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ObjectivesTo investigate the association of primary acute cerebral venous thrombosis (CVT) with COVID-19 vaccination through complete ascertainment of all diagnosed CVT in the population of Scotland.DesignCase-crossover study comparing recent (1-14 days after vaccination) with less recent exposure to vaccination among cases of CVT.SettingNational data for Scotland from 1 December 2020, with diagnosed CVT case ascertainment through neuroimaging studies up to 17 May 2021 and diagnostic coding of hospital discharges up to 28 April 2021 and with linkage to vaccination records.Main outcome measurePrimary acute cerebral venous thrombosisResultsOf 50 primary acute CVT cases, 29 were ascertained only from neuroimaging studies, 2 were ascertained only from hospital discharges, and 19 were ascertained from both sources. Of these 50 cases, 14 had received the Astra-Zeneca ChAdOx1 vaccine and 3 the Pfizer BNT162b2 vaccine. The incidence of CVT per million doses in the first 14 days after vaccination was 2.2 (95% credible interval 0.9 to 4.1) for ChAdOx1 and 1 (95% credible interval 0.1 to 2.9) for BNT162b2. The rate ratio for CVT associated with exposure to ChAdOx1 in the first 14 days compared with exposure 15-84 days after vaccination was 3.2 (95% credible interval 1.1 to 9.5). The 95% credible interval for the rate ratio associated with recent versus less recent exposure to BNT162b2 (0.6 to 95.8) was too wide for useful inference.ConclusionsThese findings support a causal association between CVT and the AstraZeneca vaccine. The absolute risk of post-vaccination CVT in this population-wide study in Scotland was lower than has been reported for populations in Scandinavia and Germany; the explanation for this is not clear.What is already known on this topicThe risk of cerebral venous thrombosis (CVT) within 28 days of receiving the AstraZeneca ChAdOx1 vaccine has been estimated as 18 to 25 per million doses in Germany and Scandinavia, but only 5 per million doses in the UK based on the Yellow Card reporting scheme. Risk estimates based on adverse event reporting systems are subject to under-ascertainment and other biases.What this study addsAll diagnosed cases of CVT in Scotland were ascertained by searching neuroimaging studies from December 2020 to May 2021 and linked to national vaccination records. The risk of CVT within 28 days of vaccination with ChAdOx1 was estimated as 3.5 per million doses with an upper bound of 6 per million doses, against a background incidence of about 12 per million adults per year. This indicates that the Yellow Card system has not seriously underestimated the risk in the UK; the explanation for higher risk in other European countries is not clear.

Background: Although graft choice may be limited in the revision setting based on previously used grafts, most surgeons believe that graft choice for anterior cruciate ligament (ACL) reconstruction is an important factor related to outcome. Hypothesis: In the ACL revision setting, there would be no difference between autograft and allograft in rerupture rate and patient-reported outcomes (PROs) at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who had revision surgery were identified and prospectively enrolled in this cohort study by 83 surgeons over 52 sites. Data collected included baseline characteristics, surgical technique and pathology, and a series of validated PRO measures. Patients were followed up at 6 years and asked to complete the identical set of PRO instruments. Incidence of additional surgery and reoperation because of graft failure were also recorded. Multivariable regression models were used to determine the predictors (risk factors) of PROs, graft rerupture, and reoperation at 6 years after revision surgery. Results: A total of 1234 patients including 716 (58%) men were enrolled. A total of 325 (26%) underwent revision using a bone-patellar tendon-bone (BTB) autograft; 251 (20%), soft tissue autograft; 289 (23%), BTB allograft; 302 (25%), soft tissue allograft; and 67 (5%), other graft. Questionnaires and telephone follow-up for subsequent surgery information were obtained for 809 (66%) patients, while telephone follow-up was only obtained for an additional 128 patients for the total follow-up on 949 (77%) patients. Graft choice was a significant predictor of 6-year Marx Activity Rating Scale scores ( P = .024). Specifically, patients who received a BTB autograft for revision reconstruction had higher activity levels than did patients who received a BTB allograft (odds ratio [OR], 1.92; 95% CI, 1.25-2.94). Graft rerupture was reported in 5.8% (55/949) of patients by their 6-year follow-up: 3.5% (16/455) of patients with autografts and 8.4% (37/441) of patients with allografts. Use of a BTB autograft for revision resulted in patients being 4.2 times less likely to sustain a subsequent graft rupture than if a BTB allograft were utilized ( P = .011; 95% CI, 1.56-11.27). No significant differences were found in graft rerupture rates between BTB autograft and soft tissue autografts ( P = .87) or between BTB autografts and soft tissue allografts ( P = .36). Use of an autograft was found to be a significant predictor of having fewer reoperations within 6 years compared with using an allograft ( P = .010; OR, 0.56; 95% CI, 0.36-0.87). Conclusion: BTB and soft tissue autografts had a decreased risk in graft rerupture compared with BTB allografts. BTB autografts were associated with higher activity level than were BTB allografts at 6 years after revision reconstruction. Surgeons and patients should consider this information when choosing a graft for revision ACL reconstruction.

Aims The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain. Methods and results In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong’s test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82–0.85] and 0.85 (95% CI 0.81–0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70–0.77) and 0.73 (95% CI 0.66–0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P Conclusion The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction. Trial registration ClinicalTrials.gov number, NCT01852123.

Introduction Frailty and multimorbidity are common in type 2 diabetes (T2D), including people Methods Analysis of UK Biobank participants (n = 20,566) with T2D aged 40-72 years comparing two frailty measures (frailty phenotype and frailty index) and two multimorbidity measures (Charlson comorbidity index and a simply count of 40 long-term conditions (LTCs)). Outomes: mortality (all-cause, cardiovascular- and cancer-related mortality), Major Adverse Cardiovascular Event (MACE), hospitalization with hypoglycaemia or fall/fracture. Results Measure choice influenced the population identified: 42% of participants were identified as frail/multimorbid by at least one measure; only 2.2% were identified by all four measures. Both frailty and multimorbidity, by all measures, were prevalent throughout the age range studied. Each measure was associated with mortality, MACE, hypoglycaemia and falls. The absolute 5-year mortality risk was higher in older versus younger participants with a given level of frailty (e.g. 1.9%, and 9.9% in men aged 45 and 65, respectively, using frailty phenotype) or multimorbidity (e.g. 1.3%, and 7.8% in men with 4 LTCs aged 45 and 65, respectively). Using frailty phenotype, the relationship between higher HbA1c and mortality was stronger in frail compared with pre-frail or robust participants. Conclusion Assessment of frailty/multimorbidity should be embedded within routine management of middle-aged and older people with T2D. Method of identification as well as features such as age impact baseline risk and should influence clinical decisions (e.g. glycaemic control).

