HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19.

SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.

What Is Important to Patients Who Are Recovering From an Open Tibial Fracture? A Qualitative Study.

BACKGROUND: Open tibial fracture research has traditionally focused on surgical techniques; however, despite technological advances, outcomes from these injuries remain poor, with patients facing a sustained reduced quality of life. Research has rarely asked patients what is important to them after an open tibial fracture, and this question could potentially offer great insight into how to support patients. A qualitative study may assist in our understanding of this subject. QUESTIONS/PURPOSES: We asked: (1) What common themes did patients who have experienced open tibial fractures share? (2) What stresses and coping strategies did those patients articulate? (3) What sources for acquiring coping strategies did patients say they benefited from? METHODS: Semistructured interviews were conducted with patients who had sustained an open tibial fracture between January 1, 2016 and January 1, 2019. All participants were recruited from a Level 1 trauma center in England, and 26 participants were included. The mean age was 44 ± 17 years, and 77% (20 of 26) were men. The patients' injuries ranged in severity, and they had a range of treatments and complications. Transcripts were analyzed using framework analysis, with codes subsequently organized into themes and subthemes. RESULTS: Four themes were identified, which included recouping physical mobility, values around treatment, fears about poor recovery, and coping strategies to reduce psychological burden. Coping strategies were important in mitigating the psychological burden of injury. Task-focused coping strategies were preferred by patients and perceived as taking a proactive approach to recovery. Healthcare practitioners, and others with lived experience were able to educate patients on coping, but such resources were scant and therefore probably less accessible to those with the greatest need. CONCLUSION: Most individuals fail to return to previous activities, and it is unlikely that improvements in surgical techniques will make major improvements in patient outcomes in the near future. Investment in psychosocial support could potentially improve patient experience and outcomes. Digital information platforms and group rehabilitation clinics were identified as potential avenues for development that could offer individuals better psychosocial support with minimal additional burden for surgeons. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Acute and chronic kidney disease in elderly patients with hip fracture: prevalence, risk factors and outcome with development and validation of a risk prediction model for acute kidney injury.

BACKGROUND: Hip fracture is a common injury in older people with a high rate of postoperative morbidity and mortality. This patient group is also at high risk of acute kidney injury (AKI) and chronic kidney disease (CKD), but little is known of the impact of kidney disease on outcome following hip fracture. METHODS: An observational cohort of consecutive patients with hip fracture in a large UK secondary care hospital. Predictive modelling of outcomes using development and validation datasets. Inclusion: all patients admitted with hip fracture with sufficient serum creatinine measurements to define acute kidney injury. Main outcome measures - development of acute kidney injury during admission; mortality (in hospital, 30-365 day and to follow-up); length of hospital stay. RESULTS: Data were available for 2848 / 2959 consecutive admissions from 2007-2011; 776 (27.2%) male. Acute kidney injury occurs in 24%; development of acute kidney injury is independently associated with male sex (OR 1.48 (1.21 to 1.80), premorbid chronic kidney disease stage 3B or worse (OR 1.52 (1.19 to 1.93)), age (OR 3.4 (2.29 to 5.2) for >85 years) and greater than one major co-morbidities (OR 1.61 (1.34 to 1.93)). Acute kidney injury of any stage is associated with an increased hazard of death, and increased length of stay (Acute kidney injury: 19.1 (IQR 13 to 31) days; no acute kidney injury 15 (11 to 23) days). A simplified predictive model containing Age, CKD stage (3B-5), two or more comorbidities, and male sex had an area under the ROC curve of 0.63 (0.60 to 0.67). CONCLUSIONS: Acute kidney injury following hip fracture is common and associated with worse outcome and greater hospital length of stay. With the number of people experiencing hip fracture predicted to rise, recognition of risk factors and optimal perioperative management of acute kidney injury will become even more important.

Early Motion and Directed Exercise (EMADE) following ankle fracture fixation: a pragmatic randomized controlled trial.

