Management of a large outbreak of COVID-19 at a British Army training centre: lessons for the future.

INTRODUCTION: The COVID-19 pandemic has posed major challenges for infection control within training centres, both civilian and military. Here we present a narrative review of an outbreak that occurred at the Royal Military Academy Sandhurst (RMAS) in January-March 2021, in the context of the circulating, highly transmissible SARS-CoV-2 variant B.1.1.7. METHODS: Testing for SARS-CoV-2 was performed using a combination of reverse transcriptase PCR and Lateral Flow Devices (LFDs). Testing and isolation procedures were conducted in line with a pre-established symptom stratification system. Genomic sequencing was performed on 10 sample isolates. RESULTS: By the end of the outbreak, 185 cases (153 Officer Cadets, 32 permanent staff) had contracted confirmed COVID-19. This represented 15% of the total RMAS population. This resulted in 0 deaths and 0 hospitalisations, but due to necessary isolation procedures did represent an estimated 12 959 person-days of lost training. 9 of 10 (90%) of sequenced isolates had a reportable lineage. All of those reported were found to be the Alpha lineage B.1.1.7. CONCLUSIONS: We discuss the key lessons learnt from the after-action review by the Incident Management Team. These include the importance of multidisciplinary working, the utility of sync matrices to monitor outbreaks in real time, issues around Officer Cadets reporting symptoms, timing of high-risk training activities, infrastructure and use of LFDs. COVID-19 represents a vital learning opportunity to minimise the impact of potential future pandemics, which may produce considerably higher morbidity and mortality in military populations.

Nosocomial or not? A combined epidemiological and genomic investigation to understand hospital-acquired COVID-19 infection on an elderly care ward.

BACKGROUND: COVID-19 has the potential to cause outbreaks in hospitals. Given the comorbid and elderly cohort of patients hospitalized, hospital-acquired COVID-19 infection is often fatal. Pathogen genome sequencing is becoming increasingly important in infection prevention and control (IPC). AIM: To inform the understanding of in-hospital SARS-CoV-2 transmission in order to improve IPC practices and to inform the future development of virological testing for IPC. METHODS: Patients detected COVID-19 positive by polymerase chain reaction on Ward A in April and May 2020 were included with contact tracing to identify other potential cases. Genome sequencing was undertaken for a subgroup of cases. Epidemiological, genomic, and cluster analyses were performed to describe the epidemiology and to identify factors contributing to the outbreak. FINDINGS: Fourteen cases were identified on Ward A. Contact tracing identified 16 further patient cases; in addition, eight healthcare workers (HCWs) were identified as being COVID-19 positive through a round of asymptomatic testing. Genome sequencing of 16 of these cases identified viral genomes differing by two single nucleotide polymorphisms or fewer, with further cluster analysis identifying two groups of infection (a five-person group and a six-person group). CONCLUSION: Despite the temporal relationship of cases, genome sequencing identified that not all cases shared transmission events. However, 11 samples were found to be closely related and these likely represented in-hospital transmission. This included three HCWs, thereby confirming transmission between patients and HCWs.

Managing junctional haemorrhage in the combat environment.

Tactical combat casualty care and the application of extremity tourniquets have saved lives in combat. In the modern combat environment junctional injuries are common and difficult to treat. Recently, junctional tourniquets have emerged as a potential solution to this problem. Junctional tourniquets can be used as an adjunct to persistent haemorrhage despite application of conventional tourniquets or in the persistently hypotensive casualty. Surgeons must have an approach to receiving patients with junctional tourniquets in place in the operating room. The algorithms presented allow for an evidence-based and command-driven implantation of junctional tourniquets as part of tactical combat casualty care.

The future of resuscitative endovascular balloon occlusion in combat operations.

Damage control resuscitation and early thoracotomy have been used to increase survival after severe injury in combat. There has been a renewed interest in resuscitative endovascular balloon occlusion of the aorta (REBOA) in both civilian and military medical practices. REBOA may result in visceral and limb ischaemia that could be harmful if use of REBOA is premature or prolonged. The purpose of this paper is to align our experience of combat injuries with the known capability of REBOA to suggest an implementation strategy for the use of REBOA in combat care. It may replace the resuscitative effect of thoracotomy; can provide haemostasis of non-compressible torso injuries such as the junctional and pelvic haemorrhage caused by improvised explosive devices. However, prehospital use of REBOA must be in the context of an overall surgical plan and should be restricted to deployment in the distal aorta. Although REBOA is technically easier than a thoracotomy, it requires operator training and skill to add to the beneficial effect of damage control resuscitation and surgery.

