Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial.

BACKGROUND: Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer-BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). METHODS: Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8-12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. FINDINGS: Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. INTERPRETATION: Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. FUNDING: UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.

COVID-19 vaccine safety in Scotland - background rates of adverse events of special interest.

OBJECTIVES: Mass COVID-19 vaccination commenced in December 2020 in Scotland. Monitoring vaccine safety relies on accurate background incidence rates (IRs) for health outcomes potentially associated with vaccination. This study aimed to quantify IRs in Scotland of adverse events of special interest (AESI) potentially associated with COVID-19 vaccination. STUDY DESIGN AND METHODS: IRs and 95% confidence intervals (CIs) for 36 AESI were calculated retrospectively for the pre-COVID-19 pandemic period (01 January 2015-31 December 2019) and the COVID-19 pandemic period (01 April 2020-30 November 2020), with age-sex stratification, and separately by calendar month and year. Incident cases were determined using International Classification of Diseases-10th Revision (ICD-10)-coded hospitalisations. RESULTS: Prepandemic population-wide IRs ranged from 0.4 (0.3-0.5 CIs) cases per 100,000 person-years (PYRS) for neuromyelitis optica to 478.4 (475.8-481.0 CIs) cases per 100,000 PYRS for acute renal failure. Pandemic population-wide IRs ranged from 0.3 (0.2-0.5 CIs) cases per 100,000 PYRS for Kawasaki disease to 483.4 (473.2-493.7 CIs) cases per 100,000 PYRS for acute coronary syndrome. All AESI IRs varied by age and sex. Ten AESI (acute coronary syndrome, acute myocardial infarction, angina pectoris, heart failure, multiple sclerosis, polyneuropathies and peripheral neuropathies, respiratory failure, rheumatoid arthritis and polyarthritis, seizures and vasculitis) had lower pandemic than prepandemic period IRs overall. Only deep vein thrombosis and pulmonary embolism had a higher pandemic IR. CONCLUSION: Lower pandemic IRs likely resulted from reduced health-seeking behaviours and healthcare provision. Higher IRs may be associated with SARS-CoV-2 infections. AESI IRs will facilitate future vaccine safety studies in Scotland.

Tibial rotational osteotomy and distal tuberosity transfer for patella subluxation secondary to excessive external tibial torsion: surgical technique and clinical outcome.

PURPOSE: Recurrent patella subluxation may be secondary to excessive external tibial torsion. The purpose of this study is to evaluate the clinical and radiographic outcome of patients undergoing tibial derotation osteotomy and tibial tuberosity transfer for recurrent patella subluxation in association with excessive external tibial torsion. METHODS: A combined tibial derotation osteotomy and tibial tuberosity transfer was performed in 15 knees (12 patients) with recurrent patella subluxation secondary to excessive external tibial torsion. Clinical evaluation was carried out using preoperative and post-operative Knee Society Score (KSS), Kujala Patellofemoral score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, the short form-12 (SF-12) and a visual analogue score (VAS) pain scale. RESULTS: The median follow-up period was 84 months (range 15-156) and median patient age was 34 years (range 19-57 years). The median preoperative external tibial torsion was 62° (range 55°-70°), with a median rotational correction of 36° (range 30°-45°) after surgery. Significant improvement (p < 0.05) was found in the KSS part I (37 ± 14 to 89 ± 11 points), KSS part II (25 ± 26 to 85 ± 14 points), Kujala score, the SF-12 outcome, WOMAC score and VAS score (8.8 ± 1.9 to 2.4 ± 1.5). Two patients had a nonunion of the tibial osteotomy site; one patient required bone grafting, while another patient required revision to total knee arthroplasty. CONCLUSION: Patients presenting with recurrent patella subluxation secondary to excessive external tibial torsion >45° who underwent tibial derotation osteotomy and tibial tuberosity transfer achieved a satisfactory outcome in terms of pain relief and improved function. A significant complication was seen in 2/15 patients. LEVEL OF EVIDENCE: Case series, Level IV.

