Experiences of hospital care for people with multiple long-term conditions: a scoping review of qualitative research.

BACKGROUND: Multiple long-term conditions-the co-existence of two or more chronic health conditions in an individual-present an increasing challenge to populations and healthcare systems worldwide. This challenge is keenly felt in hospital settings where care is oriented around specialist provision for single conditions. The aim of this scoping review was to identify and summarise published qualitative research on the experiences of hospital care for people living with multiple long-term conditions, their informal caregivers and healthcare professionals. METHODS: We undertook a scoping review, following established guidelines, of primary qualitative research on experiences of hospital care for people living with multiple long-term conditions published in peer-reviewed journals between Jan 2010 and June 2022. We conducted systematic electronic searches of MEDLINE, CINAHL, PsycInfo, Proquest Social Science Premium, Web of Science, Scopus and Embase, supplemented by citation tracking. Studies were selected for inclusion by two reviewers using an independent screening process. Data extraction included study populations, study design, findings and author conclusions. We took a narrative approach to reporting the findings. RESULTS: Of 8002 titles and abstracts screened, 54 papers reporting findings from 41 studies conducted in 14 countries were identified as eligible for inclusion. The perspectives of people living with multiple long-term conditions (21 studies), informal caregivers (n = 13) and healthcare professionals (n = 27) were represented, with 15 studies reporting experiences of more than one group. Findings included poor service integration and lack of person-centred care, limited confidence of healthcare professionals to treat conditions outside of their specialty, and time pressures leading to hurried care transitions. Few studies explored inequities in experiences of hospital care. CONCLUSIONS: Qualitative research evidence on the experiences of hospital care for multiple long-term conditions illuminates a tension between the desire to provide and receive person-centred care and time pressures inherent within a target-driven system focussed on increasing specialisation, reduced inpatient provision and accelerated journeys through the care system. A move towards more integrated models of care may enable the needs of people living with multiple long-term conditions to be better met. Future research should address how social circumstances shape experiences of care.

Myoprotective whole foods, muscle health and sarcopenia in older adults.

PURPOSE OF REVIEW: Sarcopenia increases in prevalence at older ages and may be exacerbated by poor diet. Whole foods rich in specific nutrients may be myoprotective and mitigate the risk of sarcopenia. Here we review recent evidence published from observational and intervention studies regarding myoprotective foods and explore their benefit for the prevention and/or treatment of sarcopenia in older adults. RECENT FINDINGS: We found limited new evidence for the role of whole foods in sarcopenia and sarcopenia components (muscle mass, strength, physical performance). There was some evidence for higher consumption of protein-rich foods (milk and dairy) being beneficial for muscle strength in observational and intervention studies. Higher consumption of antioxidant-rich foods (fruit and vegetables) was associated with better physical performance and lower odds of sarcopenia in observational studies. Evidence for other protein- and antioxidant-rich foods were inconsistent or lacking. There remains a clear need for intervention studies designed to identify the role of whole foods for the treatment of sarcopenia. SUMMARY: Although evidence for myoprotective roles of dairy, fruit and vegetables is emerging from observational studies, higher level evidence from intervention studies is needed for these foods to be recommended in diets of older adults to prevent and/or treat sarcopenia.

Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

The use of natural language processing for the identification of ageing syndromes including sarcopenia, frailty and falls in electronic healthcare records: a systematic review.

BACKGROUND: Recording and coding of ageing syndromes in hospital records is known to be suboptimal. Natural Language Processing algorithms may be useful to identify diagnoses in electronic healthcare records to improve the recording and coding of these ageing syndromes, but the feasibility and diagnostic accuracy of such algorithms are unclear. METHODS: We conducted a systematic review according to a predefined protocol and in line with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Searches were run from the inception of each database to the end of September 2023 in PubMed, Medline, Embase, CINAHL, ACM digital library, IEEE Xplore and Scopus. Eligible studies were identified via independent review of search results by two coauthors and data extracted from each study to identify the computational method, source of text, testing strategy and performance metrics. Data were synthesised narratively by ageing syndrome and computational method in line with the Studies Without Meta-analysis guidelines. RESULTS: From 1030 titles screened, 22 studies were eligible for inclusion. One study focussed on identifying sarcopenia, one frailty, twelve falls, five delirium, five dementia and four incontinence. Sensitivity (57.1%-100%) of algorithms compared with a reference standard was reported in 20 studies, and specificity (84.0%-100%) was reported in only 12 studies. Study design quality was variable with results relevant to diagnostic accuracy not always reported, and few studies undertaking external validation of algorithms. CONCLUSIONS: Current evidence suggests that Natural Language Processing algorithms can identify ageing syndromes in electronic health records. However, algorithms require testing in rigorously designed diagnostic accuracy studies with appropriate metrics reported.