Randomised controlled trial comparing marksmanship following application of a tourniquet or haemostatic clamp in healthy volunteers.

BACKGROUND: In a care under fire situation, a first line response to haemorrhage is to apply a tourniquet and return fire. However, there is little understanding of how tourniquets and other haemorrhage control devices impact marksmanship. METHODS: We compared the impact of the iTClamp and the Combat Application Tourniquet (CAT) on marksmanship. Following randomisation (iTClamp or CAT), trained marksmen fired an AR15 at a scaled silhouette target in prone unsupported position (shooting task). Subjects then attempted to complete the shooting task at 5, 10, 15, 30 and 60 min post-haemorrhage control device application. RESULTS: All of the clamp groups (n=7) completed the 60 min shooting task. Five CAT groups (n=6) completed the 5 min shooting task and one completed the 5 and 10 min shooting task before withdrawing. Four CAT groups were stopped due to unsafe handling; two stopped due to pain. When examining hits on mass (HOM) for the entire shooting task, there was no significant difference between tourniquet and iTClamp HOM at 5 min (p=0.18). However, there was a significant difference at 10 min, p=0.003 with tourniquet having significantly fewer HOM (1.7±2.7 HOM) than the iTClamp (8.1±3.3 HOM) group. The total effective HOM for the entire 60 min shooting task showed that the iTClamp group achieved significantly (p=0.001) more HOM than the tourniquet group. Over the entire 60 min shooting exercise, the iTClamp group achieved a median 72% (52/72) of available HOM while the tourniquet group obtained 19% (14/72). CONCLUSIONS: Application of a tourniquet to the dominant arm negates effective return of fire in a care under fire setting after a brief time window. Haemorrhage control devices that preserve function may have a role in care under fire situations, as preserving effectiveness in returning fire has obvious operational merits.

Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial.

BACKGROUND: Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. METHODS: Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. RESULTS: Overall, 96% (43/45) [95% CI 86-99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL - 1 vs. 1.8 mg dL - 1; P<0.01). The 28-day mortality and thromboembolic complications were similar between groups. CONCLUSIONS: Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.

Bacterial viability on chemically modified silicon nanowire arrays.

The global threat of antimicrobial resistance is driving an urgent need for novel antimicrobial strategies. Functional surfaces are essential to prevent spreading of infection and reduce surface contamination. In this study we have fabricated and characterized multiscale-functional nanotopographies with three levels of functionalization: (1) nanostructure topography in the form of silicon nanowires, (2) covalent chemical modification with (3-aminopropyl)triethoxysilane, and (3) incorporation of chlorhexidine digluconate. Cell viability assays were carried out on two model microorganisms E. coli and S. aureus over these nanotopographic surfaces. Using SEM we have identified two growth modes producing distinctive multicellular structures, i.e. in plane growth for E. coli and out of plane growth for S. aureus. We have also shown that these chemically modified SiNWs arrays are effective in reducing the number of planktonic and surface-attached microorganisms.

Contribution of large scale biases in decoding of direction-of-motion from high-resolution fMRI data in human early visual cortex.

Previous studies have demonstrated that the perceived direction of motion of a visual stimulus can be decoded from the pattern of functional magnetic resonance imaging (fMRI) responses in occipital cortex using multivariate analysis methods (Kamitani and Tong, 2006). One possible mechanism for this is a difference in the sampling of direction selective cortical columns between voxels, implying that information at a level smaller than the voxel size might be accessible with fMRI. Alternatively, multivariate analysis methods might be driven by the organization of neurons into clusters or even orderly maps at a much larger scale. To assess the possible sources of the direction selectivity observed in fMRI data, we tested how classification accuracy varied across different visual areas and subsets of voxels for classification of motion-direction. To enable high spatial resolution functional MRI measurements (1.5mm isotropic voxels), data were collected at 7T. To test whether information about the direction of motion is represented at the scale of retinotopic maps, we looked at classification performance after combining data across different voxels within visual areas (V1-3 and MT+/V5) before training the multivariate classifier. A recent study has shown that orientation biases in V1 are both necessary and sufficient to explain classification of stimulus orientation (Freeman et al., 2011). Here, we combined voxels with similar visual field preference as determined in separate retinotopy measurements and observed that classification accuracy was preserved when averaging in this 'retinotopically restricted' way, compared to random averaging of voxels. This insensitivity to averaging of voxels (with similar visual angle preference) across substantial distances in cortical space suggests that there are large-scale biases at the level of retinotopic maps underlying our ability to classify direction of motion.

