Adoptive cell therapy for high grade gliomas using simultaneous temozolomide and intracranial mgmt-modified γδ t cells following standard post-resection chemotherapy and radiotherapy: current strategy and future directions.

Cellular therapies, including chimeric antigen receptor T cell therapies (CAR-T), while generally successful in hematologic malignancies, face substantial challenges against solid tumors such as glioblastoma (GBM) due to rapid growth, antigen heterogeneity, and inadequate depth of response to cytoreductive and immune therapies, We have previously shown that GBM constitutively express stress associated NKG2D ligands (NKG2DL) recognized by gamma delta (γδ) T cells, a minor lymphocyte subset that innately recognize target molecules via the γδ T cell receptor (TCR), NKG2D, and multiple other mechanisms. Given that NKG2DL expression is often insufficient on GBM cells to elicit a meaningful response to γδ T cell immunotherapy, we then demonstrated that NKG2DL expression can be transiently upregulated by activation of the DNA damage response (DDR) pathway using alkylating agents such as Temozolomide (TMZ). TMZ, however, is also toxic to γδ T cells. Using a p140K/MGMT lentivector, which confers resistance to TMZ by expression of O(6)-methylguanine-DNA-methyltransferase (MGMT), we genetically engineered γδ T cells that maintain full effector function in the presence of therapeutic doses of TMZ. We then validated a therapeutic system that we termed Drug Resistance Immunotherapy (DRI) that combines a standard regimen of TMZ concomitantly with simultaneous intracranial infusion of TMZ-resistant γδ T cells in a first-in-human Phase I clinical trial (NCT04165941). This manuscript will discuss DRI as a rational therapeutic approach to newly diagnosed GBM and the importance of repeated administration of DRI in combination with the standard-of-care Stupp regimen in patients with stable minimal residual disease.

Improved patient safety with a simplified operating room to pediatric intensive care unit handover tool (PATHQS).

Introduction: Patient handover is a crucial transition requiring a high level of coordination and communication. In the BC Children's Hospital (BCCH) pediatric intensive care unit (PICU), 10 adverse events stemming from issues that should have been addressed at the operating room (OR) to PICU handover were reported into the patient safety learning system (PSLS) within 1 year. We aimed to undertake a quality improvement project to increase adherence to a standardized OR to PICU handover process to 100% within a 6-month time frame. In doing so, the secondary aim was to reduce adverse events by 50% within the same 6-month period. Methods: The model for improvement and a Plan, Do, Study, Act method of quality improvement was used in this project. The adverse events were reviewed to identify root causes. The findings were reviewed by a multidisciplinary inter-departmental group comprised of members from surgery, anesthesia, and intensive care. Issues were batched into themes to address the most problematic parts of handover that were contributing to risk. Intervention: A bedside education campaign was initiated to familiarize the team with an existing handover standard. The project team then formulated a new simplified visual handover tool with the mnemonic "PATHQS" where each letter denoted a step addressing a theme that had been noted in the pre-intervention work as contributing to adverse events. Results: Adherence to standardized handover at 6 months improved from 69% to 92%. This improvement was sustained at 12 months and 3 years after the introduction of PATHQS. In addition, there were zero PSLS events relating to handover at 6 and 12 months, with only one filed by 36 months. Notably, staff self-reporting of safety concerns during handover reduced from 69% to 13% at 6 months and 0% at 3 years. The PATHQS tool created in this work also spread to six other units within the hospital as well as to one adult teaching hospital. Conclusion: A simplified handover tool built collaboratively between departments can improve the quality and adherence of OR to PICU handover and improve patient safety. Simplification makes it adaptable and applicable in many different healthcare settings.

Validation of dried blood spot sampling for detecting SARS-CoV-2 antibodies and total immunoglobulins in a large cohort of asymptomatic young adults.