Aims: This study aimed to compare the outcomes of two different postoperative management approaches following surgical fixation of ankle fractures: traditional cast immobilization versus the Early Motion and Directed Exercise (EMADE) programme. Methods: A total of 157 patients aged 18 years or older who underwent successful open reduction and internal fixation (ORIF) of Weber B (AO44B) ankle fractures were recruited to this randomized controlled trial. At two weeks post-surgical fixation, participants were randomized to either light-weight cast-immobilization or the EMADE programme, consisting of progressive home exercises and weekly advice and education. Both groups were restricted to non-weightbearing until six weeks post-surgery. The primary outcome was assessed using the Olerud-Molander Ankle Score (OMAS) questionnaire at 12 weeks post-surgery, with secondary measures at two, six, 24, and 52 weeks. Exploratory cost-effectiveness analyses were also performed. Results: Overall, 130 participants returned their 12-week OMAS questionnaires. The mean OMAS was significantly higher in the EMADE group compared with the immobilized group (62.0 (SD 20.9) vs 48.8 (SD 22.5)), with a clinically meaningful mean difference of 13.2 (95% CI 5.66 to 20.73; p < 0.001). These differences were maintained at week 24, with convergence by week 52. No intervention-related adverse events, including instability, were reported. Conclusion: The EMADE programme demonstrated an accelerated recovery compared to traditional six-week cast immobilization for those who have undergone ORIF surgery to stabilize Weber B (AO44B) ankle fractures. The study found the EMADE intervention to be safe.

Development and validation of a trauma frailty scale in severely injured patients: the Nottingham Trauma Frailty Index.

Aims: Frailty greatly increases the risk of adverse outcome of trauma in older people. Frailty detection tools appear to be unsuitable for use in traumatically injured older patients. We therefore aimed to develop a method for detecting frailty in older people sustaining trauma using routinely collected clinical data. Methods: We analyzed prospectively collected registry data from 2,108 patients aged ≥ 65 years who were admitted to a single major trauma centre over five years (1 October 2015 to 31 July 2020). We divided the sample equally into two, creating derivation and validation samples. In the derivation sample, we performed univariate analyses followed by multivariate regression, starting with 27 clinical variables in the registry to predict Clinical Frailty Scale (CFS; range 1 to 9) scores. Bland-Altman analyses were performed in the validation cohort to evaluate any biases between the Nottingham Trauma Frailty Index (NTFI) and the CFS. Results: In the derivation cohort, five of the 27 variables were strongly predictive of the CFS (regression coefficient B = 6.383 (95% confidence interval 5.03 to 7.74), p < 0.001): age, Abbreviated Mental Test score, admission haemoglobin concentration (g/l), pre-admission mobility (needs assistance or not), and mechanism of injury (falls from standing height). In the validation cohort, there was strong agreement between the NTFI and the CFS (mean difference 0.02) with no apparent systematic bias. Conclusion: We have developed a clinically applicable tool using easily and routinely measured physiological and functional parameters, which clinicians and researchers can use to guide patient care and to stratify the analysis of quality improvement and research projects.

Metagenomic changes in response to antibiotic treatment in severe orthopedic trauma patients.

We investigated changes in microbiome composition and abundance of antimicrobial resistance (AMR) genes post-antibiotic treatment in severe trauma patients. Shotgun sequencing revealed beta diversity (Bray-Curtis) differences between 16 hospitalized multiple rib fractures patients and 10 age- and sex-matched controls (p = 0.043), and between antibiotic-treated and untreated patients (p = 0.015). Antibiotic-treated patients had lower alpha diversity (Shannon) at discharge (p = 0.003) and 12-week post-discharge (p = 0.007). At 12 weeks, they also exhibited a 5.50-fold (95% confidence interval [CI]: 2.86-8.15) increase in Escherichia coli (p = 0.0004) compared to controls. Differential analysis identified nine AMRs that increased in antibiotic-treated compared to untreated patients between hospital discharge and 6 and 12 weeks follow-up (false discovery rate [FDR] < 0.20). Two aminoglycoside genes and a beta-lactamase gene were directly related to antibiotics administered, while five were unrelated. In trauma patients, lower alpha diversity, higher abundance of pathobionts, and increases in AMRs persisted for 12 weeks post-discharge, suggesting prolonged microbiome disruption. Probiotic or symbiotic therapies may offer future treatment avenues.

Preoperative inflammatory biomarkers reveal renal involvement in postsurgical mortality in hip fracture patients: an exploratory study.