Comparing associations of handgrip strength and chair stand performance with all-cause mortality-implications for defining probable sarcopenia: the Tromsø Study 2015-2020.

BACKGROUND: Widely adopted criteria suggest using either low handgrip strength or poor chair stand performance to identify probable sarcopenia. However, there are limited direct comparisons of these measures in relation to important clinical endpoints. We aimed to compare associations between these two measures of probable sarcopenia and all-cause mortality. METHODS: Analyses included 7838 community-dwelling participants (55% women) aged 40-84 years from the seventh survey of the Tromsø Study (2015-2016), with handgrip strength assessed using a Jamar + Digital Dynamometer and a five-repetition chair stand test (5-CST) also undertaken. We generated sex-specific T-scores and categorised these as "not low", "low", and "very low" handgrip strength or 5-CST performance. Cox Proportional Hazard regression models were used to investigate associations between these two categorised performance scores and time to death (up to November 2020 ascertained from the Norwegian Cause of Death registry), adjusted for potential confounders including lifestyle factors and specific diseases. RESULTS: A total of 233 deaths occurred (median follow-up 4.7 years) with 1- and 5-year mortality rates at 3.1 (95% confidence interval [CI] 2.1, 4.6) and 6.3 (95% CI 5.5, 7.2) per 1000 person-years, respectively. There was poor agreement between the handgrip strength and 5-CST categories for men (Cohen's kappa [κ] = 0.19) or women (κ = 0.20). Fully adjusted models including handgrip strength and 5-CST performance mutually adjusted for each other, showed higher mortality rates among participants with low (hazard ratio [HR] 1.22, 95% CI 0.87, 1.71) and very low (HR 1.68, 95% CI 1.02, 2.75) handgrip strength compared with the not low category. Similar associations, although stronger, were seen for low (HR 1.88, 95% CI 1.38, 2.56) and very low (HR 2.64, 95% CI 1.73, 4.03) 5-CST performance compared with the not low category. CONCLUSIONS: We found poor agreement between T-score categories for handgrip strength and 5-CST performance and independent associations with mortality. Our findings suggest that these tests identify different people at risk when case-finding probable sarcopenia. As discussions on an international consensus for sarcopenia definitions proceed, testing both handgrip strength and chair stand performance should be recommended rather than viewing these as interchangeable assessments.

Simple approaches to characterising multiple long-term conditions (multimorbidity) and rates of emergency hospital admission: Findings from 495,465 UK Biobank participants.

BACKGROUND: Numerous approaches are used to characterise multiple long-term conditions (MLTC), including counts and indices. Few studies have compared approaches within the same dataset. We aimed to characterise MLTC using simple approaches, and compare their prevalence estimates of MLTC and associations with emergency hospital admission in the UK Biobank. METHODS: We used baseline data from 495,465 participants (age 38-73 years) to characterise MLTC using four approaches: Charlson index (CI), Byles index (BI), count of 43 conditions (CC) and count of body systems affected (BC). We defined MLTC as more than two conditions using CI, BI and CC, and more than two body systems using BC. We categorised scores (incorporating weightings for the indices) from each approach as 0, 1, 2 and 3+. We used linked hospital episode statistics and performed survival analyses to test associations with an endpoint of emergency hospital admission or death over 5 years. RESULTS: The prevalence of MLTC was 44% (BC), 33% (CC), 6% (BI) and 2% (CI). Higher scores using all approaches were associated with greater outcome rates independent of sex and age group. For example, using CC, compared with score 0, score 2 had 1.95 (95% CI: 1.91, 1.99) and a score of 3+ had 3.12 (95% CI: 3.06, 3.18) times greater outcome rates. The discriminant value of all approaches was modest (C-statistics 0.60-0.63). CONCLUSIONS: The counts classified a greater proportion as having MLTC than the indices, highlighting that prevalence estimates of MLTC vary depending on the approach. All approaches had strong statistical associations with emergency hospital admission but a modest ability to identify individuals at risk.