BACKGROUND: Detecting antibody responses following infection with SARS-CoV-2 is necessary for sero-epidemiological studies and assessing the role of specific antibodies in disease, but serum or plasma sampling is not always viable due to logistical challenges. Dried blood spot sampling (DBS) is a cheaper, simpler alternative and samples can be self-collected and returned by post, reducing risk for SARS-CoV-2 exposure from direct patient contact. The value of large-scale DBS sampling for the assessment of serological responses to SARS-CoV-2 has not been assessed in depth and provides a model for examining the logistics of using this approach to other infectious diseases. The ability to measure specific antigens is attractive for remote outbreak situations where testing may be limited or for patients who require sampling after remote consultation. METHODS: We compared the performance of SARS-CoV-2 anti-spike and anti-nucleocapsid antibody detection from DBS samples with matched serum collected by venepuncture in a large population of asymptomatic young adults (N = 1070) living and working in congregate settings (military recruits, N = 625); university students, N = 445). We also compared the effect of self-sampling (ssDBS) with investigator-collected samples (labDBS) on assay performance, and the quantitative measurement of total IgA, IgG and IgM between DBS eluates and serum. RESULTS: Baseline seropositivity for anti-spike IgGAM antibody was significantly higher among university students than military recruits. Strong correlations were observed between matched DBS and serum samples in both university students and recruits for the anti-spike IgGAM assay. Minimal differences were found in results by ssDBS and labDBS and serum by Bland Altman and Cohen kappa analyses. LabDBS achieved 82.0% sensitivity and 98.2% specificity and ssDBS samples 86.1% sensitivity and 96.7% specificity for detecting anti-spike IgGAM antibodies relative to serum samples. For anti-SARS-CoV-2 nucleocapsid IgG there was qualitatively 100% agreement between serum and DBS samples and weak correlation in ratio measurements. Strong correlations were observed between serum and DBS-derived total IgG, IgA, and IgM. CONCLUSIONS: This is the largest validation of DBS against paired serum for SARS-CoV-2 specific antibody measurement and we have shown that DBS retains performance from prior smaller studies. There were no significant differences regarding DBS collection methods, suggesting that self-collected samples are a viable sampling collection method. These data offer confidence that DBS can be employed more widely as an alternative to classical serology.

The 2022 monkeypox outbreak: A UK military perspective.

With the emergence of SARS-CoV-2 and now monkeypox, the UK Defence Medical Services have been required to provide rapid advice in the management of patients with airborne high consequence infectious diseases (A-HCID). The Defence Public Health Network (DPHN) cadre, consisting of closely aligned uniformed and civilian public health specialists have worked at pace to provide evidence-based recommendations on the clinical management, public health response and policy for monkeypox, with military medicine and pathology clinicians (primarily infectious disease physicians and medical microbiologists). Military environments can be complicated and nuanced requiring specialist input and advice to non-specialists as well as unit commanders both in the UK and overseas. DPHN and military infection clinicians have close links with the UK National Health Service (NHS) and the UK Health Security Agency (UKHSA), allowing for a dynamic two-way relationship that encompasses patient management, public health response, research and development of both UK military and national guidelines. This is further demonstrated with the Royal Air Force (RAF) Air Transport Isolator (ATI) capability, provided by Defence to support the UK Government and UKHSA. Military infectious disease clinicians are also embedded within NHS A-HCID units. In this manuscript we provide examples of the close interdisciplinary working of the DPHN and Defence clinicians in managing military monkeypox patients, co-ordinating the public health response, advising the Command and developing monkeypox policy for Defence through cross-government partnership. We also highlight the co-operation between civilian and military medical authorities in managing the current outbreak.

Does vitamin D supplementation prevent SARS-CoV-2 infection in military personnel? Review of the evidence.

For most individuals residing in Northwestern Europe, maintaining replete vitamin D status throughout the year is unlikely without vitamin D supplementation and deficiency remains common. Military studies have investigated the association with vitamin D status, and subsequent supplementation, with the risk of stress fractures particularly during recruit training. The expression of nuclear vitamin D receptors and vitamin D metabolic enzymes in immune cells additionally provides a rationale for the potential role of vitamin D in maintaining immune homeostasis. One particular area of interest has been in the prevention of acute respiratory tract infections (ARTIs). The aims of this review were to consider the evidence of vitamin D supplementation in military populations in the prevention of ARTIs, including SARS-CoV-2 infection and consequent COVID-19 illness. The occupational/organisational importance of reducing transmission of SARS-CoV-2, especially where infected young adults may be asymptomatic, presymptomatic or paucisymptomatic, is also discussed.

Case of eosinophilic fasciitis during military training in a Nepalese British infantry soldier.