IntroductionCOVID-19 deaths are commoner among care-home residents, but the mortality burden has not been quantified.MethodsCare-home residency was identified via a national primary care registration database linked to national mortality data. Life expectancy was estimated using Makeham-Gompertz models, to (i) describe yearly life expectancy from Nov 2015 to Oct 2020 (ii) compare life expectancy (during 2016-2018) between care-home residents and the wider Scottish population and (iii) apply care-home life expectancy estimates to COVID-19 death counts to estimate years of life lost (YLL).ResultsAmong care-home residents, life expectancy in 2015/16 to 2019/20 ranged from 2.7 to 2.3 years for women and 2.3 to 1.8 years for men. Life expectancy was lowest in 2019/20. Age-sex specific life expectancy in 2016-2018 in care-home residents was lower than in the Scottish population (10 and 2.5 years in those aged 70 and 90 respectively). Rather than using national life tables, applying care-home specific life expectancies to COVID-19 deaths yields, mean YLLs for care-home residents were 2.6 and 2.2 for women and men respectively, with total care-home resident YLLs of 3,560 years in women and 2,046 years in men. In people aged over-70, approximately half of deaths and a quarter of YLL attributed to COVID-19 were accounted for by the 5% of over-70s who were care-home residents.ConclusionPrioritising care-home residents for vaccination is justified not only in terms of total deaths, but also in terms of years of life lost.Research in contextEvidence before this studyWe searched PubMed to 1st December 2020, with the terms (“nursing home” OR “care-home” OR “long-term care” OR “residential care”) AND (“mortality” OR “life expectancy” OR “length of stay”). We also searched for studies specific to the impact of the COVID-19 pandemic on those living in care-homes. We restricted our search to publications in English. Usual care-home life expectancy, in a UK context, has not previously been defined. One systematic review of length of stay was identified, which found significant heterogeneity in factors and associations. The impact of COVID-19 on excess mortality among care-home residents was noted, but the impact on life expectancy was not reported. Studies evaluating life expectancy among older people in the COVID-19 pandemic have not taken account of residency in their estimates.Added value of this studyUsing Scottish national representative linked data we describe the usual life expectancy of older adults (aged ≥70 years) living in care-homes, compared to older people living elsewhere. Deaths among care-home residents account for a considerable proportion of all mortality in older adults, around 19% for men and 30% for women. Life expectancy in care-home residents during the pandemic fell by almost 6 months, from 2.7 to 2.3 years in men and 2.1 to 1.8 years in women. In total, over 5,600 Years of Life were Lost (YLL) by care-home residents in Scotland who died with COVID-19. Around half of COVID-19 deaths and a quarter of YLL in those aged 70 years and over occurred among care-home residents. During the COVID-19 pandemic a smaller proportion of deaths among care-home residents occurred in hospitals.Implications of all the available evidencePrioritising the 5% of older adults who are care-home residents for vaccination against COVID-19 is justified both in terms of total deaths and total years of life lost. Individual and societal planning for care needs in older age relies on understanding usual care-home life expectancy and patterns of mortality. Understanding life expectancy may help clinicians, residents and their families make decisions about their health care, facilitating more informed discussions around their priorities and wishes. Population-wide estimates of YLL and burden of disease should take account of residency status, given the significant differences between life expectancy of those living in care-homes from their peers in other settings.

Background Frailty, an age-related state of vulnerability to adverse health outcomes, is an important factor in the management of diabetes. This systematic review aims to summarise the observational data on prevalence of frailty in diabetes and the association between frailty and generic (e.g. mortality) and diabetes specific (e.g. hypoglycaemia) outcomes. Methods We searched three electronic databases for observational studies assessing frailty in adults (≥18 years) with diabetes (type 1, type 2, or unspecified). Eligible studies quantified the prevalence or incidence of frailty or the association between frailty and clinical outcomes in the context of diabetes. Results 118 studies included, using 18 different frailty measures. Frailty phenotype was the most used (n = 69) followed by frailty index (n = 16) and the FRAIL scale (n = 10). Studies were highly heterogenous in terms of setting (88 community, 18 outpatient, 10 inpatient, 2 residential care), population demographics, and inclusion criteria. The median frailty prevalence in community-based studies using the frailty phenotype was 13% (interquartile range 7-18%). Frailty was identified in “middle-aged” (9%) or low ( Conclusions Frailty in diabetes is common but inconsistently measured. Frailty is associated with a range of adverse outcomes. Research gaps include the relationship between frailty and glycaemia (particularly hypoglycaemia and the relationship between HbA1c and outcomes in the context of frailty), and the impact of frailty in specific groups such as middle-aged people and in low and low-middle income countries.

Introduction Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD). Methods We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI >0.24 were considered “frail”. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex and disease severity. In negative binomial regression we modelled serious adverse event rates on FI, and combined results for each index condition in a random-effects meta-analysis. Results All trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. Increased disease severity and female sex were associated with higher FI in all trials. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87) and 1.99 (1.43–2.76) for T2DM, RA and COPD, respectively. Conclusion Frailty is identifiable and prevalent among middle aged and older participants in phase 3/4 drug trials and has clinically important safety implications. Trial data may be harnessed to better understand chronic disease management in people living with frailty.

Introduction Fewer clinical trials are carried out in older people. It is unclear how representative and applicable clinical trials carried out exclusively in older people are. We compared clinical trials recruiting older people exclusively “older trials” to those recruiting adults of all ages “all age trials”, using anti-hypertensives acting on the renin-angiotensin aldosterone system (RAAS drugs) as an exemplar. Method We searched the US clinical trials register 1, to identify all trials carried out exclusively in those aged over 60. From these we selected trials of RAAS drugs. These were matched in a 2:1 ratio to trials carried out in adults of all ages. Data regarding baseline characteristics, adverse events and eligibility criteria were collected from clinical trial reports and clinicaltrials.gov. Estimated associations were calculated for age, sex and adverse events. Eligibility criteria were described and ICD- 10 coded, as appropriate. Results 71 clinical trials were carried out exclusively in older people.13 related to RAAS drugs. Participants in “Older trials” had higher mean age (73.1 and 55.9 respectively), mean difference 16.17 (CI 15.31–17.02). Older trials had fewer male participants. Participants in older trials had lower mean body mass index (BMI). A higher rate of participants in older trials experienced serious adverse events. (2.07, CI 1.55–2.75.) Few older trials had upper age limits (23.1% V 27% all age trials). All trials had exclusion criteria in multiple ICD blocks. Concurrent medications were a more common exclusion criterion in older trials (61.5% v 40.9%). Conclusions Clinical trials carried out exclusively in older people are representative in terms of age, serious adverse events and eligibility. Although there are multiple exclusion criteria for clinical trial participation in both groups, this is not prohibitive. This supports carrying out more trials exclusively in older people. References 1. NIH, US national library of medicine.ClinicalTrials.gov Available at https://clinicaltrials.gov/