Background: Hip fractures in frail patients result in excess mortality not accounted for by age or comorbidities. The mechanisms behind the high risk of mortality remain undetermined but are hypothesized to be related to the inflammatory status of frail patients. Methods: In a prospective observational exploratory cohort study of hospitalized frail hip fracture patients, 92 inflammatory markers were tested in pre-operative serum samples and markers were tested against 6-month survival post-hip fracture surgery and incidence of acute kidney injury (AKI). After correcting for multiple testing, adjustments for comorbidities and demographics were performed on the statistically significant markers. Results: Of the 92 markers tested, circulating levels of fibroblast growth factor 23 (FGF-23) and interleukin-15 receptor alpha (IL15RA), both involved in renal disease, were significantly correlated with 6-month mortality (27.5% overall) after correcting for multiple testing. The incidence of postoperative AKI (25.4%) was strongly associated with 6-month mortality, odds ratio = 10.57; 95% CI [2.76-40.51], and with both markers plus estimated glomerular filtration rate (eGFR)- cystatin C (CYSC) but not eGFR-CRE. The effect of these markers on mortality was significantly mediated by their effect on postoperative AKI. Conclusion: High postoperative mortality in frail hip fracture patients is highly correlated with preoperative biomarkers of renal function in this pilot study. The effect of preoperative circulating levels of FGF-23, IL15RA, and eGFR-CYSC on 6-month mortality is in part mediated by their effect on postoperative AKI. Creatinine-derived preoperative renal function measures were very poorly correlated with postoperative outcomes in this group.

Genetic and gut microbiome determinants of SCFA circulating and fecal levels, postprandial responses and links to chronic and acute inflammation.

Short-chain fatty acids (SCFA) are involved in immune system and inflammatory responses. We comprehensively assessed the host genetic and gut microbial contribution to a panel of eight serum and stool SCFAs in two cohorts (TwinsUK, n = 2507; ZOE PREDICT-1, n = 328), examined their postprandial changes and explored their links with chronic and acute inflammatory responses in healthy individuals and trauma patients. We report low concordance between circulating and fecal SCFAs, significant postprandial changes in most circulating SCFAs, and a heritable genetic component (average h2: serum = 14%(SD = 14%); stool = 12%(SD = 6%)). Furthermore, we find that gut microbiome can accurately predict their fecal levels (AUC>0.71) while presenting weaker associations with serum. Finally, we report different correlation patterns with inflammatory markers depending on the type of inflammatory response (chronic or acute trauma). Our results illustrate the breadth of the physiological relevance of SCFAs on human inflammatory and metabolic responses highlighting the need for a deeper understanding of this important class of molecules.

Surgical fixation of rib fractures improves 30-day survival after significant chest injury : an analysis of ten years of prospective registry data from England and Wales.

AIMS: The last decade has seen a marked increase in surgical rib fracture fixation (SRF). The evidence to support this comes largely from retrospective cohorts, and adjusting for the effect of other injuries sustained at the same time is challenging. This study aims to assess the impact of SRF after blunt chest trauma using national prospective registry data, while controlling for other comorbidities and injuries. METHODS: A ten-year extract from the Trauma Audit and Research Network formed the study sample. Patients who underwent SRF were compared with those who received supportive care alone. The analysis was performed first for the entire eligible cohort, and then for patients with a serious (thoracic Abbreviated Injury Scale (AIS) ≥ 3) or minor (thoracic AIS < 3) chest injury without significant polytrauma. Multivariable logistic regression was performed to identify predictors of mortality. Kaplan-Meier estimators and multivariable Cox regression were performed to adjust for the effects of concomitant injuries and other comorbidities. Outcomes assessed were 30-day mortality, length of stay (LoS), and need for tracheostomy. RESULTS: A total of 86,838 cases were analyzed. The rate of SRF was 1.2%. SRF significantly reduced risk of mortality (odds ratio (OR) 0.27 (95 confidence interval (CI) 0.128 to 0.273); p < 0.001) and need for tracheostomy (OR 0.22 (95% CI 0.191 to 0.319); p < 0.001) after adjustment for other covariables across the whole cohort. SRF remained protective in patients with a serious chest injury (hazard ratio (HR) 0.24 (95% CI 0.13 to 0.45); p < 0.001). The benefit in more minor chest injury was less clear. Mean LoS for patients who survived was longer in the SRF group (24.29 days (SD 26.54) vs 16.60 days (SD 26.35); p < 0.001). CONCLUSION: SRF reduces mortality after significant chest trauma associated with both major and minor polytrauma. The rate of fixation in the UK is low and potentially underused as a treatment for severe chest wall injury. Cite this article: Bone Joint J 2022;104-B(6):729-735.

