What can the Defence Medical Services learn from the COVID-19 pandemic in order to be ready for the future?

The COVID-19 pandemic placed significant global pressure on public health, with the demand for specialist clinical input, equipment and therapeutics often outweighing supply in many well-established healthcare systems. The UK was no exception to this burden, resulting in unprecedented demands being placed on its NHS. Throughout the pandemic, the UK Defence Medical Services (DMS) aided the civilian healthcare sector, while concurrently adapting as an organisation to meet its enduring commitment in promoting the operational output of the wider UK Armed Forces. This paper serves to provide an overview of some of these key activities while offering proposed lessons which can be learnt, in order to promote the DMS' output in times of future crises. Of note, the DMS aided to mitigate surge demands placed on the NHS' supply chain, assisting in promoting its resilience to provide key materials to civilian clinical personnel. Adaptation of military policy generation mechanisms, together with adoption of novel technological approaches to promote remote working, empowered efficient DMS operational output throughout the pandemic. Direct provision of personnel to assist in the NHS' clinical output served to foster mutually beneficial interorganisational relationships, while providing objective benefit for the UK public.This paper was selected as the BMJ Military Health Royal Society of Medicine Colt Foundation National Essay Prize Winner 2021.

Fatal Multisystem Inflammatory Syndrome in Adult after SARS-CoV-2 Natural Infection and COVID-19 Vaccination.

We describe a fatal case of multisystem inflammatory syndrome in an adult with onset 22 days after a second dose of mRNA coronavirus disease vaccine. Serologic and clinical findings indicated severe acute respiratory syndrome coronavirus 2 infection occurred before vaccination. The immunopathology of this syndrome, regardless of vaccination status, remains poorly understood.

Effect of losartan on performance and physiological responses to exercise at high altitude (5035 m).

OBJECTIVE: Altitude-related and exercise-related elevations in blood pressure (BP) increase the likelihood of developing pulmonary hypertension and high-altitude illness during high-altitude sojourn. This study examined the antihypertensive effect and potential exercise benefit of the angiotensin II receptor antagonist losartan when taken at altitude. METHODS: Twenty participants, paired for age and ACE genotype status, completed a double-blinded, randomised study, where participants took either losartan (100 mg/day) or placebo for 21 days prior to arrival at 5035 m (Whymper Hut, Mt Chimborazo, Ecuador). Participants completed a maximal exercise test on a supine cycle ergometer at sea level (4 weeks prior) and within 48 hours of arrival to 5035 m (10-day ascent). Power output, beat-to-beat BP, oxygen saturation (SpO2) and heart rate (HR) were recorded during exercise, with resting BP collected from daily medicals during ascent. Before and immediately following exercise at 5035 m, extravascular lung water prevalence was assessed with ultrasound (quantified via B-line count). RESULTS: At altitude, peak power was reduced relative to sea level (p<0.01) in both groups (losartan vs placebo: down 100±29 vs 91±28 W, p=0.55), while SpO2 (70±6 vs 70±5%, p=0.96) and HR (146±21 vs 149±24 bpm, p=0.78) were similar between groups at peak power, as was the increase in systolic BP from rest to peak power (up 80±37 vs 69±33 mm Hg, p=0.56). Exercise increased B-line count (p<0.05), but not differently between groups (up 5±5 vs 8±10, p=0.44). CONCLUSION: Losartan had no observable effect on resting or exercising BP, exercise-induced symptomology of pulmonary hypertension or performance at 5035 m.

Hypoxia is not the primary mechanism contributing to exercise-induced proteinuria.

INTRODUCTION: Proteinuria increases at altitude and with exercise, potentially as a result of hypoxia. Using urinary alpha-1 acid glycoprotein (α1-AGP) levels as a sensitive marker of proteinuria, we examined the impact of relative hypoxia due to high altitude and blood pressure-lowering medication on post-exercise proteinuria. METHODS: Twenty individuals were pair-matched for sex, age and ACE genotype. They completed maximal exercise tests once at sea level and twice at altitude (5035 m). Losartan (100 mg/day; angiotensin-receptor blocker) and placebo were randomly assigned within each pair 21 days before ascent. The first altitude exercise test was completed within 24-48 hours of arrival (each pair within ~1 hour). Acetazolamide (125 mg two times per day) was administrated immediately after this test for 48 hours until the second altitude exercise test. RESULTS: With placebo, post-exercise α1-AGP levels were similar at sea level and altitude. Odds ratio (OR) for increased resting α1-AGP at altitude versus sea level was greater without losartan (2.16 times greater). At altitude, OR for reduced post-exercise α1-AGP (58% lower) was higher with losartan than placebo (2.25 times greater, p=0.059) despite similar pulse oximetry (SpO2) (p=0.95) between groups. Acetazolamide reduced post-exercise proteinuria by approximately threefold (9.3±9.7 vs 3.6±6.0 µg/min; p=0.025) although changes were not correlated (r=-0.10) with significant improvements in SpO2 (69.1%±4.5% vs 75.8%±3.8%; p=0.001). DISCUSSION: Profound systemic hypoxia imposed by altitude does not result in greater post-exercise proteinuria than sea level. Losartan and acetazolamide may attenuate post-exercise proteinuria, however further research is warranted.