Lymphocyte contamination of laryngoscope blades--a possible vector for transmission of variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD) is associated with extensive prion infection of lymphoreticular tissues during the prolonged asymptomatic incubation period. Instruments exposed to infected tissues of preclinically infected individuals during medical or surgical procedures represent a potential risk of iatrogenic transmission of vCJD prions. We assessed the frequency of contamination with lymphoid tissue of single-use laryngoscope blades used for tracheal intubation for general anaesthesia. Using a cyto-centrifugation technique, lymphocytes were detected from 30% of laryngoscope blades studied. As prions resist routine sterilisation procedures, the use of non-disposable laryngoscope blades poses a risk of transmitting vCJD from patient to patient. The use of such instruments should be abandoned and disposable alternatives used.

Diagnosis of duck circovirus infections by conventional and real-time polymerase chain reaction tests.

Development of the first conventional and real-time polymerase chain reaction (PCR) tests for the diagnoses of duck circovirus (DuCV) infections is described. Both tests amplified a 230 bp fragment specific to the DuCV Rep gene. Although both tests had the same detection limit (13 x 10(3) target DNA/ml) when the target DNA was diluted in water, the detection limit of the real-time test (13 x 10(4) target DNA/ml) was 10-fold less than the conventional test (13 x 10(5) target DNA/ml) when the amplifications were performed in the presence of cellular DNA. Using the conventional PCR test, DuCV DNA was detected in 85 (84%) of 101 bursa of Fabricius samples from dead or sick ducks, aged between 1 and 12 weeks, and in samples from 35 (94%) of 37 flocks. Application of the SYBR Green-based real-time PCR test to 54 selected bursa of Fabricius samples indicated that more samples were positive by real-time PCR than by conventional PCR, allowed the numbers of genome copies to be estimated and showed that some bursa of Fabricius samples contained over 10(13) genome copies/g tissue. Although DuCV infections were detected in birds aged from 1 to 12 weeks, higher virus DNA levels were detected in ducks aged older than 5 weeks than in ducks younger than 5 weeks. An in situ hybridization method for the detection of DuCV in histological samples was also developed. Additional work is required to determine the clinicopathological significance of DuCV infections.

Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment.

OBJECTIVE: To compare PGP9.5 and transient receptor potential vanilloid receptor (TRPV1) suburothelial immunoreactivity between controls and patients with spinal neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, as suburothelial PGP9.5-staining nerve fibres decrease in patients with spinal NDO who respond to intravesical capsaicin, and TRPV1 is present on these suburothelial nerve fibres in normal and overactive human urinary bladder. PATIENTS AND METHODS: Patients with refractory NDO were enrolled in a prospective, randomized, parallel-group, double-blind, placebo-controlled trial using escalating doses of resiniferatoxin to a maximum of 1 micro mol/L. Flexible cystoscopic bladder biopsies obtained at baseline, 4 weeks after each instillation and at the time of maximum clinical response were compared with biopsies taken from control subjects. Frozen sections were incubated with rabbit antibodies to TRPV1 and PGP9.5, and assessed using standard immunohistochemical methods. PGP9.5 nerve density was analysed using a nerve-counting graticule by an observer unaware of sample origin. Another two independent observers unaware of each other's results used a random grading scale to evaluate TRPV1 nerve fibre density and intensity. The immunohistochemistry results were compared with histology findings (haematoxylin-eosin), and the Mann-Whitney test used to assess any differences (P < 0.05 significant) and the Pearson test for correlation. RESULTS: There were eight controls and 20 patients with spinal NDO, 14 (five clinical responders and nine not) who received the maximum dose of resiniferatoxin. There were more PGP9.5 and TRPV1 nerve fibres in patients with NDO than in controls (P = 0.007 and 0.002, respectively). Immunoreactivity before resiniferatoxin was similar in both groups for both PGP9.5 and TRPV1. In responders there were fewer PGP9.5 and TRPV1-positive fibres after treatment (P = 0.008 for each) but no change in those not responding. Changes after treatment for TRPV1 correlated well with those for PGP9.5 (r = 0.88, P < 0.001). CONCLUSIONS: The decrease of PGP9.5 and TRPV1 immunoreactive nerve fibres in responders to resiniferatoxin (to levels in control tissues) suggests that the increased numbers of nerve fibres in patients with NDO are mainly of sensory origin and express TRPV1. As baseline nerve fibre values were similar in responders and nonresponders, an additional factor may account for the difference in treatment outcome.