Has a change in established care pathways during the first wave of the COVID-19 pandemic led to an excess death rate in the fragility fracture population? A longitudinal cohort study of 1846 patients.

OBJECTIVE: During the first wave of the COVID-19 pandemic, changes to established care pathways and discharge thresholds for patients with fragility fractures were made. This was to increase hospital bed capacity and minimise the inpatient risk of contracting COVID-19. This study aims to identify the excess death rate in this population during the first wave of the pandemic. DESIGN: A longitudinal cohort study of patients with fragility fractures identified by specific International Classification of Diseases (ICD)-10 codes. The first wave of the pandemic was defined as the 3-month period between 1 March and 1 June 2020. The control group presented between 1 March and 1 June 2019. SETTING: Two acute National Health Service hospitals within the East Midlands region of England. PARTICIPANTS: 1846 patients with fragility fractures over the aforementioned two specified matched time points. PRIMARY AND SECONDARY OUTCOME MEASURES: Four-month mortality of all patients with fragility fractures with a subanalysis of patients with fragility hip fractures. RESULTS: 832 patients with fragility fracture were admitted during the pandemic period (104 diagnosed with COVID-19). 1014 patients presented with fragility fractures in the control group. Mortality in patients with fragility fracture without COVID-19 was significantly higher among pandemic period admissions (14.7%) than the pre-pandemic cohort (10.2%) (HR=1.86; 95% CI 1.41 to 2.45; p<0.001) adjusted for age and sex. Length of stay was shorter during the pandemic period (effect size=-4.2 days; 95% CI -5.8 to -3.1, p<0.001). Subanalysis of patients with fragility hip fracture revealed a mortality of 8.4% in the pre-pandemic cohort, and 15.48% during pandemic admissions with no COVID-19 diagnosis (HR=2.08; 95% CI 1.11 to 3.90; p=0.021). CONCLUSIONS: There is a significant increase in excess death, not explained by confirmed COVID-19 infections. Altered care pathways and aggressive discharge criteria during the pandemic are likely responsible for the increase in excess deaths.

Erector Spinae Plane Blocks for the Early Analgesia of Rib Fractures in Trauma (ESPEAR): protocol for a multicentre pilot randomised controlled trial with feasibility and embedded qualitative assessment.

INTRODUCTION: Patients with rib fractures commonly experience significant acute pain and are at risk of hypoxia, retained secretions, respiratory failure and death. Effective analgesia improves these outcomes. There is widespread variation in analgesic treatments given to patients including oral, intravenous and epidural routes of administration. Erector spinae plane (ESP) blockade, a novel regional analgesic technique, may be effective, but high-quality evidence is lacking. METHODS AND ANALYSIS: To determine if a definitive trial of ESP blockade in rib fractures is possible, we are conducting a multicentre, randomised controlled pilot study with feasibility and qualitative assessment. Fifty adult patients with rib fractures will be randomised in a 1:1 ratio to ESP blockade with multimodal analgesia or placebo ESP blockade with multimodal analgesia. Participants and outcome assessors will be blinded. The primary feasibility outcomes are recruitment rate, retention rate and trial acceptability assessed by interview. ETHICS AND DISSEMINATION: The study was approved by the Oxford B Research Ethics Committee on 22 February 2022 (REC reference: 22/SC/0005). All participants will provide written consent. Trial results will be reported via peer review and to grant funders. TRIAL REGISTRATION NUMBER: ISRCTN49307616.

Deep infection after hip hemiarthroplasty: risk factors for infection and outcome of treatments.