We present the case of a Nepalese British soldier with peripheral oedema and a significantly raised eosinophil count. After extensive investigation looking for a parasitic cause of his illness, he was diagnosed with eosinophilic fasciitis, a connective tissue disorder, often triggered by heavy exertion and responsiveness to immunosuppression. In a military setting, in which clinicians are likely to encounter patients who have spent time in tropical areas, it is important to still consider non-infectious causes of eosinophilia.

Staphylococcus aureus colonization and acquisition of skin and soft tissue infection among Royal Marines recruits: a prospective cohort study.

OBJECTIVES: Skin and soft tissue infections (SSTIs) are a serious health issue for military personnel. Of particular importance are those caused by methicillin-resistant Staphylococcus aureus and Panton-Valentine leucocidin (PVL)-positive S. aureus (PVL-SA), as they have been associated with outbreaks of SSTIs. A prospective observational study was conducted in Royal Marine (RM) recruits to investigate the prevalence of PVL-SA carriage and any association with SSTIs. METHODS: A total of 1012 RM recruits were followed through a 32-week training programme, with nose and throat swabs obtained at weeks 1, 6, 15 and 32. S. aureus isolates were characterized by antibiotic susceptibility testing, spa typing, presence of mecA/C and PVL genes. Retrospective review of the clinical notes for SSTI acquisition was conducted. RESULTS: S. aureus colonization decreased from Week 1 to Week 32 (41% to 26%, p < 0.0001). Of 1168 S. aureus isolates, three out of 1168 (0.3%) were MRSA and ten out of 1168 (0.9%) PVL-positive (all MSSA) and 169 out of 1168 (14.5%) were resistant to clindamycin. Isolates showed genetic diversity with 238 different spa types associated with 25 multi-locus sequence type (MLST) clonal complexes. SSTIs were seen in 35% (351/989) of recruits with 3 training days lost per recruit. SSTI acquisition rate was reduced amongst persistent carriers (p < 0.0283). CONCLUSIONS: Nose and throat carriage of MRSA and PVL-SA was low among recruits, despite a high incidence of SSTIs being reported, particularly cellulitis. Carriage strains were predominantly MSSA with a marked diversity of genotypes. Persistent nose and/or throat carriage was not associated with SSTI acquisition. Putative person-to-person transmission within troops was identified based on spa typing requiring further research to confirm and explore potential transmission routes.

Hepatitis B in a vaccinated soldier: a case report.

Assessing for an adequate immunological response to a pre-exposure course of hepatitis B vaccine is not routinely recommended in all vaccinated individuals. Current UK guidelines advise checking hepatitis B surface antibody titres only in those considered at high occupational risk such as healthcare and laboratory workers. We present a case of an infantry soldier who developed acute hepatitis B despite having a complete course of hepatitis B vaccinations. This case emphasises that hepatitis B is still an important differential diagnosis for all returning military personnel who present with compatible symptoms despite being vaccinated.

Impact of contusion injury on intramuscular emm1 group a streptococcus infection and lymphatic spread.

Invasive group A Streptococcus (iGAS) is frequently associated with emm1 isolates, with an attendant mortality of around 20%. Cases occasionally arise in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion, and no obvious portal of entry. Using a new murine model of contusion, we determined the impact of contusion on iGAS bacterial burden and phenotype. Calibrated mild blunt contusion did not provide a focus for initiation or seeding of GAS that was detectable following systemic GAS bacteremia, but instead enhanced GAS migration to the local draining lymph node following GAS inoculation at the same time and site of contusion. Increased migration to lymph node was associated with emergence of mucoid bacteria, although was not specific to mucoid bacteria. In one study, mucoid colonies demonstrated a significant increase in capsular hyaluronan that was not linked to a covRS or rocA mutation, but to a deletion in the promoter of the capsule synthesis locus, hasABC, resulting in a strain with increased fitness for lymph node migration. In summary, in the mild contusion model used, we could not detect seeding of muscle by GAS. Contusion promoted bacterial transit to the local lymph node. The consequences of contusion-associated bacterial lymphatic migration may vary depending on the pathogen and virulence traits selected.

Modelling invasive group A streptococcal disease using bioluminescence.