Milk intake across adulthood and muscle strength decline from mid- to late life: the MRC National Survey of Health and Development.

Milk is a source of several nutrients which may be beneficial for skeletal muscle. Evidence that links lower milk intake with declines in muscle strength from midlife to old age is lacking. We used data from the Medical Research Council National Survey of Health and Development to test sex-specific associations between milk consumption from age 36 to 60-64 years, low grip strength (GS) or probable sarcopenia, and GS decline from age 53 to 69 years. We included 1340 men and 1383 women with at least one measure of both milk intake and GS. Milk intake was recorded in 5-d food diaries (aged 36, 43, 53 and 60-64 years), and grand mean of total, reduced-fat and full-fat milk each categorised in thirds (T1 (lowest) to T3 (highest), g/d). GS was assessed at ages 53, 60-64, and 69 years, and probable sarcopenia classified at the age of 69 years. We employed logistic regression to examine the odds of probable sarcopenia and multilevel models to investigate decline in GS in relation to milk intake thirds. Compared with T1, only T2 (58·76-145·25 g/d) of reduced-fat milk was associated with lower odds of sex-specific low GS at the age of 69 years (OR (95 % CI): 0·59 (0·37, 0·94), P = 0·03). In multilevel models, only T3 of total milk (≥ 237·52 g/d) was associated with stronger GS in midlife in men (ß (95 % CI) = 1·82 (0·18, 3·45) kg, P = 0·03) compared with T1 (≤ 152·0 g/d), but not with GS decline over time. A higher milk intake across adulthood may promote muscle strength in midlife in men. Its role in muscle health in late life needs further examination.

"I was Close to Helping him but Couldn't Quite get There": Psychiatrists' Experiences of a Patient's Death by Suicide.

OBJECTIVES: A patient's death by suicide is a common experience for psychiatrists, ranging from 33% to 80%, however, research about the impact of patient suicide on psychiatrists is limited to a few survey studies. This study had three main objectives: (1) understanding the emotional and behavioural impact of a patient's suicide on psychiatrists, (2) exploring if and how the experience of a patient's suicide results in changes in psychiatrist practice patterns, and (3) understanding the tangible steps that psychiatrists and institutions take to manage the emotional and behavioural impact of patient suicide on psychiatrists. METHODS: Eighteen psychiatrists were recruited using snowball sampling and interviewed to collect demographic data, followed by an in-depth exploration of their experiences of patient suicide. Interviews were then transcribed verbatim and analysed using constructivist grounded theory. RESULTS: Study participants described strong emotional reactions in response to patient suicide. Emotional reactions were mediated by a physician, patient, relationship and institutional factors. While psychiatrists did not change the acuity or setting of their practice in response to patient suicide, they made several changes in their practice, including increased caution regarding discharges and passes from inpatient units, more thorough documentation and continuing education about suicide. CONCLUSIONS: Patient suicide has a profound impact on psychiatrists and based on the findings of this study, we propose steps that psychiatrists and institutions can take to manage the emotional, psychological and behavioural burden of this event.

DLX6 and MSX1 from saliva samples as potential predictors of mandibular size: A cross-sectional study.

INTRODUCTION: Morphologic features of the mandible are influenced by the genes of each individual. Mandible size is important to orthodontists because the mandible is the mechanism by which the lower face influences facial esthetics and dental function. To date, no biological marker has been identified that indicates eventual mandible size. This study aimed to correlate the expression of DLX5, DLX6, EDN1, HAND2, PRRX1, and MSX1 to mandible size. METHODS: Fifty-nine orthodontic patients aged >6 years who had available cephalometric radiographs were studied. Patients were classified on the basis of condylion-to-gnathion measurements. Messenger RNA was isolated from saliva and subjected to real-time quantitative polymerase chain reaction. RESULTS: Threshold cycle values for subjects with small mandibles (>1 standard deviation [SD] from the mean) had the least expression of DLX6 and MSX1. Threshold cycle values for subjects with large mandibles (>1 SD) had less expression of DLX6 and MSX1 than subjects within 1 SD but more than those with small mandibles. CONCLUSIONS: DLX6 and MSX1 are related to mandible development and size. This finding could be used to improve treatment planning for medical and dental professionals seeking to understand the impact of genetics on bone growth.