AIMS: Deep surgical site infection (SSI) remains an unsolved problem after hip fracture. Debridement, antibiotic, and implant retention (DAIR) has become a mainstream treatment in elective periprosthetic joint infection; however, evidence for DAIR after infected hip hemiarthroplaty is limited. METHODS: Patients who underwent a hemiarthroplasty between March 2007 and August 2018 were reviewed. Multivariable binary logistic regression was performed to identify and adjust for risk factors for SSI, and to identify factors predicting a successful DAIR at one year. RESULTS: A total of 3,966 patients were identified. The overall rate of SSI was 1.7% (51 patients (1.3%) with deep SSI, and 18 (0.45%) with superficial SSI). In all, 50 patients underwent revision surgery for infection (43 with DAIR, and seven with excision arthroplasty). After adjustment for other variables, only concurrent urinary tract infection (odds ratio (OR) 2.78, 95% confidence interval (CI) 1.57 to 4.92; p < 0.001) and increasing delay to theatre for treatment of the fracture (OR 1.31 per day, 95% CI 1.12 to 1.52; p < 0.001) were predictors of developing a SSI, while a cemented arthroplasty was protective (OR 0.54, 95% CI 0.31 to 0.96; p = 0.031). In all, nine patients (20.9%) were alive at one year with a functioning hemiarthroplasty following DAIR, 20 (46.5%) required multiple surgical debridements after an initial DAIR, and 18 were converted to an excision arthroplasty due to persistent infection, with six were alive at one year. The culture of any gram-negative organism reduced success rates to 12.5% (no cases were successful with methicillin-resistant Staphylococcus aureus or Pseudomonas infection). Favourable organisms included Citrobacter and Proteus (100% cure rate). The all-cause mortality at one year after deep SSI was 55.87% versus 24.9% without deep infection. CONCLUSION: Deep infection remains a devastating complication regardless of the treatment strategy employed. Success rates of DAIR are poor compared to total hip arthroplasty, and should be reserved for favourable organisms in patients able to tolerate multiple surgical procedures. Cite this article: Bone Jt Open 2021;2(11):958-965.

Methicillin-resistant Staphylococcus aureus in hip fracture.

AIMS: Infection after surgery increases treatment costs and is associated with increased mortality. Hip fracture patients have historically had high rates of methicillin-resistant Staphylococcus aureus (MRSA) colonization and surgical site infection (SSI). This paper reports the impact of routine MRSA screening and the "cleanyourhands" campaign on rates of MRSA SSI and patient outcome. METHODS: A total of 13,503 patients who presented with a hip fracture over 17 years formed the study population. Multivariable logistic regression was performed to determine risk factors for MRSA and SSI. Autoregressive integrated moving average (ARIMA) modelling adjusted for temporal trends in rates of MRSA. Kaplan-Meier estimators were generated to assess for changes in mortality. RESULTS: In all, 6,189 patients were identified before the introduction of screening and 7,314 in the post-screening cohort. MRSA infection fell from 69 cases to 15 in the post-screening cohort (p < 0.001). The ARIMA confirmed a significant reduction in MRSA SSI post-screening (p = 0.043) but no significant impact after hand hygiene alone (p = 0.121). Overall SSI fell (2.4% to 1.5%), however deep infection increased slightly (0.89% to 1.06%). ARIMA showed neither intervention affected overall SSI ("cleanyourhands" -0.172% (95% confidence interval (CI) -0.39% to 0.21); p = 0.122, screening -0.113% per year, (95% CI -0.34 to 0.12); p = 0.373). One-year mortality after deep SSI was unchanged after screening (50% vs 45%; p = 0.415). Only warfarinization (OR 3.616 (95% CI 1.366 to 9.569); p = 0.010) and screening (OR 0.189 (95% CI 0.086 to 0.414); p < 0.001) were significant covariables for developing MRSA SSI. CONCLUSION: While screening and decolonization may reduce MRSA-associated SSI, the benefit to patient outcome remains unclear. Overall deep SSI remains an unsolved problem that has seen little improvement over time. Preventing other hospital-associated infections should not be forgotten in the fight against MRSA. Cite this article: Bone Joint J 2021;103-B(1):170-177.

Comparison of rehabilitation interventions in nonoperatively treated distal radius fractures: a randomized controlled trial of effectiveness.