Exploiting Real-Time Genomic Surveillance Data To Assess 4CMenB Meningococcal Vaccine Performance in Scotland, 2015 to 2022.

The United Kingdom implemented the first national infant immunization schedule for the meningococcal vaccine 4CMenB (Bexsero) in September 2015, targeting serogroup B invasive meningococcal disease (IMD). Bexsero contains four variable subcapsular proteins, and postimplementation IMD surveillance was necessary, as nonhomologous protein variants can evade Bexsero-elicited protection. We investigated postimplementation IMD cases reported in Scotland from 1 September 2015 to 30 June 2022. Patient demographics and vaccination status were combined with genotypic data from the causative meningococci, which were used to assess vaccine coverage with the meningococcal deduced vaccine antigen reactivity (MenDeVAR) index. Eighty-two serogroup B IMD cases occurred in children >5 years of age, 48 (58.5%) of which were in unvaccinated children and 34 (41%) of which were in children who had received ≥1 Bexsero dose. Fifteen of the 34 vaccinated children had received one dose, 17 had received two doses, and two had received three doses. For 39 cases, meningococcal sequence data were available, enabling MenDeVAR index deductions of vaccine-preventable (M-VP) and non-vaccine-preventable (M-NVP) meningococci. Notably, none of the 19 of the children immunized ≥2 times had IMD caused by M-VP meningococci, with 2 cases of NVP meningococci, and no deduction possible for 17. Among the 15 children partially vaccinated according to schedule (1 dose), 7 were infected by M-VP meningococci and 2 with M-NVP meningococci, with 6 for which deductions were not possible. Of the unvaccinated children with IMD, 40/48 were ineligible for vaccination and 20/48 had IMD caused by M-VP meningococci, with deductions not being possible for 14 meningococci. IMPORTANCE This study demonstrates the value of postimplementation genomic surveillance of vaccine-preventable pathogens in providing information on real-world vaccine performance. The data are consistent with 2 and 3 doses of Bexsero, delivered according to schedule, providing good protection against invasive disease caused by meningococci deduced from genomic data to be vaccine preventable. Single doses provide poorer protection to infants. In practical terms, these data can provide public health reassurance when vaccinated individuals develop IMD with non-vaccine-preventable variants. They further indicate that additional testing is needed on variants for which no immunological data exist to improve estimates of protection, although these data suggest that the uncharacterized variants are unlikely to be covered by Bexsero. Finally, the confirmation that incomplete or absent doses in infancy lead to reduced protection supports public health and general practitioners in promoting vaccination according to schedule.

Prospective surveillance study of the management of intussusception in UK and Irish infants.

BACKGROUND: Intussusception is the most common cause of acute intestinal obstruction in infants. This study examined the clinical presentation, management and outcomes of intussusception in this age group. METHODS: Prospective surveillance of intussusception in infants was carried out between March 2008 and March 2009 in the UK and Ireland. Monthly cards were sent to paediatric clinicians who were requested to notify cases of intussusception. RESULTS: The study identified 261 confirmed cases. The commonest presenting symptom/sign was non-bilious vomiting, in 210 (80·5 per cent) of the infants. Abdominal ultrasonography was done in 247 infants (94·6 per cent) and was diagnostic in 242 (98·0 per cent), compared with plain abdominal X-ray, which was diagnostic in 33 (23·6 per cent) of 140 infants. Enema reduction was carried out in 240 (92·0 per cent) of the 261 infants; the majority (237, 98·8 per cent) had pneumatic reduction with a success rate of 61·2 per cent (145 of 237). Surgery was required in 111 infants (42·5 per cent); 92 operations were as a result of unsuccessful enema reduction, and the remaining 19 infants (17·1 per cent) had primary surgery. Forty-four infants (39·6 per cent of operations) needed a bowel resection. The majority of children (238, 91·2 per cent) recovered uneventfully; 21 (8·0 per cent) had sequelae, one child died (0·4 per cent), and the outcome was unknown for one infant. CONCLUSION: This study described current treatment patterns for intussusception in infancy; these represent a benchmark for improved standards of care for this condition.