Adiposity and grip strength: a Mendelian randomisation study in UK Biobank.

BACKGROUND: Muscle weakness, which increases in prevalence with age, is a major public health concern. Grip strength is commonly used to identify weakness and an improved understanding of its determinants is required. We aimed to investigate if total and central adiposity are causally associated with grip strength. METHODS: Up to 470,786 UK Biobank participants, aged 38-73 years, with baseline data on four adiposity indicators (body mass index (BMI), body fat percentage (BF%), waist circumference (WC) and waist-hip-ratio (WHR)) and maximum grip strength were included. We examined sex-specific associations between each adiposity indicator and grip strength. We explored whether associations varied by age, by examining age-stratified associations (< 50 years, 50-59 years, 60-64 years,65 years +). Using Mendelian randomisation (MR), we estimated the strength of the adiposity-grip strength associations using genetic instruments for each adiposity trait as our exposure. RESULTS: In males, observed and MR associations were generally consistent: higher BMI and WC were associated with stronger grip; higher BF% and WHR were associated with weaker grip: 1-SD higher BMI was associated with 0.49 kg (95% CI: 0.45 kg, 0.53 kg) stronger grip; 1-SD higher WHR was associated with 0.45 kg (95% CI:0.41 kg, 0.48 kg) weaker grip (covariate adjusted observational analyses). Associations of BMI and WC with grip strength were weaker at older ages: in males aged < 50 years and 65 years + , 1-SD higher BMI was associated with 0.93 kg (95% CI: 0.84 kg, 1.01 kg) and 0.13 kg (95% CI: 0.05 kg, 0.21 kg) stronger grip, respectively. In females, higher BF% was associated with weaker grip and higher WC was associated with stronger grip; other associations were inconsistent. CONCLUSIONS: Using different methods to triangulate evidence, our findings suggest causal links between adiposity and grip strength. Specifically, higher BF% (in both sexes) and WHR (males only) were associated with weaker grip strength.

Cannabis Use Among Young Adults in Washington State After Legalization of Nonmedical Cannabis.

Objectives. To examine changes in prevalence of cannabis use and of cannabis use disorder symptomatology among young adults from 2014 to 2019 in Washington State, where nonmedical (or "recreational") cannabis was legalized in 2012 and retail stores opened in July 2014. Methods. We used 6 years of cross-sectional data collected annually from 2014 (premarket opening) to 2019 from 12 963 (∼2000 per year) young adults aged 18 to 25 years residing in Washington. Logistic regression models estimated yearly change in prevalence of cannabis use at different margins and related outcomes. Results. Prevalence of past-year, at least monthly, at least weekly, and daily use of cannabis increased for young adults, although increases were driven by changes among those aged 21 to 25 years. There was also a statistically significant increase in prevalence of endorsing at least 2 of 5 possible symptoms associated with cannabis use disorder. Conclusions. Among young adults in Washington, particularly those of legal age, prevalences of cannabis use and cannabis use disorder symptomatology have increased since legalization. This trend may require continued monitoring as the nonmedical cannabis market continues to evolve. (Am J Public Health. 2022;112(4):638-645. https://doi.org/10.2105/AJPH.2021.306641).

Prepartying and incapacitated rape: Is drinking a risk factor or an outcome?