AIMS: Following cast removal for nonoperatively treated distal radius fractures, rehabilitation facilitated by advice leaflet and advice video were compared to a course of face-to-face therapy. METHODS: Adults with an isolated, nonoperatively treated distal radius fracture were included at six weeks post-cast removal. Participants were randomized to delivery of rehabilitation interventions in one of three ways: an advice leaflet; an advice video; or face-to-face therapy session(s). The primary outcome measure was the Disabilities of the Arm, Shoulder and Hand (DASH) score at six weeks post intervention and secondary outcome measures included DASH at one year, DASH work subscale, grip strength, and range of motion at six weeks and one year. RESULTS: A total of 116 (97%) of 120 enrolled participants commenced treatment. Of those, 21 were lost to follow-up, resulting in 30 participants in the advice leaflet, 32 in the advice video, and 33 face-to-face therapy arms, respectively at six weeks of follow-up. There was no significant difference between the treatment groups in the DASH at six weeks (advice leaflet vs face-to-face therapy, p = 0.69; advice video vs face-to-face therapy, p = 0.56; advice leaflet vs advice video, p = 0.37; advice leaflet vs advice video vs face-to-face therapy, p = 0.63). At six weeks, there were no differences in any secondary outcome measures except for the DASH work subscale, where face-to-face therapy conferred benefit over advice leaflet (p = 0.01). CONCLUSION: Following cast removal for nonoperatively treated distal radius fractures, offering an advice leaflet or advice video for rehabilitation gives equivalent patient-reported outcomes to a course of face-to-face therapy. Cite this article: Bone Joint J 2021;103-B(6):1033-1039.

Longitudinal assessment of symptoms and risk of SARS-CoV-2 infection in healthcare workers across 5 hospitals to understand ethnic differences in infection risk.

BACKGROUND: : Healthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population. We aimed to understand ethnic differences in SARS-CoV-2 seropositivity among hospital healthcare workers depending on their hospital role, socioeconomic status, Covid-19 symptoms and basic demographics. METHODS: A prospective longitudinal observational cohort study. 1364 HCWs at five UK hospitals were studied with up to 16 weeks of symptom questionnaires and antibody testing (to both nucleocapsid and spike protein) during the first UK wave in five NHS hospitals between March 20 and July 10 2020. The main outcome measures were SARS-CoV-2 infection (seropositivity at any time-point) and symptoms. Registration number: NCT04318314. FINDINGS: 272 of 1364 HCWs (mean age 40.7 years, 72% female, 74% White, ≥6 samples per participant) seroconverted, reporting predominantly mild or no symptoms. Seropositivity was lower in Intensive Therapy Unit (ITU) workers (OR=0.44 95%CI 0.24, 0.77; p=0.0035). Seropositivity was higher in Black (compared to White) participants, independent of age, sex, role and index of multiple deprivation (OR=2.61 95%CI 1.47-4.62 p=0.0009). No association was seen between White HCWs and other minority ethnic groups. INTERPRETATION: In the UK first wave, Black ethnicity (but not other ethnicities) more than doubled HCWs likelihood of seropositivity, independent of age, sex, measured socio-economic factors and hospital role.

Two doses of the SARS-CoV-2 BNT162b2 vaccine enhance antibody responses to variants in individuals with prior SARS-CoV-2 infection.

Understanding the impact of prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the response to vaccination is a priority for responding to the coronavirus disease 2019 (COVID-19) pandemic. In particular, it is necessary to understand how prior infection plus vaccination can modulate immune responses against variants of concern. To address this, we sampled 20 individuals with and 25 individuals without confirmed previous SARS-CoV-2 infection from a large cohort of health care workers followed serologically since April 2020. All 45 individuals had received two doses of the Pfizer-BioNTech BNT162b2 vaccine with a delayed booster at 10 weeks. Absolute and neutralizing antibody titers against wild-type SARS-CoV-2 and variants were measured using enzyme immunoassays and pseudotype neutralization assays. We observed antibody reactivity against lineage A, B.1.351, and P.1 variants with increasing antigenic exposure, through either vaccination or natural infection. This improvement was further confirmed in neutralization assays using fixed dilutions of serum samples. The impact of antigenic exposure was more evident in enzyme immunoassays measuring SARS-CoV-2 spike protein­specific IgG antibody concentrations. Our data show that multiple exposures to SARS-CoV-2 spike protein in the context of a delayed booster expand the neutralizing breadth of the antibody response to neutralization-resistant SARS-CoV-2 variants. This suggests that additional vaccine boosts may be beneficial in improving immune responses against future SARS-CoV-2 variants of concern.