Summary Background HIV enhances human papillomavirus (HPV)-induced carcinogenesis. However, the contribution of HIV to cervical cancer burden at a population level has not been quantified. We aimed to investigate cervical cancer risk among women living with HIV and to estimate the global cervical cancer burden associated with HIV. Methods We did a systematic literature search and meta-analysis of five databases (PubMed, Embase, Global Health [ CABI.org ], Web of Science, and Global Index Medicus) to identify studies analysing the association between HIV infection and cervical cancer. We estimated the pooled risk of cervical cancer among women living with HIV across four continents (Africa, Asia, Europe, and North America). The risk ratio (RR) was combined with country-specific UNAIDS estimates of HIV prevalence and GLOBOCAN 2018 estimates of cervical cancer to calculate the proportion of women living with HIV among women with cervical cancer and population attributable fractions and age-standardised incidence rates (ASIRs) of HIV-attributable cervical cancer. Findings 24 studies met our inclusion criteria, which included 236 127 women living with HIV. The pooled risk of cervical cancer was increased in women living with HIV (RR 6·07, 95% CI 4·40–8·37). Globally, 5·8% (95% CI 4·6–7·3) of new cervical cancer cases in 2018 (33 000 new cases, 95% CI 26 000–42 000) were diagnosed in women living with HIV and 4·9% (95% CI 3·6–6·4) were attributable to HIV infection (28 000 new cases, 20 000–36 000). The most affected regions were southern Africa and eastern Africa. In southern Africa, 63·8% (95% CI 58·9–68·1) of women with cervical cancer (9200 new cases, 95% CI 8500–9800) were living with HIV, as were 27·4% (23·7–31·7) of women in eastern Africa (14 000 new cases, 12 000–17 000). ASIRs of HIV-attributable cervical cancer were more than 20 per 100 000 in six countries, all in southern Africa and eastern Africa. Interpretation Women living with HIV have a significantly increased risk of cervical cancer. HPV vaccination and cervical cancer screening for women living with HIV are especially important for countries in southern Africa and eastern Africa, where a substantial HIV-attributable cervical cancer burden has added to the existing cervical cancer burden. Funding WHO, US Agency for International Development, and US President's Emergency Plan for AIDS Relief.

The ACCESS Study is a prospective, multicenter registry to evaluate the efficacy and safety of trans-subclavian and axillary transcatheter aortic valve replacement (TAx-TAVR) with the latest-genera...

Infection is a rare occurrence after revision anterior cruciate ligament reconstruction (rACLR). Because of the low rates of infection, it has been difficult to identify risk factors for infection in this patient population. The purpose of this study was to report the rate of infection following rACLR and assess whether infection is associated with patient- and surgeon- dependent risk factors. We reviewed two large prospective cohorts to identify patients with postoperative infections following rACLR. Age, sex, body mass index (BMI), smoking status, history of diabetes, and graft choice were recorded for each patient. The association of these factors with postoperative infection following rACLR was assessed. There were 1423 rACLR cases in the combined cohort, with 9 (0.6%) reporting post-operative infections. Allografts had a higher risk of infection than autografts (odds ratio=6.8; 95% CI: 0.9-54.5; p=0.045). Diabetes (odds ratio=28.6; 95% CI: 5.5-149.9; p=0.004) was a risk factor for infection. Patient age, sex, BMI and smoking status were not associated with risk of infection after rACLR. STATEMENT OF CLINICAL SIGNIFICANCE: While there is a low rate of infection following rACLR, use of allograft and comorbidity with diabetes are associated with a higher risk of infection following this surgery.

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health. This has been a successful intervention in patients with isolated tears and tears associated with anterior cruciate ligament (ACL) reconstruction. However, the results of meniscal repair in the setting of revision ACL reconstruction have not been documented. Purpose: To examine the prevalence and 2-year operative success rate of meniscal repairs in the revision ACL setting. Study Design: Case-control study; Level of evidence, 3. Methods: All cases of revision ACL reconstruction with concomitant meniscal repair from a multicenter group between 2006 and 2011 were selected. Two-year follow-up was obtained by phone and email to determine whether any subsequent surgery had occurred to either knee since the initial revision ACL reconstruction. If so, operative reports were obtained, whenever possible, to verify the pathologic condition and subsequent treatment. Results: In total, 218 patients (18%) from 1205 revision ACL reconstructions underwent concurrent meniscal repairs. There were 235 repairs performed: 153 medial, 48 lateral, and 17 medial and lateral. The majority of these repairs (n = 178; 76%) were performed with all-inside techniques. Two-year surgical follow-up was obtained on 90% (197/218) of the cohort. Overall, the meniscal repair failure rate was 8.6% (17/197) at 2 years. Of the 17 failures, 15 were medial (13 all-inside, 2 inside-out) and 2 were lateral (both all-inside). Four medial failures were treated in conjunction with a subsequent repeat revision ACL reconstruction. Conclusion: Meniscal repair in the revision ACL reconstruction setting does not have a high failure rate at 2-year follow-up. Failure rates for medial and lateral repairs were both

Background: Despite improvements in management, infective endocarditis remains associated with high mortality and morbidity. We describe temporal changes in the incidence, microbiology, and outcomes of infective endocarditis and the effect of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis. Methods: Using a Scotland-wide, individual-level linkage approach, all patients hospitalized with infective endocarditis from 1990 to 2014 were identified and linked to national microbiology, prescribing, and morbidity and mortality datasets. Linked data were used to evaluate trends in the crude and age- and sex-adjusted incidence and outcomes of infective endocarditis hospitalizations. From 2008, microbiology data and associated outcomes adjusted for patient demographics and comorbidity were also analyzed. An interrupted time series analysis was performed to evaluate incidence before and after changes to national antibiotic prophylaxis guidelines. Results: There were 7638 hospitalizations (65±17 years, 51% females) with infective endocarditis. The estimated crude hospitalization rate increased from 5.3/100 000 (95% CI, 4.8-5.9) to 8.6/100 000 (95% CI, 8.1–9.1) between 1990 and 1995 but remained stable thereafter. There was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines (relative risk of change 1.06 [95% CI, 0.94–1.20]). The incidence rate in patients >80 years of age doubled from 1990 to 2014 (17.7/100 000 [95% CI, 13.4–23.3] to 37.9/100 000 [95% CI, 31.5–45.5]). The predicted 1-year age- and comorbidity-adjusted case fatality rate for a 65-year-old patient decreased in women (27.3% [95% CI, 24.6–30.2] to 23.7% [95% CI, 21.1–26.6]) and men (30.7% [95% CI, 27.7–33.8] to 26.8% [95% CI, 24.0–29.7]) from 1990 to 2014. Blood culture data were available from 2008 (n=2267/7638, 30%), with positive blood cultures recorded in 42% (950/2267). Staphylococcus (403/950, 42.4%) and streptococcus (337/950, 35.5%) species were most common. Staphylococcus aureus and enterococcus had the highest 1-year mortality (adjusted odds ratio 4.34 [95% CI, 3.12–6.05] and 3.41 [95% CI, 2.04–5.70], respectively). Conclusions: Despite changes in antibiotic prophylaxis guidelines, the crude incidence of infective endocarditis has remained stable. However, the incidence rate has doubled in the elderly. Positive blood cultures were observed in less than half of patients, with Staphylococcus aureus and enterococcus bacteremia associated with worse outcomes.

Purpose of Review We review the pathophysiology of Shiga-Toxin Enteropathogenic–Hemolytic Uremic Syndrome (STEC-HUS), strategies to ameliorate or prevent evolution of STEC-HUS, management and the improved recognition of long-term adverse outcomes. Recent Findings Following on from the preclinical evidence of a role for the complement system in STEC-HUS, the use of complement blocking agents has been the major focus of most recent clinical research. Novel therapies to prevent or lessen HUS have yet to enter the clinical arena. The long-term outcomes of STEC-HUS, similarly to other causes of AKI, are not as benign as previously thought. Summary Optimizing supportive care in STEC-HUS is the only current recommended treatment. The administration of early isotonic fluids may reduce the severity and duration of STEC-HUS. The role of complement blockade in the management of STEC-HUS remains unclear. The long-term sequelae from STEC-HUS are significant and patients with apparent full renal recovery remain at risk.