The ovijector of Ascaris suum: multiple response types revealed by Caenorhabditis elegans FMRFamide-related peptides.

Caenorhabditis elegans possesses 22 FMRFamide-like peptide (flp) genes predicted to encode 60 different FMRFamide-related peptides with a range of C-terminal signatures. Peptides from five flp genes (1, 6, 8, 9 and 14) are known to modulate the ovijector of Ascaris suum in vitro. This study examines the physiological effects of peptides from the remaining 17 flp genes such that the variety of FMRFamide-related peptide-induced ovijector response types can be delineated. Five categories of response were identified according to the pattern of changes in contractile behaviour and baseline tension. Peptides encoded on 16 flp genes (1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 20) had qualitatively similar inhibitory (response type 1) actions, with the lowest activity thresholds (1 nM) recorded for peptides with FIRFamide or FLRFamide C-terminal signatures. Peptides encoded on four flp genes (2, 18, 19 and 21), and on the A. suum afp-1 gene, had excitatory actions on the ovijector (response type 2), with PGVLRFamides having the lowest activity threshold (1 nM). An flp-2 peptide (LRGEPIRFamide) induced a transient contraction of the ovijector (activity threshold, 10nM) that was designated response type 3. Response type 4 comprised a transient contraction followed by an extended period of inactivity and was observed with peptides encoded on flp-5 (AGAKFIRFamide, APKPKFIRFamide), flp-8 (KNEFIRFamide) and flp-22 (SPSAKWMRFamide). SPSAKWMRFamide was the most potent peptide tested with an activity threshold of 0.1 nM. A single peptide (AMRNALVRFamide; activity threshold 0.1 microM), encoded on flp-11, induced response type 5, a shortening of the ovijector coupled with an increase in contraction frequency. Although most flp genes encode structurally related peptides that trigger one of the five ovijector response types, flp-2 and flp-11 co-encode FMRFamide-related peptides that induce distinct responses. Within the ovijector of A. suum FaRPs play a complex role involving at least five receptor subtypes or signalling pathways.

Brief communication: detecting depression: providing high quality primary care for HIV-infected patients.

Depression is common among HIV-infected patients, but little is known about risk factors for depression in this population. Several studies before protease inhibitors became available have reported inconsistent associations between depression and disease severity. Delivering high quality HIV care includes adequate detection and treatment of depression. The objective of this study was to describe the prevalence and correlates of depression among a contemporary group of HIV-infected patients. The setting and design for the study was a chart abstraction for HIV-infected patients in a primary care practice in Boston, Mass, in June 1997. Among 275 HIV-infected patients, depression was documented in 147 patient charts (53%), half of whom (n = 73, 27%) also received antidepressant medications. We used multivariable logistic regression to identify risk factors for depression among patients with both a chart diagnosis of depression and current antidepressant medication use. We observed increased risk of depression among patients with a history of substance use (odds ratio 2.7, 95% confidence interval 1.5-4.7), recent medical hospitalization (2.6, 1.4-5.0), and homosexual risk behavior (2.1, 1.1-4.2). Depression remains a common problem for HIV-infected patients, particularly among those with history of substance abuse, medical hospitalization, or homosexual risk behavior. Routine screening for depression in this population with special attention to those at higher risk may offer opportunities for earlier diagnosis and treatment.

Microdysgenesis with abnormal cortical myelinated fibres in temporal lobe epilepsy: a histopathological study with calbindin D-28-K immunohistochemistry.

Microdysgenesis is a microscopic cortical malformation reported to occur with varying incidence in surgical lobectomies from patients with temporal lobe epilepsy (TLE). It may act as a substrate for the seizures. Four patients are reported with TLE, hippocampal sclerosis and cortical microdysgenesis which was also characterized by the presence of abnormal myelinated fibres running tangentially in the superficial cortical laminae and closely associated with abnormal clusters of neurones. Similar abnormal cortical fibres have been described in other malformations of cortical development including polymicrogyria and focal cortical dysplasia and it is therefore likely that these fibres represent part of the microdysgenetic malformation not hitherto reported. The possibility is discussed that they may also be of functional significance in terms of influencing local seizure propagation and the secondary cortical neuronal loss observed, predominantly affecting layer II. Studies of calbindin interneuronal populations showed preservation of these cells in the microdysgenetic cortex, when compared with non-malformed temporal lobes, despite an overall reduction in cortical neuronal density. In addition, prominent numbers of neurogliaform calbindin-positive nerve cells were observed in the microdysgenesis cases and the nature of these cells is speculated upon.