BACKGROUND: The development of vaccines and evaluation of novel treatment strategies for invasive group A streptococcal (iGAS) disease requires suitable models of human infection that can be monitored longitudinally and are preferably non-invasive. Bio-photonic imaging provides an opportunity to reduce use of animals in infection modelling and refine the information that can be obtained, however the range of bioluminescent GAS strains available is limited. In this study we set out to develop bioluminescent iGAS strains for use in in vivo pneumonia and soft tissue disease models. RESULTS: Using clinical emm1, emm3, and emm89 GAS strains that were transformed with constructs carrying the luxABCDE operon, growth and bioluminescence of transformed strains were characterised in vitro and in vivo. Emm3 and emm89 strains expressed detectable bioluminescence when transformed with a replicating plasmid and light production correlated with viable bacterial counts in vitro, however plasmid instability precluded use in the absence of antimicrobial pressure. Emm89 GAS transformed with an integrating construct demonstrated stable bioluminescence that was maintained in the absence of antibiotics. Bioluminescence of the emm89 strain correlated with viable bacterial counts both in vitro and immediately following infection in vivo. Although bioluminescence conferred a detectable fitness burden to the emm89 strain during soft tissue infection in vivo, it did not prevent dissemination to distant tissues. CONCLUSION: Development of stably bioluminescent GAS for use in vitro and in vivo models of infection should facilitate development of novel therapeutics and vaccines while also increasing our understanding of infection progression and transmission routes.

Snakebites in Africa and Europe: a military perspective and update for contemporary operations.

Snakebite envenoming is rare among military patients, with few cases reported in recent years. Increasingly, however, military operations are taking place in remote parts of Africa, which are inhabited by numerous species of venomous snake, and in Europe, where dangerous species exist but are less common. Bites from a venomous snake may prove fatal, and therefore military medics must be adequately prepared to manage them. This paper reviews the most medically significant species of venomous snake present in Africa and Europe, before suggesting an evidence-based approach to snakebite prevention and management, including possible changes to the UK's Clinical Guidelines for Operations.

Is a stepdown unit safe for patients with mild traumatic intracranial hemorrhages?

PURPOSE: Traumatic brain injuries (TBIs) are a major source of disability in the United States. The ideal unit in the hospital for patients with mild traumatic intracranial hemorrhages (ICHs) has not been elucidated. We sought to investigate whether patients treated in the surgical stepdown area had worse outcomes than those treated in the surgical ICU. METHODS: We compared patients with ICHs and a Glasgow Coma Scale (GCS) upon admission of 14 or 15 who went to the ICU to those who went to the stepdown area from April 2014 to November 2016. We compared age, gender, Injury Severity Score (ISS), admission GCS (14 or 15), operative intervention, discharge destination, hospital length of stay (HLOS), mortality, and cost between these two groups. RESULTS: Patients admitted to the ICU had a significantly longer HLOS. Admission costs for patients admitted to ICU were also significantly higher than their stepdown area counterparts. This was true for both total charges (p = 0.0001) and for net revenue (p = 0.002) (Table 2). There was no statistically significant difference in mortality, operative intervention, or discharge destination. CONCLUSION: A surgical stepdown unit can be a safe disposition for patients with mild traumatic ICHs and represents an effective use of hospital resources.

Enhanced case management can be delivered for patients with EVD in Africa: Experience from a UK military Ebola treatment centre in Sierra Leone.

BACKGROUND: Limited data exist describing supportive care management, laboratory abnormalities and outcomes in patients with Ebola virus disease (EVD) in West Africa. We report data which constitute the first description of the provision of enhanced EVD case management protocols in a West African setting. METHODS: Demographic, clinical and laboratory data were collected by retrospective review of clinical and laboratory records of patients with confirmed EVD admitted between 5 November 2014 and 30 June 2015. RESULTS: A total of 44 EVD patients were admitted (median age 37 years (range 17-63), 32/44 healthcare workers), and excluding those evacuated, the case fatality rate was 49% (95% CI 33%-65%). No pregnant women were admitted. At admission 9/44 had stage 1 disease (fever and constitutional symptoms only), 12/44 had stage 2 disease (presence of diarrhoea and/or vomiting) and 23/44 had stage 3 disease (presence of diarrhoea and/or vomiting with organ failure), with case fatality rates of 11% (95% CI 1%-58%), 27% (95% CI 6%-61%), and 70% (95% CI 47%-87%) respectively (p = 0.009). Haemorrhage occurred in 17/41 (41%) patients. The majority (21/40) of patients had hypokalaemia with hyperkalaemia occurring in 12/40 patients. Acute kidney injury (AKI) occurred in 20/40 patients, with 14/20 (70%, 95% CI 46%-88%) dying, compared to 5/20 (25%, 95% CI 9%-49%) dying who did not have AKI (p = 0.01). Ebola virus (EBOV) PCR cycle threshold value at baseline was mean 20.3 (SD 4.3) in fatal cases and 24.8 (SD 5.5) in survivors (p = 0.007). Mean national early warning score (NEWS) at admission was 5.5 (SD 4.4) in fatal cases and 3.0 (SD 1.9) in survivors (p = 0.02). Central venous catheters were placed in 37/41 patients and intravenous fluid administered to 40/41 patients (median duration of 5 days). Faecal management systems were inserted in 21/41 patients, urinary catheters placed in 27/41 and blood component therapy administered to 20/41 patients. CONCLUSIONS: EVD is commonly associated life-threatening electrolyte imbalance and organ dysfunction. We believe that the enhanced levels of protocolized care, scale and range of medical interventions we report, offer a blueprint for the future management of EVD in resource-limited settings.