Dietary nitrate supplementation for preventing and reducing the severity of winter infections, including COVID-19, in care homes (BEET-Winter): a randomised placebo-controlled feasibility trial.

PURPOSE: Infections cause considerable care home morbidity and mortality. Nitric oxide (NO) has broad-spectrum anti-viral, bacterial and yeast activity in vitro. We assessed the feasibility of supplementing dietary nitrate (NO substrate) intake in care home residents. METHODS: We performed a cluster-randomised placebo-controlled trial in UK residential and nursing care home residents and compared nitrate containing (400 mg) versus free (0 mg daily) beetroot juice given for 60 days. Outcomes comprised feasibility of recruitment, adherence, salivary and urinary nitrate, and ordinal infection/clinical events. RESULTS: Of 30 targeted care homes in late 2020, 16 expressed interest and only 6 participated. 49 residents were recruited (median 8 [interquartile range 7-12] per home), mean (standard deviation) age 82 (8) years, with proxy consent 41 (84%), advance directive for hospital non-admission 8 (16%) and ≥ 1 doses of COVID-19 vaccine 37 (82%). Background dietary nitrate was < 30% of acceptable daily intake. 34 (76%) residents received > 50% of juice. Residents randomised to nitrate vs placebo had higher urinary nitrate levels, median 50 [18-175] v 18 [10-50] mg/L, difference 25 [0-90]. Data paucity precluded clinical between-group comparisons; the outcome distribution was as follows: no infection 32 (67%), uncomplicated infection 0, infection requiring healthcare support 11 (23%), all-cause hospitalisation 5 (10%), all-cause mortality 0. Urinary tract infections were most common. CONCLUSIONS: Recruiting UK care homes during the COVID-19 pandemic was partially successful. Supplemented dietary nitrate was tolerated and elevated urinary nitrate. Together, infections, hospitalisations and deaths occurred in 33% of residents over 60 days. A larger trial is now required. TRIAL REGISTRATION: ISRCTN51124684. Application date 7/12/2020; assignment date 13/1/2021.

Chronic anterior cruciate ligament deficiency. Long-term results of MacIntosh's lateral substitution reconstruction.

The lateral substitution reconstruction operation described by MacIntosh has been evaluated in 27 patients with chronic anterior cruciate ligament deficiency of the knee. The results, at an average of 11.3 years after operation, have been assessed by a scoring system which allocates a maximum of 25 points each for function and for clinical evaluation. Emphasis was placed on subjective giving way and objective evidence of a positive anterior drawer sign and a positive lateral pivot shift test. A score of 46 to 50 was classified as excellent, 41 to 46 as fair, and less than 41 was a poor result: 52% scored excellent, 26% fair and 22% were poor. Most of those with poor results had had evidence of osteoarthritis at the time of operation. Despite the recorded scores, no less than 75% of the patients at long-term follow-up were subjectively improved, and able to maintain an active life style.

Management of medial collateral ligament laxity.

Assessment of axial alignment with 3-foot radiographs and valgus-varus stress radiographs is important when managing symptomatic MCL instability. Realignment of the anatomical axis to 0 degrees to reduce the stress on the MCL reduces the symptomatic laxity. The assessment of MCL laxity is important when considering valgus HTO for medial compartment arthritis. A combined opening and closing wedge osteotomy reduces the size of the fragment needed and tensions the MCL at the same time. Interposition proximal tibial allografts may be used to retention combined MCL/LCL laxity as well as to correct associated deformities. As one would expect, defunctioning of the MCL in patients with valgus is best achieved using a varus distal femoral osteotomy.

Ifosfamide neurotoxicity. A challenge for nurses, a potential nightmare for patients.