Objective Children are relatively protected from COVID-19, due to a range of potential mechanisms. We investigated if contact with children also affords adults a degree of protection from COVID-19. Design Cohort study based on linked administrative data. Setting Scotland. Study population All National Health Service Scotland healthcare workers and their household contacts as of March 2020. Main exposure Number of young children (0–11 years) living in the participant’s household. Main outcomes COVID-19 requiring hospitalisation, and any COVID-19 (any positive test for SARS-CoV-2) in adults aged ≥18 years between 1 March and 12 October 2020. Results 241 266, 41 198, 23 783 and 3850 adults shared a household with 0, 1, 2 and 3 or more young children, respectively. Over the study period, the risk of COVID-19 requiring hospitalisation was reduced progressively with increasing numbers of household children—fully adjusted HR (aHR) 0.93 per child (95% CI 0.79 to 1.10). The risk of any COVID-19 was similarly reduced, with the association being statistically significant (aHR per child 0.93; 95% CI 0.88 to 0.98). After schools reopened to all children in August 2020, no association was seen between exposure to young children and risk of any COVID-19 (aHR per child 1.03; 95% CI 0.92 to 1.14). Conclusion Between March and October 2020, living with young children was associated with an attenuated risk of any COVID-19 and COVID-19 requiring hospitalisation among adults living in healthcare worker households. There was no evidence that living with young children increased adults’ risk of COVID-19, including during the period after schools reopened., Many parents know that having young children in the house means they get frequent respiratory viral infections. Is this the same for COVID, which is less frequent and less severe in children? This cohort study finds that having young children in the house reduces the risk of COVID.

SummaryBackgroundThe objective of this study was to investigate how protection against COVID-19 conferred by previous infection is modified by vaccination.MethodsIn a cohort of all 152655 individuals in Scotland alive at 90 days after a positive test for SARS-CoV-2 (confirmed by cycle threshold < 30, or two tests) followed till 22 September 2021, rate ratios for reinfection were estimated with calendar time or tests as timescale.FindingsRates of detected and hospitalised reinfection with COVID-19 while unvaccinated were respectively 6.8 (95% CI 6.4 to 7.2) and 0.18 (95% CI 0.12 to 0.25) per 1000 person-months. These rates were respectively 68% and 74% lower than in a matched cohort of individuals who had not previously tested positive. Efficacy of two doses of vaccine in those with previous infection was estimated as as 84% (95 percent CI 81% to 86%) against detected reinfection and 71% (95 percent CI 29% to 88%) against hospitalised or fatal reinfection. The rate of detected reinfection after two doses of vaccine was 1.35 (95% CI 1.02 to 1.78) times higher in those vaccinated before first infection than in those unvaccinated at first infection.InterpretationThe combination of natural infection and vaccination provides maximal protection against new infection with SARS-CoV-2: prior vaccination does not impair this protection.FundingNo specific funding was received for this work.Research in contextEvidence before this studyIn a recent systematic review of cohort studies reported up to July 2021, the average reduction in COVID-19 infection rates in those with previous infection compared with those without evidence of previous infection was 90%. There is little information about the protective effect of previous infection against severe COVID-19, or about how the protective effects of previous infection against reinfection and severe disease are modified by vaccination.What this paper addsIn unvaccinated individuals the protection against hospitalised COVID-19 conferred by previous infection is similar to that induced by vaccination. In those with previous infection, vaccination reduces the rates of reinfection and hospitalised COVID-19 by about 70%.Implications of all the available evidenceThe combination of natural infection and vaccination provides maximal protection against COVID-19: prior vaccination does not seriously impair this protection.

Background Chronic kidney disease (CKD) typically co-exists with multimorbidity (presence of 2 or more long-term conditions: LTCs). The associations between CKD, multimorbidity and hospitalisation rates are not known. The aim of this study was to examine hospitalisation rates in people with multimorbidity with and without CKD. Amongst people with CKD, the aim was to identify risk factors for hospitalisation. Methods Two cohorts were studied in parallel: UK Biobank (a prospective research study: 2006-2020) and Secure Anonymised Information Linkage Databank (SAIL: a routine care database, Wales, UK: 2011-2018). Adults were included if their kidney function was measured at baseline. Nine categories of participants were used: zero LTCs; one, two, three and four or more LTCs excluding CKD; and one, two, three and four or more LTCs including CKD. Emergency hospitalisation events were obtained from linked hospital records. Results Amongst 469,339 UK Biobank participants, those without CKD had a median of 1 LTC and those with CKD had a median of 3 LTCs. Amongst 1,620,490 SAIL participants, those without CKD had a median of 1 LTC and those with CKD had a median of 5 LTCs. Compared to those with zero LTCs, participants with four or more LTCs (excluding CKD) had high event rates (rate ratios UK Biobank 4.95 (95% confidence interval 4.82–5.08)/SAIL 3.77 (3.71–3.82)) with higher rates if CKD was one of the LTCs (rate ratios UK Biobank 7.83 (7.42–8.25)/SAIL 9.92 (9.75–10.09)). Amongst people with CKD, risk factors for hospitalisation were advanced CKD, age over 60, multiple cardiometabolic LTCs, combined physical and mental LTCs and complex patterns of multimorbidity (LTCs in three or more body systems). Conclusions People with multimorbidity have high rates of hospitalisation. Importantly, the rates are two to three times higher when CKD is one of the multimorbid conditions. Further research is needed into the mechanism underpinning this to inform strategies to prevent hospitalisation in this very high-risk group.

Background Cardiac troponin concentrations differ in women and men, but how this influences risk prediction and whether a sex-specific approach is required is unclear. We evaluated whether sex influences the predictive ability of cardiac troponin I and T for cardiovascular events in the general population. Methods High-sensitivity cardiac troponin (hs-cTn) I and T were measured in the Generation Scotland Scottish Family Health Study of randomly selected volunteers drawn from the general population between 2006 and 2011. Cox-regression models evaluated associations between hs-cTnI and hs-cTnT and the primary outcome of cardiovascular death, myocardial infarction, or stroke. Results In 19 501 (58% women, mean age 47 years) participants, the primary outcome occurred in 2.7% (306/11 375) of women and 5.1% (411/8126) of men during the median follow-up period of 7.9 (IQR, 7.1–9.2) years. Cardiac troponin I and T concentrations were lower in women than men (P Conclusions Cardiac troponin concentrations differ in women and men and are stronger predictors of cardiovascular events in women. Sex-specific approaches are required to provide equivalent risk prediction.

Background We investigated the clinical features, microbiology, and short‐ and long‐term outcomes of incident infective endocarditis (IE) hospitalizations in patients with end‐stage kidney disease (ESKD) requiring dialysis or with a kidney transplant over 25 years in Scotland. Methods and Results In this retrospective, population‐based cohort study linking national hospitalization and mortality data, we identified patients with a history of ESKD and hospitalized with IE in Scotland between January 1, 1990 and December 31, 2014. From January 1, 2008, individual IE hospitalizations were additionally linked to national microbiology data. Multivariable logistic regression, adjusting for patient demographics and comorbidities, evaluated the association between ESKD and all‐cause death at 1 and 3 years. Of 7638 incident IE hospitalizations between 1990 and 2014, 2.8% (216/7638) occurred in 210 patients with ESKD and 97.2% (7422/7638) occurred in 7303 patients without ESKD. Positive findings from blood cultures were identified in 42% (950/2267) of incident IE hospitalizations from 2008. Staphylococcus aureus was isolated in 25.9% (21/81) and 12.8% (280/2186) of patients with and without ESKD, respectively ( P =0.002). ESKD was associated with an increased odds of death at 1 (44.9% versus 31.4%; adjusted odds ratio [aOR], 2.47, 95% CI, 1.85–3.30;, P P Conclusions IE is associated with a poor prognosis in patients with ESKD, especially in the longer term. Compared with patients without ESKD, patients with ESKD were twice as likely to die within 1 year, and 3 times as likely to die within 3 years of IE hospitalization.