Asymptomatic group A Streptococcal throat carriage in Royal Marines recruits and Young Officers.

AIMS: A prospective observational study was conducted in Royal Marines (RM) recruits to investigate throat carriage of group A Streptococcus (GAS) and incidence of soft tissue infections. METHODS: 1012 RM recruits were followed through a 32-week training programme, with throat swabs being obtained in weeks 1, 6, 15, and 32. Alongside a separate cohort of 46 RM Young Officers (YO) undergoing training were sampled in parallel. RESULTS: Carriage of group A Streptococcus was detected in only 5/1012 (0.49%) recruits at the beginning of training and remained low throughout training. There was no association between GAS carriage and development of soft tissue infection. There was no carriage of GAS in the smaller YO cohort at the start of training, (0/46). At week 6, a surge in GAS carriage was detected in 8/46 (17%) YO, that could be ascribed to a cluster of GAS genotype emm83. CONCLUSIONS: Asymptomatic GAS carriage is very infrequent among young adults in England and this should be borne in mind when considering the relevance of a positive throat swab result in symptomatic patients or outbreaks. Despite low prevalence, there is however potential for GAS to rapidly and transiently disseminate among adults during outbreaks.

Ex vivo T-cell depletion in allogeneic hematopoietic stem cell transplant: past, present and future.

The most common cause of post-transplant mortality in patients with hematological malignancy is relapse, followed by GvHD, infections, organ toxicity and second malignancy. Immune-mediated complications such as GvHD continue to be challenging, yet amenable to control through manipulation of the T-cell compartment of the donor graft with subsequent immunomodulation after transplant. However, risk of both relapse and infection increase concomitantly with T-cell depletion (TCD) strategies that impair immune recovery. In this review, we discuss the clinical outcome of current and emerging strategies of TCD in allogeneic hematopoietic stem cell transplant that have developed during the modern transplantation era, focusing specifically on ex vivo strategies that target selected T-cell subsets.

Safety and feasibility of a strategy of early central venous catheter insertion in a deployed UK military Ebola virus disease treatment unit.

PURPOSE: Early central venous catheter (CVC) insertion in Ebola virus disease (EVD) is a novel approach and has not previously been described. This report delineates the safety, feasibility and clinical implications of early CVC insertion as the optimum means of vascular access in patients with EVD, in the setting of a deployed military Ebola virus disease treatment unit in Sierra Leone. METHODS: In the gastrointestinal phase of EVD, a 7-French 20-cm triple-lumen CVC was inserted using aseptic technique. Data were collected prospectively on all cases to include baseline and subsequent blood test variables, insertion site and technique, and complications associated with CVC placement. RESULTS: Twenty-three patients underwent CVC insertion as follows: subclavian, 21 (88 %); internal jugular, 2 (8 %); axillary, 1 (4 %). The mean duration of CVC placement was 5 days. There were no significant procedure-related adverse events. Despite coagulopathy being present in 75 % of cases, CVC insertion was safe, and there was only 1 case of significant catheter site bleeding. A total of 152 needle venepunctures were avoided owing to the presence of a CVC, a mean of 7 (±3.8) per case over the average stay. CONCLUSION: The early use of CVCs in Ebola virus disease is safe, effective and facilitates patient care. It should be considered a feasible additional route of venous access, where physician expertise and resources allow.