BACKGROUND: Incapacitated rape (IR) is common in college and has been linked to heavier post-assault drinking and consequences, including blackouts. Following IR, college students may adjust their drinking in ways meant to increase perceived safety, such as enhancing situational control over one's drinks through prepartying, which is drinking before going out to a main social event. Although it is possible that prepartying could influence risk related to IR, it is unclear whether or how prepartying and IR are associated. METHODS: To address these gaps, we examined prepartying as both a risk factor and a consequence of IR, including the reasons for prepartying. Across two studies (Study 1 N = 1074; Study 2 N = 1753) of college women and men, we examined associations between IR and prepartying motives, alcohol consumption, and alcohol-related blackouts. RESULTS: Within the cross-sectional Study 1, negative binomial regressions revealed that having a history of IR was associated with more alcohol consumption and blackouts when prepartying. In a multivariate model, past-year IR was associated with preparty motives related to interpersonal enhancement, intimate pursuit, and barriers to consumption, but not situational control. Within the prospective Study 2, a path model revealed that preparty drinking was a prospective predictor of IR in the following year, but past-year IR did not predict subsequent prepartying. CONCLUSIONS: Findings revealed a robust link between recent history of IR and prepartying regardless of gender. Prepartying was a prospective risk factor for subsequent IR. Although more research in this area is needed, addressing prepartying in alcohol interventions may contribute to the prevention of negative outcomes, including sexual assault.

Combined PET-CT and MRI for response evaluation in patients with squamous cell anal carcinoma treated with curative-intent chemoradiotherapy.

OBJECTIVES: To assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) positron-emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) for response assessment post curative-intent chemoradiotherapy (CRT) in anal squamous cell carcinoma (ASCC). METHODS: Consecutive ASCC patients treated with curative-intent CRT at a single centre between January 2018 and April 2020 were retrospectively identified. Clinical meta-data including progression-free survival (PFS) and overall survival (OS) outcomes were collated. Three radiologists evaluated PET-CT and MRI using qualitative response assessment criteria and agreed in consensus. Two-proportion z test was used to compare diagnostic performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy). Kaplan-Meier analysis (Mantel-Cox log-rank) was performed. RESULTS: MRI (accuracy 76%, PPV 44.8%, NPV 95.7%) and PET-CT (accuracy 69.3%, PPV 36.7%, NPV 91.1%) performance metrics were similar; when combined, there were statistically significant improvements (accuracy 94.7%, PPV 78.9%, NPV 100%). Kaplan-Meier analysis demonstrated significant differences in PFS between responders and non-responders at PET-CT (p = 0.007), MRI (p = 0.005), and consensus evaluation (p < 0.001). Cox regression analysis of PFS demonstrated a lower hazard ratio (HR) and narrower 95% confidence intervals for consensus findings (HR = 0.093, p < 0.001). Seventy-five patients, of which 52 (69.3%) were females, with median follow-up of 17.8 months (range 5-32.6) were included. Fifteen of the 75 (20%) had persistent anorectal and/or nodal disease after CRT. Three patients died, median time to death 6.2 months (range 5-18.3). CONCLUSION: Combined PET-CT and MRI response assessment post-CRT better predicts subsequent outcome than either modality alone. This could have valuable clinical benefits by guiding personalised risk-adapted patient follow-up. KEY POINTS: • MRI and PET-CT performance metrics for assessing response following chemoradiotherapy (CRT) in patients with anal squamous cell carcinoma (ASCC) were similar. • Combined MRI and PET-CT treatment response assessment 3 months after CRT in patients with ASCC was demonstrated to be superior to either modality alone. • A combined MRI and PET-CT assessment 3 months after CRT in patients with ASCC has the potential to improve accuracy and guide optimal patient management with a greater ability to predict outcome than either modality alone.

Associations between childhood and adulthood socioeconomic position and grip strength at age 46 years: findings from the 1970 British Cohort Study.

BACKGROUND: Muscle weakness is a key criterion for important age-related conditions, including sarcopenia and frailty. Research suggests lower childhood socioeconomic position (SEP) may be associated with muscle weakness in later life but there is little evidence on associations in younger adults closer to peak muscle strength. We aimed to examine relationships between indicators of SEP in childhood and adulthood and grip strength at age 46y. METHODS: We examined 7,617 participants from the 1970 British Cohort Study with grip strength measurements at 46y. We used sex-specific linear regression models to test associations between five different indicators of SEP in childhood and adulthood (paternal occupational class and parental education levels at age 5 and own occupational class and education level at age 46) and maximum grip strength. Models were adjusted for birth weight, BMI in childhood and adulthood, adult height, disability in childhood, leisure-time physical activity in childhood and adulthood, sedentary behaviour in childhood and adulthood, occupational activity and smoking at age 46. RESULTS: Among women, lower SEP in childhood and adulthood was associated with weaker grip strength even after adjustments for covariates. For example, in fully-adjusted models, women whose mothers had no qualifications at age five had mean grip strength 0.99 kg (95% CI: -1.65, -0.33) lower than women whose mothers were educated to degree and higher. Among men, lower levels of father's education and both adult SEP indicators were associated with stronger grip. The association between own occupational class and grip strength deviated from linearity; men in skilled-manual occupations (i.e. the middle occupational group) had stronger grip than men in the highest occupational group (Difference in means: 1.33 kg (0.60, 2.06)) whereas there was no difference in grip strength between the highest and lowest occupational groups. Adjustment for occupational activity largely attenuated these associations. CONCLUSION: Findings highlight the need to identify age and sex-specific interventions across life to tackle inequalities in important age-related conditions related to weakness.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