ObjectivesTo determine whether COVID-19 efficacy varies with clinical risk category and to investigate risk factors for severe COVID-19 in those who have received two doses of vaccine.DesignMatched case-control study (REACT-SCOT).SettingPopulation of Scotland from 1 December 2020 to 8 September 2021.Main outcome measureSevere COVID-19, defined as cases with entry to critical care or fatal outcome.ResultsEfficacy against severe COVID-19 of two doses of vaccine was 94% (95 percent CI 93% to 96%) in those without designated risk conditions, 89% (95 percent CI 86% to 91%) in those with moderate risk conditions, but only 73% (95 percent CI 64% to 79%) in those designated as clinically extremely vulnerable (CEV) and eligible for shielding. Of the 641 cases of severe COVID-19 in double-vaccinated individuals, 47% had moderate risk conditions and 38% were CEV. In the double-vaccinated CEV group, the rate ratio for severe disease (with no risk condition as reference category) was highest in solid organ transplants at 101 (95% CI 47 to 214) but even in this subgroup the absolute risk of severe COVID-19 was low (35 cases in 23678 person-months of follow-up).ConclusionsTwo doses of vaccine protect against severe COVID-19 in CEV individuals but the residual risk in double-vaccinated individuals remains far higher in those who are CEV than in those who are not. These results lay a basis for determining eligibility for additional measures including passive immunization to protect those at highest risk.

IntroductionChildhood malnutrition is widespread in low-income and middle-income countries (LMICs) and increases the frequency and severity of infections such as pneumonia. We aimed to identify studies investigating pneumonia deaths in malnourished children and estimate mortality risk by malnutrition severity.MethodsWe conducted a systematic review of MEDLINE, EMBASE and Global Health databases to identify relevant studies. We used a network meta-analysis to derive ORs of death from pneumonia for moderately and severely underweight children using low weight-for-age, the most reported measure of malnutrition. We compared meta-estimates of studies conducted before and after 2000 to assess changes in mortality risk over time. We estimated the prevalence of underweight hospitalised children from hospital-based cohort studies and calculated the population attributable fraction of in-hospital pneumonia deaths from being underweight using our results.ResultsOur network meta-analysis included 33 544 underweight children from 23 studies. The estimated OR of death from pneumonia was 2.0 (95% CI 1.6 to 2.6) and 4.6 (95% CI 3.7 to 5.9) for children moderately and severely underweight, respectively. The OR of death from pneumonia for those severely underweight was 5.3 (95% CI 3.9 to 7.4) pre-2000 and remained high post-2000 at 4.1 (95% CI 3.0 to 6.0). Prevalence of underweight children hospitalised with pneumonia varied (median 40.2%, range 19.6–66.3) but was high across many LMIC settings. We estimated a median 18.3% (range 10.8–34.6) and 40.9% (range 14.7–69.9) of in-hospital pneumonia deaths were attributable to being moderately and severely underweight, respectively.ConclusionsThe risk of death from childhood pneumonia dramatically increases with malnutrition severity. This risk has remained high in recent years with an estimated over half of in-hospital pneumonia deaths attributable to child malnutrition. Prevention and treatment of all child malnutrition must be prioritised to maintain progress on reducing pneumonia deaths.

Objective To determine the risk of hospital admission with covid-19 and severe covid-19 among teachers and their household members, overall and compared with healthcare workers and adults of working age in the general population. Design Population based nested case-control study. Setting Scotland, March 2020 to July 2021, during defined periods of school closures and full openings in response to covid-19. Participants All cases of covid-19 in adults aged 21 to 65 (n=132 420) and a random sample of controls matched on age, sex, and general practice (n=1 306 566). Adults were identified as actively teaching in a Scottish school by the General Teaching Council for Scotland, and their household members were identified through the unique property reference number. The comparator groups were adults identified as healthcare workers in Scotland, their household members, and the remaining general population of working age. Main outcome measures The primary outcome was hospital admission with covid-19, defined as having a positive test result for SARS-CoV-2 during hospital admission, being admitted to hospital within 28 days of a positive test result, or receiving a diagnosis of covid-19 on discharge from hospital. Severe covid-19 was defined as being admitted to intensive care or dying within 28 days of a positive test result or assigned covid-19 as a cause of death. Results Most teachers were young (mean age 42), were women (80%), and had no comorbidities (84%). The risk (cumulative incidence) of hospital admission with covid-19 was Conclusion Compared with adults of working age who are otherwise similar, teachers and their household members were not found to be at increased risk of hospital admission with covid-19 and were found to be at lower risk of severe covid-19. These findings should reassure those who are engaged in face-to-face teaching.

Effect of Vaccination on Transmission of SARS-CoV-2 In this report from Scotland, vaccination of health care workers for SARS-CoV-2 was associated with a decrease in household transmission.

Background: \ud Understanding trends in the incidence and outcomes of myocardial infarction and stroke, and how these are influenced by changes in cardiovascular risk factors can inform health policy and healthcare provision.\ud \ud Methods: \ud We identified all patients 30 years or older with myocardial infarction or stroke in Scotland. Risk factor levels were determined from national health surveys. Incidence, potential impact fractions and burden attributable to risk factor changes were calculated. Risk of subsequent fatal and non-fatal events (myocardial infarction, stroke, bleeding and heart failure hospitalization) were calculated with multi-state models.\ud \ud Findings: \ud From 1990 to 2014, there were 372,873 (71±13 years) myocardial infarctions and 290,927 (74±13 years) ischemic or hemorrhagic strokes. Age-standardized incidence per 100,000 fell from 1,069 (95% confidence interval, 1,024-1,116) to 276 (263-290) for myocardial infarction and from 608 (581-636) to 188 (178-197) for ischemic stroke. Systolic blood pressure, smoking and cholesterol decreased, but body-mass index increased, and diabetes prevalence doubled. Changes in risk factors accounted for a 74% (57-91%) reduction in myocardial infarction and 68% (55-83%) reduction in ischemic stroke. Following myocardial infarction, the risk of death decreased (30% to 20%), but non-fatal events increased (20% to 24%) whereas the risk of both death (47% to 34%) and non-fatal events (22% to 17%) decreased following stroke.\ud \ud Interpretation: \ud Over the last 25 years, substantial reductions in myocardial infarction and ischemic stroke incidence are attributable to major shifts in risk factor levels. Deaths following the index event decreased for both myocardial infarction and stroke, but rates remained substantially higher for stroke.\ud \ud Funding: \ud British heart foundation.

