways that govern these processes, and the investigative techniques used to interrogate them.

GLI3 repressor controls functional development of the mouse ureter.

Obstructive and nonobstructive forms of hydronephrosis (increased diameter of the renal pelvis and calyces) and hydroureter (dilatation of the ureter) are the most frequently detected antenatal abnormalities, yet the underlying molecular mechanisms are largely undefined. Hedgehog (Hh) proteins control tissue patterning and cell differentiation by promoting GLI-dependent transcriptional activation and by inhibiting the processing of GLI3 to a transcriptional repressor. Genetic mutations that generate a truncated GLI3 protein similar in size to the repressor in humans with Pallister-Hall syndrome (PHS; a disorder whose characteristics include renal abnormalities) and hydroureter implicate Hh-dependent signaling in ureter morphogenesis and function. Here, we determined that Hh signaling controls 2 cell populations required for the initiation and transmission of coordinated ureter contractions. Tissue-specific inactivation of the Hh cell surface effector Smoothened (Smo) in the renal pelvic and upper ureteric mesenchyme resulted in nonobstructive hydronephrosis and hydroureter characterized by ureter dyskinesia. Mutant mice had reduced expression of markers of cell populations implicated in the coordination of unidirectional ureter peristalsis (specifically, Kit and hyperpolarization-activation cation-3 channel [Hcn3]), but exhibited normal epithelial and smooth muscle cell differentiation. Kit deficiency in a mouse model of PHS suggested a pathogenic role for GLI3 repressor in Smo-deficient embryos; indeed, genetic inactivation of Gli3 in Smo-deficient mice rescued their hydronephrosis, hydroureter, Kit and Hcn3 expression, and ureter peristalsis. Together, these data demonstrate that Hh signaling controls Kit and Hcn3 expression and ureter peristalsis.