Surgical Stabilization Improves 30-day Mortality in Patients With Traumatic Flail Chest: A Comparative Case Series at a Major Trauma Center.

OBJECTIVES: To evaluate the outcomes including early mortality after surgical rib fixation using a locking plate system as part of a newly introduced chest trauma pathway. DESIGN: Prospective cohort study with retrospective case-controlled matching with a minimum of 1-year follow-up. SETTING: Regional Level 1 trauma center. PATIENTS/PARTICIPANTS: Consecutive patients undergoing surgical rib fixation were prospectively recruited over a 3-year period (56 patients) and matched to similar patients managed nonoperatively (89 patients) using our local trauma registry. Matching was based on injury severity scores and patient demographics. INTERVENTION: Surgical rib fixation with locking plates. MAIN OUTCOME MEASUREMENTS: The primary outcome measure was 30-day mortality with secondary outcomes of hospital length of stay, intensive care unit length of stay, and patient-reported outcome measures including quality of life (EuroQol-EQ-5D-5L). Official causes of death were obtained from the coroner including postmortem results. RESULTS: There was a significant reduction in 30-day mortality in the fixed patients with 1.8% (1/56) compared to 12.4% (11/89) of the nonfixed patients (P = 0.03). This difference remained significant after further exclusion of other nonsurvivable injuries (P = 0.046). Although hospital length of stay was significantly longer in the fixed group, there was no difference on multivariable analysis. Other secondary outcomes were comparable between the groups with no significant differences in any patient-reported measures. CONCLUSIONS: Mortality was significantly lower in patients who underwent rib stabilization. Quality of life and other patient-reported measures were similar, demonstrating no evidence of detrimental longer-term effects of rib stabilization. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Early motion and directed exercise (EMADE) versus usual care post ankle fracture fixation: study protocol for a pragmatic randomised controlled trial.

BACKGROUND: Following surgical fixation of ankle fractures, the traditional management has included immobilisation for 6 weeks in a below-knee cast. However, this can lead to disuse atrophy of the affected leg and joint stiffness. While early rehabilitation from 2 weeks post surgery is viewed as safe, controversy remains regarding its benefits. We will compare the effectiveness of early motion and directed exercise (EMADE) ankle rehabilitation, against usual care, i.e. 6 weeks' immobilisation in a below-knee cast. METHOD/DESIGN: We have designed a pragmatic randomised controlled trial (p-RCT) to compare the EMADE intervention against usual care. We will recruit 144 independently living adult participants, absent of tissue-healing comorbidities, who have undergone surgical stabilisation of isolated Weber B ankle fractures. The EMADE intervention consists of a non-weight-bearing progressive home exercise programme, complemented with manual therapy and education. Usual care consists of immobilisation in a non-weight-bearing below-knee cast. The intervention period is between week 2 and week 6 post surgery. The primary outcome is the Olerud and Molander Ankle Score (OMAS) patient-reported outcome measure (PROM) at 12 weeks post surgery. Secondary PROMs include the EQ-5D-5 L questionnaire, return to work and return to driving, with objective outcomes including ankle range of motion. Analysis will be on an intention-to-treat basis. An economic evaluation will be included. DISCUSSION: The EMADE intervention is a package of care designed to address the detrimental effects of disuse atrophy and joint stiffness. An advantage of the OMAS is the potential of meta-analysis with other designs. Within the economic evaluation, the cost-utility analysis, may be used by commissioners, while the use of patient-relevant outcomes, such as return to work and driving, will ensure that the study remains pertinent to patients and their families. As it is being conducted in the clinical environment, this p-RCT has high external validity. Accordingly, if significant clinical benefits and cost-effectiveness are demonstrated, EMADE should become a worthwhile treatment option. A larger-scale, multicentre trial may be required to influence national guidelines. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN11212729 . Registered retrospectively on 20 March 2017.