Technical note on endovascular treatment of concomitant carotid occlusion in large vessel occlusion stroke: The "single-cross" technique.

BACKGROUND: Emergent large vessel occlusive (ELVO) stroke secondary to underlying carotid occlusive disease is frequently encountered in endovascular ischemic stroke therapy and trials. Up to 29% of all cerebral vascular accidents are attributed to severe carotid occlusive disease, and recent interventional trials have demonstrated this occurrence in 18.6-32.2% of ELVO stroke. We present a novel technique using the stent retriever guide wire to expedite angioplasty and/or stent placement for associated carotid occlusive disease during mechanical thrombectomy of ELVO stroke. This technique utilizes the "waiting time" during stent retriever integration within the thrombus as an opportunity to initiate revascularization of the cervical carotid, using the deployed stent retriever guidewire as an ad hoc rapid exchange wire while the stentriever serves as a potential surrogate distal embolic protection device. We present 23 cases using this novel endovascular approach, which we have called the single-cross technique, as the cervical lesion is only traversed once during therapy. METHODS: A case series of 23 consecutive patients who underwent a novel endovascular technique for treating tandem ICA origin and intracranial occlusive lesions is presented. Endpoints measured were time to re-perfusion, rates of intracranial hemorrhage and clinical outcomes (mRS at 30 and 90 days). RESULTS: Average procedure time for revascularizing both the carotid and intracranial lesions was 52 min. A symptomatic ICH rate of 9% was observed. Seventy-four percent of patients had an mRS of 0-2 at follow-up. CONCLUSIONS: The single-cross technique appears to be a safe and effective option for treating tandem occlusive lesions in the setting of ELVO.

Hemoglobin Providence (ß82 Lys > Asn, Asp) and lower-than-expected HbA1c in a nonadherent teenager with type 1 diabetes: a case report and literature review.

Endocrinologists should have a high index of suspicion for a Hb variant when the HbA1c is not consistent with other indices of glycemic control.

Diagnosis of abnormally invasive posterior placentation: the role of MR imaging.

Abnormally invasive placentation is becoming more common with a recent increase in cesarean sections and maternal age, among other risk factors. Ultrasonography is the first line-imaging, but it can be difficult to diagnose when limiting factors are present. Failure to recognize this serious placental abnormality precludes us from making the appropriate plan for the delivery and consequently can lead to fatal results. In this report, we present a case in which magnetic resonance imaging was used to diagnose posterior placenta increta missed by multiple sonographic examinations in a patient with previous myomectomies, and we also include a review of the literature on this topic. It is our conclusion that magnetic resonance imaging is superior to sonography to diagnose abnormally invasive placentation in cases of posterior placenta previa and high pretesting probability.

Cleaning and Sterilization of Used Cardiac Implantable Electronic Devices With Process Validation: The Next Hurdle in Device Recycling.

OBJECTIVES: This study sought to develop a validated, reproducible sterilization protocol, which could be used in the reprocessing of cardiac implantable electronic devices (CIEDs). BACKGROUND: Access to cardiac CIED therapy in high-income and in low- and middle-income countries varies greatly. CIED reuse may reduce this disparity. METHODS: A cleaning and sterilization protocol was developed that includes washing CIEDs in an enzymatic detergent, screw cap and set screw replacement, brushing, inspection, and sterilization in ethylene oxide. Validation testing was performed to assure compliance with accepted standards. RESULTS: With cleaning, the total mean bioburden for each of 3 batches of 10 randomly chosen devices was reduced from 754 to 10.1 colony-forming units. After sterilization with ethylene oxide, with 3 half-cycle and 3 full-cycle processes, none of the 90 biological indicator testers exhibited growth after 7 days. Through cleaning and sterilization, protein and hemoglobin concentrations were reduced from 99.2 to 1.42 µg/cm2 and from 21.4 to 1.03 µg/cm2, respectively. Mean total organic carbon residual was 1.44 parts per million (range 0.36 to 2.9 parts per million). Endotoxin concentration was not detectable at the threshold of <0.03 endotoxin units/ml or <3.0 endotoxin units/device. Cytotoxicity and intracutaneous reactivity tests met the standards set by the Association for Advancement of Medical Instrumentation and the International Organization for Standardization. CONCLUSIONS: CIEDs can be cleaned and sterilized according to a standardized protocol achieving a 12-log reduction of inoculated product, resulting in sterility assurance level of 10-6.