Review question / Objective: P - patients with type 2 diabetes melllitus already receiving routine medical therapy; I - patients receiving glucagon like peptide 1 receptor agonist (GLP1 receptor agonist) therapy (semaglutide, dulaglutide, liraglutide, exenatide, lixisenatide, efpeglenatide, abiglutide); C - patients receiving standard therapy for diabetes mellitus but not receiving GLP1 agonist therapy; O - composite end point as per invididual trial, cardiovascular mortality, all-cause mortality, myocardial infarction, stoke. Condition being studied: Type 2 diabetes mellitus. Study designs to be included: Randomised controlled trials which enroll a large number of patients (defined as > 500) and are multinational in origin. Studies included will need to have published Kaplan and Meier curves for the end-points presented in the manuscript.

Background: \ud Representativeness of antihypertensive drug trials is uncertain, as many trials recruit few or no older people. Some trials specifically recruit older participants to address this. Here, we assess the representativeness of trials focusing on older people by comparing the rates of serious adverse events in these trials with the rates in trials of a general adult population (ie, standard trials), and comparing these findings to the rate of hospitalisations and deaths in people with hypertension starting a similar treatment in routine clinical practice.\ud \ud Methods: \ud For this observational study, we identified randomised controlled trials (phase 2/3, 3, or 4) of renin-angiotensin-aldosterone system (RAAS) drugs for hypertension registered from 1999 onwards with ClinicalTrials.gov. Serious adverse events are routinely included in trial reports and are predominantly accounted for by all-cause hospitalisations and deaths. We compared serious adverse event rates in older-people trials (minimum inclusion age ≥60 years) and standard trials (minimum inclusion age

Supplemental Digital Content is available in the text., Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early rule-out pathway is safe and effective for patients with suspected acute coronary syndrome. Methods: We performed a stepped-wedge cluster randomized controlled trial in the emergency departments of 7 acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were

IntroductionCOVID-19 has spread rapidly worldwide, causing significant morbidity and mortality. People from ethnic minorities, particularly those working in healthcare settings, have been disproportionately affected. Current evidence of the association between ethnicity and COVID-19 outcomes in people working in healthcare settings is insufficient to inform plans to address health inequalities.Methods and analysisThis study combines anonymised human resource databases with professional registration and National Health Service data sets to assess associations between ethnicity and COVID-19 diagnosis, hospitalisation and death in healthcare workers in the UK. Adverse COVID-19 outcomes will be assessed between 1 February 2020 (date following first confirmed COVID-19 case in UK) and study end date (31 January 2021), allowing 1-year of follow-up. Planned analyses include multivariable Poisson, logistic and flexible parametric time-to-event regression within each country, adjusting for core predictors, followed by meta-analysis of country-specific results to produce combined effect estimates for the UK. Mediation analysis methods will be explored to examine the direct, indirect and mediated interactive effects between ethnicity, occupational group and COVID-19 outcomes.Ethics and disseminationEthical approval for the UK-REACH programme has been obtained via the expedited HRA COVID-19 processes (REC ref: 20/HRA/4718, IRAS ID: 288316). Research information will be anonymised via the Secure Anonymised Information Linkage Databank before release to researchers. Study results will be submitted for publication in an open access peer-reviewed journal and made available on our dedicated website (https://uk-reach.org/).Trial registration numberISRCTN11811602.

ObjectiveTo assess the diagnostic accuracy of antigen compared with reverse transcriptase (RT)-PCR testing in an asymptomatic athlete screening programme and to monitor infection in college athletes.MethodsQuidel Sofia-2 SARS-CoV-2 Antigen Tests were performed daily before sports participation for football, basketball, wrestling and water polo from 29 September 2020 to 28 February 2021. Paired RT-PCR and antigen tests were performed at least once a week. Positive antigen tests were confirmed with RT-PCR.Results81 175 antigen and 42 187 RT-PCR tests were performed, including 23 462 weekly paired antigen/RT-PCR screening tests in 1931 athletes. One hundred and seventy-two athletes had a positive screening RT-PCR (0.4%), of which 83 (48%) occurred on paired testing days. The sensitivity of antigen tests varied with the frequency of RT-PCR testing and prevalence of COVID-19. The sensitivity of antigen testing was 35.7% (95% CI: 17% to 60%) and specificity 99.8% (95% CI: 99.7% to 99.9%) with once-a-week RT-PCR testing after adjusting for school prevalence. Daily antigen testing was similar to RT-PCR testing two to three times a week in identifying infection. Antigen testing identified infection before the next scheduled PCR on 89 occasions and resulted in 234 days where potentially infectious athletes were isolated before they would have been isolated with RT-PCR testing alone. Two athletic-related outbreaks occurred; 86% of total infections were community acquired.ConclusionAntigen testing has high specificity with a short turnaround time but is not as sensitive as RT-PCR. Daily antigen testing or RT-PCR testing two to three times a week is similar. There are benefits and drawbacks to each testing approach.

Frailty and multimorbidity are common in type 2 diabetes (T2D), including people

Background: Anterior cruciate ligament (ACL) revision cohorts continually report lower outcome scores on validated knee questionnaires than primary ACL cohorts at similar time points after surgery. It is unclear how these outcomes are associated with physical activity after physician clearance for return to recreational or competitive sports after ACL revision surgery. Hypotheses: Participants who return to either multiple sports or a singular sport after revision ACL surgery will report decreased knee symptoms, increased activity level, and improved knee function as measured by validated patient-reported outcome measures (PROMs) and compared with no sports participation. Multisport participation as compared with singular sport participation will result in similar increased PROMs and activity level. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 1205 patients who underwent revision ACL reconstruction were enrolled by 83 surgeons at 52 clinical sites. At the time of revision, baseline data collected included the following: demographics, surgical characteristics, previous knee treatment and PROMs, the International Knee Documentation Committee (IKDC) questionnaire, Marx activity score, Knee injury and Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). A series of multivariate regression models were used to evaluate the association of IKDC, KOOS, WOMAC, and Marx Activity Rating Scale scores at 2 years after revision surgery by sports participation category, controlling for known significant covariates. Results: Two-year follow-up was obtained on 82% (986 of 1205) of the original cohort. Patients who reported not participating in sports after revision surgery had lower median PROMs both at baseline and at 2 years as compared with patients who participated in either a single sport or multiple sports. Significant differences were found in the change of scores among groups on the IKDC ( P < .0001), KOOS-Symptoms ( P = .01), KOOS–Sports and Recreation ( P = .04), and KOOS–Quality of Life ( P < .0001). Patients with no sports participation were 2.0 to 5.7 times more likely than multiple-sport participants to report significantly lower PROMs, depending on the specific outcome measure assessed, and 1.8 to 3.8 times more likely than single-sport participants (except for WOMAC-Stiffness, P = .18), after controlling for known covariates. Conclusion: Participation in either a single sport or multiple sports in the 2 years after ACL revision surgery was found to be significantly associated with higher PROMs across multiple validated self-reported assessment tools. During follow-up appointments, surgeons should continue to expect that patients who report returning to physical activity after surgery will self-report better functional outcomes, regardless of baseline activity levels.