Early-Life Socioeconomic Position and the Accumulation of Health-Related Deficits by Midlife in the 1958 British Birth Cohort Study.

Reducing population levels of frailty is an important goal, and preventing its development in midadulthood could be pivotal. There is limited evidence on associations between childhood socioeconomic position (SEP) and frailty. Using data on the 1958 British birth cohort (followed from 1958 to 2016; n = 8,711), we aimed to 1) establish the utility of measuring frailty in midlife, by examining associations between a 34-item frailty index at age 50 years (FI50y) and mortality at ages 50-58 years, and 2) examine associations between early-life SEP and FI50y and investigate whether these associations were explained by adult SEP. Hazard ratios for mortality increased with increasing frailty; for example, the sex-adjusted hazard ratio for the highest quintile of FI50y versus the lowest was 4.07 (95% confidence interval (CI): 2.64, 6.25). Lower early-life SEP was associated with higher FI50y. Compared with participants born in the highest social class, the estimated total effect on FI50y was 42.0% (95% CI: 35.5, 48.4) for participants born in the lowest class, with the proportion mediated by adult SEP being 0.45% (95% CI: 0.35, 0.55). Mediation by adult SEP was negligible for other early-life SEP classes. Findings suggest that early-life SEP is associated with frailty and that adult SEP only partially explains this association. Results highlight the importance of improving socioeconomic circumstances across the life course to reduce inequalities in midlife frailty.

Cytometric analysis of T cell phenotype using cytokine profiling for improved manufacturing of an EBV-specific T cell therapy.

Adoptive immunotherapy using Epstein-Barr Virus (EBV)-specific T cells is a potentially curative treatment for patients with EBV-related malignancies where other clinical options have proved ineffective. We describe improved good manufacturing practice (GMP)-compliant culture and analysis processes for conventional lymphoblastoid cell line (LCL)-driven EBV-specific T cell manufacture, and describe an improved phenotyping approach for analysing T cell products. We optimized the current LCL-mediated clinical manufacture of EBV-specific T cells to establish an improved process using xenoprotein-free GMP-compliant reagents throughout, and compared resulting products with our previous banked T cell clinical therapy. We assessed effects of changes to LCL:T cell ratio in T cell expansion, and developed a robust flow cytometric marker panel covering T cell memory, activation, differentiation and intracellular cytokine release to characterize T cells more effectively. These data were analysed using a t-stochastic neighbour embedding (t-SNE) algorithm. The optimized GMP-compliant process resulted in reduced cell processing time and improved retention and expansion of central memory T cells. Multi-parameter flow cytometry determined the optimal protocol for LCL stimulation and expansion of T cells and demonstrated that cytokine profiling using interleukin (IL)-2, tumour necrosis factor (TNF)-α and interferon (IFN)-γ was able to determine the differentiation status of T cells throughout culture and in the final product. We show that fully GMP-compliant closed-process culture of LCL-mediated EBV-specific T cells is feasible, and profiling of T cells through cytokine expression gives improved characterization of start material, in-process culture conditions and final product. Visualization of the complex multi-parameter flow cytometric data can be simplified using t-SNE analysis.

Estimation of manufacturing development costs of cell-based therapies: a feasibility study.