The alkylator-like agent ifosfamide, which has been found to be useful in the treatment of a number of solid tumors, can have severe central nervous system (CNS) side effects in addition to causing myelosuppression, nephrotoxicity, nausea and vomiting, pulmonary edema, and interstitial pneumonitis. This article, including a case study and a protocol, prepares nurses to do patient education and to observe, assess, and provide care for patients who may experience the CNS toxicity that ranges from mild changes to severe disturbances of mental state.

Constipation related to narcotic therapy. A protocol for nurses and patients.

Constipation is a well-known side effect of narcotics and can add to the total burden of pain of cancer patients in need of pain medication. There is little literature on this topic, and it has been suggested that one reason is that the definitions are vague and socially bound. It has also been suggested that some physicians consider constipation a trivial problem, resulting in a relative lack of attention to the subject. Although this article addresses narcotic-induced constipation, other types related to poor dietary and exercise habits and to disease are mentioned and may be contributing factors. There are a number of drugs and treatments available to treat the problem, but the emphasis of nursing care should be on prevention of constipation. Senna derivatives have been noted to reverse the major constipating effect of narcotics, i.e., the decrease in propulsive movements of the colon, and it is recommended they be given right along with narcotics as a preventive measure. A protocol that incorporates a schedule of drugs and dosages and specific patient and nursing guidelines for daily evaluation of bowel function, with education about dietary, fluid, and exercise requirements, will help nurses practice prevention and contribute to patients' comfort.

Public health aspects of tuberculosis.

This article covers public health aspects of the investigation and management of people who are infected with tuberculosis (TB). It contains a brief overview of the recent epidemiology of TB in Scotland, focusing on changes in Scottish TB incidence and describing some epidemiological associations. We then describe the initial public health assessment of those with suspected TB and responses that should be initiated. It does not address issues relating to the clinical treatment of patients with TB.

Total knee replacement with rotational proximal tibial osteotomy for osteoarthritis with severe external tibial torsion and patellar instability.

The management of osteoarthritis of the knee associated with patellar instability secondary to external tibial torsion > 45 degrees is challenging. Patellofemoral biomechanics in these patients cannot be achieved by intra-articular correction using standard techniques of total knee replacement. We reviewed seven patients (eight knees) with recurrent patellar dislocation and one with bilateral irreducible lateral dislocation who had undergone simultaneous total knee replacement and internal tibial derotational osteotomy. All had osteoarthritis and severe external tibial torsion. The mean follow-up was for 47.2 months (24 to 120). The mean objective and functional Knee Society scores improved significantly (p = 0.0001) from 29.7 and 41.5 pre-operatively to 71.4 and 73.5 post-operatively, respectively. In all patients the osteotomies healed and patellar stability was restored. Excessive external tibial torsion should be identified and corrected in patients with osteoarthritis and patellar instability. Simultaneous internal rotation osteotomy of the tibia and total knee replacement is a technically demanding but effective treatment for such patients.

Severe complications of chickenpox in hospitalised children in the UK and Ireland.

AIMS: To estimate the annual incidence of hospitalisations due to severe complications of varicella, describe the complications and estimate annual mortality. METHODS: Active surveillance throughout the UK and Ireland for 13 months by paediatricians notifying cases to the British Paediatric Surveillance Unit and completing a questionnaire. The case definition was any child aged <16 years hospitalised with complicated varicella, as defined by a list of conditions, or admitted to ICU/HDU with varicella. RESULTS: 188 cases were notified for the surveillance period, of which 112 (0.82/100 000 children/year) met the case definition and were not duplicates. Confirmed cases had a median age of 3 years (range 0-14). The complications were: bacteraemia/septic shock (n = 30), pneumonia (n = 30), encephalitis (n = 26), ataxia (n = 25), toxic shock syndrome/toxin-mediated disease (n = 14), necrotising fasciitis (n = 7), purpura fulminans/disseminated coagulopathy (n = 5), fulminant varicella (n = 5) and neonatal varicella (n = 3). 52 children (46%) had additional bacterial infections. Six deaths were due, or possibly due, to varicella, including one intrauterine death. Four of the other five children who died (ages 2-14 years) had a pre-existing medical condition. Sequelae on discharge were reported for 41 cases (40%), most frequently ataxia or skin scarring. The median length of hospital stay was 7 days (range 1-68). CONCLUSIONS: This study provides a minimum estimate of severe complications and death resulting from varicella in children in the UK and Ireland. Most complications, excluding deaths, occur in otherwise healthy children and thus would be preventable only through a universal childhood immunisation programme.