Background: There is great interest in widening the use of high-sensitivity cardiac troponins for population cardiovascular disease (CVD) and heart failure screening. However, it is not clear whether cardiac troponin T (cTnT) and troponin I (cTnI) are equivalent measures of risk in this setting. We aimed to compare and contrast (1) the association of cTnT and cTnI with CVD and non-CVD outcomes, and (2) their determinants in a genome-wide association study. Methods: High-sensitivity cTnT and cTnI were measured in serum from 19 501 individuals in Generation Scotland Scottish Family Health Study. Median follow-up was 7.8 years (quartile 1 to quartile 3, 7.1–9.2). Associations of each troponin with a composite CVD outcome (1177 events), CVD death (n=266), non-CVD death (n=374), and heart failure (n=216) were determined by using Cox models. A genome-wide association study was conducted using a standard approach developed for the cohort. Results: Both cTnI and cTnT were strongly associated with CVD risk in unadjusted models. After adjusting for classical risk factors, the hazard ratio for a 1 SD increase in log transformed troponin was 1.24 (95% CI, 1.17–1.32) and 1.11 (1.04–1.19) for cTnI and cTnT, respectively; ratio of hazard ratios 1.12 (1.04–1.21). cTnI, but not cTnT, was associated with myocardial infarction and coronary heart disease. Both cTnI and cTnT had strong associations with CVD death and heart failure. By contrast, cTnT, but not cTnI, was associated with non-CVD death; ratio of hazard ratios 0.77 (0.67–0.88). We identified 5 loci (53 individual single-nucleotide polymorphisms) that had genome-wide significant associations with cTnI, and a different set of 4 loci (4 single-nucleotide polymorphisms) for cTnT. Conclusions: The upstream genetic causes of low-grade elevations in cTnI and cTnT appear distinct, and their associations with outcomes also differ. Elevations in cTnI are more strongly associated with some CVD outcomes, whereas cTnT is more strongly associated with the risk of non-CVD death. These findings help inform the selection of an optimal troponin assay for future clinical care and research in this setting.

ObjectiveTroponin and B-type natriuretic peptide (BNP) concentrations are associated with cardiovascular risk in stable patients. Understanding their determinants and identifying modifiable clinical targets may improve outcomes. We aimed to establish clinical and cardiac determinants of these biomarkers.MethodsThis was a prespecified substudy from the randomised Scottish Computed Tomography of the Heart trial, which enrolled patients 18–75 years with suspected stable angina between 2010 and 2014 (NCT01149590). We included patients from six centres in whom high-sensitivity troponin I and BNP were measured (Singulex Erenna). Patients with troponin >99th centile upper reference limit (10.2 ng/L) or BNP ≥400 ng/L were excluded to avoid inclusion of patients with myocardial injury or heart failure. Multivariable linear regression models were constructed with troponin and BNP as dependent variables.ResultsIn total, 885 patients were included; 881 (99%) and 847 (96%) had troponin and BNP concentrations above the limit of detection, respectively. Participants had a slight male preponderance (n=513; 56.1%), and the median age was 59.0 (IQR 51.0–65.0) years. The median troponin and BNP concentrations were 1.4 (IQR 0.90–2.1) ng/L and 29.1 (IQR 14.0–54.0) ng/L, respectively. Age and atherosclerotic burden were independent predictors of both biomarkers. Male sex, left ventricular mass and systolic blood pressure were independent predictors of increased troponin. In contrast, female sex and left ventricular volume were independent predictors of increased BNP.ConclusionsTroponin and BNP are associated with coronary atherosclerosis but have important sex differences and distinct and contrasting associations with CT-determined left ventricular mass and volume.Clinical Trial registrationNCT01149590; Post-results.

Background: \ud India accounts for a disproportionate burden of global childhood illnesses. To inform policies and measure progress towards achieving child health targets, we estimated the annual national and state-specific childhood mortality and morbidity attributable to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) between 2000 and 2015.\ud \ud Methods: \ud In this modelling study, we used vaccine clinical trial data to estimate the proportion of pneumonia deaths attributable to pneumococcus and Hib. The proportion of meningitis deaths attributable to each pathogen was derived from pathogen-specific meningitis case fatality and bacterial meningitis case data from surveillance studies. We applied these proportions to modelled state-specific pneumonia and meningitis deaths from 2000 to 2015 prepared by the WHO Maternal and Child Epidemiology Estimation collaboration (WHO/MCEE) on the basis of verbal autopsy studies from India. The burden of clinical and severe pneumonia cases attributable to pneumococcus and Hib was ascertained with vaccine clinical trial data and state-specific all-cause pneumonia case estimates prepared by WHO/MCEE by use of risk factor prevalence data from India. Pathogen-specific meningitis cases were derived from state-level modelled pathogen-specific meningitis deaths and state-level meningitis case fatality estimates. Pneumococcal and Hib morbidity due to non-pneumonia, non-meningitis (NPNM) invasive syndromes were derived by applying the ratio of pathogen-specific NPNM cases to pathogen-specific meningitis cases to the state-level pathogen-specific meningitis cases. Mortality due to pathogen-specific NPNM was calculated with the ratio of pneumococcal and Hib meningitis case fatality to pneumococcal and Hib meningitis NPNM case fatality. Census data from India provided the population at risk.\ud \ud Findings: \ud Between 2000 and 2015, estimates of pneumococcal deaths in Indian children aged 1–59 months fell from 166 000 (uncertainty range [UR] 110 000–198 000) to 68 700 (44 600–86 000), while Hib deaths fell from 82 600 (52 300–112 000) to 15 600 (9800–21 500), representing a 58% (UR 22–78) decline in pneumococcal deaths and an 81% (59–91) decline in Hib deaths. In 2015, national mortality rates in children aged 1–59 months were 56 (UR 37–71) per 100 000 for pneumococcal infection and 13 (UR 8–18) per 100 000 for Hib. Uttar Pradesh (18 900 [UR 12 300–23 600]) and Bihar (8600 [5600–10 700]) had the highest numbers of pneumococcal deaths in 2015. Uttar Pradesh (9300 [UR 5900–12 700]) and Odisha (1100 [700–1500]) had the highest numbers of Hib deaths in 2015. Less conservative assumptions related to the proportion of pneumonia deaths attributable to pneumococcus indicate that as many as 118 000 (UR 69 000–140 000) total pneumococcal deaths could have occurred in 2015 in India.\ud \ud Interpretation: \ud Pneumococcal and Hib mortality have declined in children aged 1–59 months in India since 2000, even before nationwide implementation of conjugate vaccines. Introduction of the Hib vaccine in several states corresponded with a more rapid reduction in morbidity and mortality associated with Hib infection. Rapid scale-up and widespread use of the pneumococcal conjugate vaccine and sustained use of the Hib vaccine could help accelerate achievement of child survival targets in India.\ud \ud Funding: \ud Bill & Melinda Gates Foundation.