Use of certificates of confidentiality in nursing research.

PURPOSE: To discuss the use of Certificates of Confidentiality in nursing research. ORGANIZING CONSTRUCT: In situations that are particularly complex, sensitive, and in which the participants are extremely vulnerable, a Certificate of Confidentiality issued by the U.S. Department of Health and Human Services (DHHS) may be useful to help ensure the privacy of research participants. SOURCES: Theoretical and research literature, DHHS documents, and research experience. FINDINGS AND CONCLUSIONS: Not all research with vulnerable populations requires the additional protection provided by Certificates of Confidentiality. However, certificates may be indicated in studies in which participants and researchers may be exposed to compelled legal disclosure of research data.

The effect of intravesical capsaicin on the suburothelial innervation in patients with detrusor hyper-reflexia.

OBJECTIVE: To determine the effect of intravesical capsaicin on the suburothelial innervation in patients with detrusor hyper-reflexia, in whom a single dose of intravesical capsaicin (1-2 mmol/L) increases the bladder capacity for 3-6 months. PATIENTS AND METHODS: Thirteen patients with detrusor hyper-reflexia underwent cystometry and had flexible cystoscopic biopsies taken before and 6 weeks after receiving instillations of intravesical capsaicin (1 mmol/L). Similar biopsies were also obtained from a control group of 12 neurologically normal patients with microscopic haematuria and normal bladders. Frozen sections were stained using antibodies to S100 and PGP 9.5. Using computerized analysis, the mean nerve density scores were expressed as nerves/mm2 for S100-positive structures and 'red%' and 'red in frame' for PGP 9.5. RESULTS: The mean (SEM) functional bladder capacity increased from 193.2 (28.17) mL before to 396.3 (41.96) mL at 6 weeks after treatment with capsaicin, in nine of the 13 patients. The mean nerve density of S100-positive structures in the control group was 83 (3.18) nerves/mm2. In hyper-reflexic patients who responded to capsaicin by improved bladder capacity, the mean nerve density of S100-positive structures was reduced from 100 (12.2) before to 66 (9.4) nerves/mm2 6 weeks after treatment. In those who did not respond to capsaicin there was no significant difference in these scores. Similarly the 'red%' and 'red in frame' reduced from 3.41 (1.06) to 1.15 (0.32) and 824.7 (246.3) to 297.9 (83.5) units, respectively, before and 6 weeks after capsaicin treatment. The difference in those not responding was not significant. CONCLUSIONS: Intravesical capsaicin causes a reduction in suburothelial nerve densities in the bladder of patients with detrusor hyper-reflexia. This may explain its prolonged beneficial effect in these patients.

Detection and localisation of HIV-1 DNA and RNA in fixed adult AIDS brain by polymerase chain reaction/in situ hybridisation technique.

In the brain of patients with AIDS, HIV-1 is localised in a productive form in mononuclear cells. One issue that still needs clarification is whether HIV is localised in cells other than those of mononuclear lineage. Gene amplification by polymerase chain reaction/in situ hybridisation (PCR-IS) could shed light on it. In this study, formalin-fixed, paraffin-embedded brain tissue from ten adult AIDS sufferers was used. Five of them showed evidence of HIV encephalitis (HIVE), five did not show any abnormality. Nested PCR revealed HIV-1 DNA in all HIVE cases and in three of the group without HIVE. HIV-1 DNA and RNA were also detected in situ in seven cases (all seven were also HIV-1 DNA positive in tube). A higher signal was located in the white than in the grey matter. HIV-1 DNA was found in microglia, macrophages, perivascular cells, multinucleated gaint cells (MGC) and in CD68-negative cells. Some of them were identified as endothelial cells, astrocytes and oligodendrocytes. Reverse transcriptase-PCR-IS was positive in macrophages, MGC, endothelial and glial cells. These results confirm infection of endothelial cells and other glial cells and give clues about the route of entry of virus into the central nervous system and the pathogenesis of the disease. This study did not give any convincing evidence supporting an infection of neurons by HIV-1.