Impact of adverse publicity on MMR vaccine uptake: a population based analysis of vaccine uptake records for one million children, born 1987-2004.

AIMS: To determine the impact of adverse publicity on MMR uptake and measles susceptibility, including whether vaccination is delayed and the role of deprivation. METHODS: A population database for all Scotland containing immunisation records for over one million children (n = 1,079,327) born 1987-2004 was analysed. MMR uptake was determined by birth cohort and deprivation category. "Final" uptake (at approx age 6 years) was predicted by linear regression by birth cohort. Measles susceptibility in 1998 and 2003 was determined by postcode sector and district for cohorts combined to construct nursery and primary school age groups. RESULTS: There is evidence of a slight rise in late uptake, but insufficient to compensate for underlying declines. Late vaccination continues to be associated with deprivation, while the most affluent tend to be vaccinated promptly, or not at all. Predicted figures for "final" MMR1 uptake are over 90%, but under 95%. Measles susceptibility has increased significantly in nursery children, with an eightfold rise in the number of districts with greater than 20% susceptibility in this group (from 3 to 25). CONCLUSIONS: Increased measles susceptibility in nursery children is concerning, particularly in the most vulnerable areas. These figures are likely to increase in the future, as MMR uptake has not yet returned to the previous higher level. Increased susceptibility levels can also be expected in primary schools in the future, as levels of late uptake are insufficient to compensate. Predicted figures for "final" MMR1 uptake are under the herd immunity threshold and campaigns may be required to increase uptake among future primary school children.

Costs of running a universal adolescent hepatitis B vaccination programme.

In the first UK study to examine feasibility and acceptability of universal adolescent hepatitis B vaccination, the costs associated with the administration and uptake (80.2 and 89.3% for three doses and at least two doses, respectively), of a three-dose regimen in pupils in Glasgow schools (2001/2002) were measured. These data were used to estimate the economic outlay for the delivery of a routine, ongoing three-dose and two-dose hepatitis B vaccine programme in schools. Vaccine, accounting for almost 70% of the overall costs, was the largest cost item for both the pilot and routine programmes, using either regimen. However, the ongoing, two-dose regimen was the cheapest option in this analysis, irrespective of vaccine price. Cost data from this study may be useful for other countries wishing to implement a similar programme.

Patella alta and recurrent dislocation of the patella.

Fifteen knees were treated with a surgical technique designed for recurrent patellar dislocations when associated with patella alta. The average number of patellar dislocations preoperatively was 12, and the determination of patella alta was made using the technique described by Insall and Salvati, which is a ratio of the length of the patellar tendon to the longest diagonal length of the patella. The normal value for this ratio is 1.02 plus or minus 20%. The average preoperative ratio in this study was 1.58 (range, 1.2-2.1), which changed to 1.08 (range, 0.99-1.14) by the time of follow-up examination. The surgical technique used involves transposing the patellar tendon insertion distally without any medialization or recessing and allows for good bone contact for healing, secure fixation, and immediate postoperative motion. There were no recurrences of patellar dislocation postoperatively and few complications. Only one patient complained of anterior knee pain in the follow-up period. This technique is thought to give good results when it is used specifically for recurrent patellar dislocations associated with patella alta.