Background: Recent studies demonstrated a 5% increase in cartilage repair procedures annually in the United States. There is currently no consensus regarding a superior technique, nor has there been a comprehensive evaluation of postoperative clinical outcomes with respect to a minimal clinically important difference (MCID). Purpose: To determine the proportion of available cartilage repair studies that meet or exceed MCID values for clinical outcomes improvement over short-, mid-, and long-term follow-up. Study Design: Systematic review and meta-analysis. Methods: A systematic review was performed via the Medline, Scopus, and Cochrane Library databases. Available studies were included that investigated clinical outcomes for microfracture (MFX), osteoarticular transfer system (OATS), osteochondral allograft transplantation, and autologous chondrocyte implantation/matrix-induced autologous chondrocyte implantation (ACI/MACI) for the treatment of symptomatic knee chondral defects. Cohorts were combined on the basis of surgical intervention by performing a meta-analysis that utilized inverse-variance weighting in a DerSimonian-Laird random effects model. Weighted mean improvements in International Knee Documentation Committee (IKDC), Lysholm, and visual analog scale for pain (VAS pain) scores were calculated from preoperative to short- (1-4 years), mid- (5-9 years), and long-term (≥10 years) postoperative follow-up. Mean values were compared with established MCID values per 2-tailed 1-sample Student t tests. Results: A total of 89 studies with 3894 unique patients were analyzed after full-text review. MFX met MCID values for all outcome scores at short- and midterm follow-up with the exception of VAS pain in the midterm. OATS met MCID values for all outcome scores at all available time points; however, long-term data were not available for VAS pain. Osteochondral allograft transplantation met MCID values for IKDC at short- and midterm follow-up and for Lysholm at short-term follow-up, although data were not available for other time points or for VAS pain. ACI/MACI met MCID values for all outcome scores (IKDC, Lysholm, and VAS pain) at all time points. Conclusion: In the age of informed consent, it is important to critically evaluate the clinical outcomes and durability of cartilage surgery with respect to well-established standards of clinical improvement. MFX failed to maintain VAS pain improvements above MCID thresholds with follow-up from 5 to 9 years. All cartilage repair procedures met MCID values at short- and midterm follow-up for IKDC and Lysholm scores; ACI/MACI and OATS additionally met MCID values in the long term, demonstrating extended maintenance of clinical benefits for patients undergoing these surgical interventions as compared with MFX.

Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes than primary ACL reconstruction. The reasons remain varied and not completely understood. METHODS: Patients undergoing revision ACL reconstruction were prospectively enrolled. Data collected included baseline demographics, surgical technique and pathological condition, prescribed rehabilitation instructions, and a series of validated patient-reported outcome instruments. Patients were followed for 2 years and asked to complete a set of outcome instruments identical to those completed at baseline. Subsequent surgical procedures on the ipsilateral knee were recorded. Regression analysis was used to control for age, sex, activity level, baseline outcome scores, and the above-mentioned rehabilitation-related variables in order to assess the factors affecting clinical outcomes 2 years after revision ACL reconstruction. RESULTS: A total of 843 patients met the inclusion criteria and were successfully enrolled, and 82% (695) were followed for 2 years. Two rehabilitation-related factors were found to influence outcome. First, patients who were prescribed an ACL brace for their return to sports had a significantly better Knee injury and Osteoarthritis Outcome Score (KOOS) for sports and recreational activities at 2 years (odds ratio [OR] =1.50, 95% confidence interval [CI] = 1.07 to 2.11; p = 0.019). Second, patients prescribed an ACL brace for the postoperative rehabilitation period were 2.3 times more likely to have subsequent surgery by 2 years (OR = 2.26, 95% CI = 1.11 to 4.60; p = 0.024). The odds of a graft rerupture were not affected by any type of brace wear. CONCLUSIONS: Rehabilitation-related factors that the physician can control at the time of an ACL reconstruction have the ability to influence clinical outcomes at 2 years. Weight-bearing and motion can be initiated immediately postoperatively. Bracing during the early postoperative period is not helpful. Use of a functional brace early in the postoperative period was associated with an increased risk of a reoperation. Use of a functional brace for a return to sports improved the KOOS on the sports/recreation subscale. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Injuries to the anterior cruciate ligament (ACL) can occur during landing from a jump or changing direction during a cutting maneuver. In these instances, the knee is subjected to combined forces and moments as it flexes under tibiofemoral compression force (TCF). We hypothesized that TCF would increase ACL forces and tibiofemoral motions under isolated and combined modes of loading relevant to knee injury. ACL force and knee kinematics were recorded in human cadaveric specimens during knee flexion from 0° to 50° under the following test conditions (alone and in combination): 2 N-m internal tibial torque (IT), 5 N-m valgus moment (VM), and 45N anterior tibial force (AF). Knees were tested with 25N (baseline), 250N, and 500N TCF. ACL force increased with knee flexion during all tests. As the knee was flexed, VM produced a coupled internal tibial rotation, and IT produced a coupled valgus rotation. ACL forces with IT + VM were significantly higher than with IT alone (beyond 10° flexion) or VM alone (at all flexion angles). Increasing the level of TCF above baseline did not significantly change valgus or tibial rotations for any loading condition, but did significantly increase anterior tibial translation (ATT) at all flexion angles and ACL force at flexion angles beyond 5° to 15°. Addition of AF to tests with IT + VM significantly increased ATT and ACL force without significantly altering internal and valgus rotations. The mechanism of high ACL force generation from increased TCF was related to ATT and not internal or valgus rotations of the tibia. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Background Within the SCOT-HEART (Scottish COmputed Tomography of the HEART Trial) trial of patients with stable chest pain, the use of coronary computed tomography angiography (CTA) reduced the rate of death from coronary heart disease or nonfatal myocardial infarction (primary endpoint). Objectives This study sought to assess the consistency and mechanisms of the 5-year reduction in this endpoint. Methods In this open-label trial, 4,146 participants were randomized to standard care alone or standard care plus coronary CTA. This study explored the primary endpoint by symptoms, diagnosis, coronary revascularizations, and preventative therapies. Results Event reductions were consistent across symptom and risk categories (p = NS for interactions). In patients who were not diagnosed with angina due to coronary heart disease, coronary CTA was associated with a lower primary endpoint incidence rate (0.23; 95% confidence interval [CI]: 0.13 to 0.35 vs. 0.59; 95% CI: 0.42 to 0.80 per 100 patient-years; p, Central Illustration

Background Contact between the tibial spine and medial femoral condyle with internal tibial rotation (ITR) has been proposed as a factor for the development of osteochondritis dissecans lesions. We hypothesized that tibial spine contact force (CF) would increase significantly with applied internal tibial torque (IT). Methods A 20 mm diameter cylinder of bone encompassing the tibial spine was cored and attached to a load cell. The isolated bone cylinder included the tibial attachments of the anterior cruciate ligament (ACL) and anterior horn of the lateral meniscus (AHLM). Eleven human cadaveric knees were flexed from 0°–50° under 200 N of tibiofemoral compression (TFC), without and with 2 N-m IT. Tests were repeated with the AHLM cut, and again with both AHLM and ACL cut, where the load cell recorded CF alone without contributions from any ligamentous attachments. Findings There were no significant differences in CF, ITR, or valgus tibial rotation (VTR) after sectioning the AHLM, without or with applied IT. With no tibial torque, mean CFs were less than 20 N throughout the flexion range. Addition of IT significantly increased 1) mean CF by 44.4 N(SD 15.8 N) at 0°(+240%) and 27.2 N(SD 5.0 N) at 20°(+675%), 2), mean ITR by 10.2°(SD 0.8°) at 0° flexion and 18.6°(SD 2.0°) at 20° flexion, and 3) mean VTR by 1.3°(SD 0.4°) at 0° flexion and 4.4°(SD 0.8°) at 20° flexion. Interpretation Our hypothesis was confirmed only between 0° and 20° of knee flexion, where the intercondylar separation distance is relatively small and the possibility of tibial spine contact with ITR is greater.