BACKGROUND AIMS: Cell-based therapies (CBTs) provide opportunities to treat rare and high-burden diseases. Manufacturing development of these innovative products is said to be complex and costly. However, little research is available providing insight into resource use and cost drivers. Therefore, this study aimed to assess the feasibility of estimating the cost of manufacturing development of two cell-based therapy case studies using a CBT cost framework specifically designed for small-scale cell-based therapies. METHODS: A retrospective costing study was conducted in which the cost of developing an adoptive immunotherapy of Epstein-Barr virus-specific cytotoxic T lymphocytes (CTLs) and a pluripotent stem cell (PSC) master cell bank was estimated. Manufacturing development was defined as products advancing from technology readiness level 3 to 6. The study was conducted in a Scottish facility. Development steps were recreated via developer focus groups. Data were collected from facility administrative and financial records and developer interviews. RESULTS: Application of the manufacturing cost framework to retrospectively estimate the manufacturing design cost of two case studies in one Scottish facility appeared feasible. Manufacturing development cost was estimated at £1,201,016 for CTLs and £494,456 for PSCs. Most costs were accrued in the facility domain (56% and 51%), followed by personnel (20% and 32%), materials (19% and 15%) and equipment (4% and 2%). CONCLUSIONS: Based on this study, it seems feasible to retrospectively estimate resources consumed in manufacturing development of cell-based therapies. This fosters inclusion of cost in the formulation and dissemination of best practices to facilitate early and sustainable patient access and inform future cost-conscious manufacturing design decisions.

Long-term conditions, multimorbidity, lifestyle factors and change in grip strength over 9 years of follow-up: Findings from 44,315 UK biobank participants.

BACKGROUND: Weak grip strength is associated with a range of adverse health outcomes and an accelerated decline in grip strength confers an even greater risk. The factors associated with change in grip strength in mid-life remain to be fully determined. METHODS: We used data from 44,315 UK Biobank participants who had grip strength measured at baseline (2006-10) and a subsequent visit approximately nine years later. At baseline, participants' long-term conditions (LTCs) were categorised against a hierarchy, with multimorbidity characterised by the number of LTC categories. Lifestyle factors were assessed. Change in grip strength was grouped into four patterns: decline, stable low, stable high or reference (no change or increase) and used as the outcome in multinomial logistic regression. RESULTS: Most LTC categories were associated with adverse patterns of change in grip strength (stable low and/or decline): for example, musculoskeletal/trauma conditions were associated with an increased risk of the stable low pattern (Relative Risk Ratio [RRR] = 1.63; 95% confidence interval [CI]: 1.49-1.79). Multimorbidity and lifestyle factors had independent associations with grip strength change. Those with 3+ categories of LTCs were more likely to experience decline in grip strength (RRR = 1.18; 95% CI: 1.08-1.28) compared to those with none. Low physical activity was associated with adverse patterns of grip strength, while raised body mass index (BMI) had divergent associations. CONCLUSIONS: Individuals living with multimorbidity and those with lifestyle risk factors such as low physical activity are at increased risk of low muscle strength and the loss of strength over time.

Patient perspectives on quality of care for depression and anxiety in primary health care teams: A qualitative study.

BACKGROUND: Widespread policy reforms in Canada, the United States and elsewhere over the last two decades strengthened team models of primary care by bringing together family physicians and nurse practitioners with a range of mental health and other interdisciplinary providers. Understanding how patients with depression and anxiety experience newer team-based models of care delivery is essential to explore whether the intended impact of these reforms is achieved, identify gaps that remain and provide direction on strengthening the quality of mental health care. OBJECTIVE: The main study objective was to understand patients' perspectives on the quality of care that they received for anxiety and depression in primary care teams. METHODS: This was a qualitative study, informed by constructivist grounded theory. We conducted focus groups and individual interviews with primary care patients about their experiences with mental health care. Focus groups and individual interviews were recorded and transcribed verbatim. Grounded theory guided an inductive analysis of the data. RESULTS: Forty patients participated in the study: 31 participated in one of four focus groups, and nine completed an individual interview. Participants in our study described their experiences with mental health care across four themes: accessibility, technical care, trusting relationships and meeting diverse needs. CONCLUSION: Greater attention by policymakers is needed to strengthen integrated collaborative practices in primary care so that patients have similar access to mental health services across different primary care practices, and smoother continuity of care across sectors. The research team is comprised of individuals with lived experience of mental health who have participated in all aspects of the research process.