Drugs for cardiovascular disease in India: perspectives of pharmaceutical executives and government officials on access and development-a qualitative analysis.

BACKGROUND: India shoulders the greatest global burden of cardiovascular diseases (CVDs), which are the leading cause of mortality worldwide. Drugs are the bedrock of treatment and prevention of CVD. India's pharmaceutical industry is the third largest, by volume, globally, but access to CVD drugs in India is poor. There is a lack of qualitative data from government and pharmaceutical sectors regarding CVD drug development and access in India. METHODS: By purposive sampling, we recruited either Indian government officials, or pharmaceutical company executives. We conducted a stakeholder analysis via semi-structured, face-to-face interviews in India. Topic guides allow for the exploration of key issues across multiple interviews, along with affording the interviewer the flexibility to examine matters arising from the discussions themselves. After transcription, interviews underwent inductive thematic analysis. RESULTS: Ten participants were interviewed (Government Officials: n = 5, and Pharmaceutical Executives: n = 5). Two themes emerged: i) 'Policy-derived Factors'; ii) 'Patient- derived Factors' with three findings. First, both government and pharmaceutical participants felt that the focus of Indian pharma is shifting to more complex, high-quality generics and to new drug development, but production of generic drugs rather than new molecular entities will remain a major activity. Second, current trial regulations in India may restrict India's potential role in the future development of CVD drugs. Third, it is likely that the Indian government will tighten its intellectual property regime in future, with potentially far-reaching implications on CVD drug development and access. CONCLUSIONS: Our stakeholder analysis provides some support for present patent regulations, whilst suggesting areas for further research in order to inform future policy decisions regarding CVD drug development and availability. Whilst interviewees suggested government policy plays an important role in shaping the industry, a significant force for change was ascribed to patient-derived factors. This suggests a potential role for Indian initiatives that market the unique advantages of its patient population for drug research in influencing national and multinational pharmaceutical companies to undertake CVD drug development in India, rather than simply IP policy-directed factors.

Computational study of a multistep height model.

An equilibrium random surface multistep height model proposed in [Abraham and Newman, EPL 86, 16002 (2009)] is studied using a variant of the worm algorithm. In one limit, the model reduces to the two-dimensional Ising model in the height representation. When the Ising model constraint of single height steps is relaxed, the critical temperature and critical exponents are continuously varying functions of the parameter controlling height steps larger than one. Numerical estimates of the critical exponents can be mapped via a single parameter, the Coulomb gas coupling, to the exponents of the O(n) loop model on the honeycomb lattice with n ≤ 1.

Ising (conformal) fields and cluster area measures.

We provide a representation for the scaling limit of the d = 2 critical Ising magnetization field as a (conformal) random field by using Schramm-Loewner Evolution clusters and associated renormalized area measures. The renormalized areas are from the scaling limit of the critical Fortuin-Kasteleyn clusters and the random field is a convergent sum of the area measures with random signs. Extensions to off-critical scaling limits, to d = 3, and to Potts models are also considered.

Initial clinical experience with frameless optically guided stereotactic radiosurgery/radiotherapy in pediatric patients.

OBJECTIVE: The objective of this study is to report our initial experience treating pediatric patients with central nervous system tumors using a frameless, optically guided linear accelerator. MATERIALS AND METHODS: Pediatric patients were selected for treatment after evaluation by a multidisciplinary neuro-oncology team including neurosurgery, neurology, pathology, oncology, and radiation oncology. Prior to treatment, all patients underwent treatment planning using magnetic resonance imaging (MRI) and treatment simulation on a standard computed tomography scanner (CT). For CT simulation, patients were fitted with a customized plastic face mask with a bite block attached to an optical array with four reflective markers. After ensuring adequate reproducibility, these markers were tracked during treatment by an infra-red camera. All treatments were delivered on a Varian Trilogy linear accelerator. The follow-up period ranges from 1-18 months, with a median follow-up of 6 months. RESULTS: Nine patients, ages ranging from 12 to 19 years old (median age 15 years old), with a variety of tumors have been treated. Patients were treated for juvenile pilocytic astrocytoma (JPA; n = 2), pontine low-grade astrocytoma (n = 1), pituitary adenoma (n = 3), metastatic medulloblastoma (n = 1), acoustic neuroma (n = 1), and pineocytoma (n = 1). We followed patients for a median of 12 months (range 3-18 months) with no in-field failures and were able to obtain encouraging toxicity profiles. CONCLUSION: Frameless stereotactic optically guided radiosurgery and radiotherapy provides a feasible and accurate tool to treat a number of benign and malignant tumors in children with minimal treatment-related morbidity.