Advancing the chemotherapy of tuberculous meningitis: a consensus view.

Tuberculous meningitis causes death or disability in approximately 50% of affected individuals and kills approximately 78 200 adults every year. Antimicrobial treatment is based on regimens used for pulmonary tuberculosis, which overlooks important differences between lung and brain drug distributions. Tuberculous meningitis has a profound inflammatory component, yet only adjunctive corticosteroids have shown clear benefit. There is an active pipeline of new antitubercular drugs, and the advent of biological agents targeted at specific inflammatory pathways promises a new era of improved tuberculous meningitis treatment and outcomes. Yet, to date, tuberculous meningitis trials have been small, underpowered, heterogeneous, poorly generalisable, and have had little effect on policy and practice. Progress is slow, and a new approach is required. In this Personal View, a global consortium of tuberculous meningitis researchers articulate a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes for this life-threatening infection.

Recent advances in understanding the human host immune response in tuberculous meningitis.

Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.

The first three reported cases of Sporothrix brasiliensis cat-transmitted sporotrichosis outside South America.

An epidemic of cat-transmitted sporotrichosis caused by Sporothrix brasiliensis has emerged as a major public health threat in Brazil in recent decades. We report the first three cases of cat-transmitted sporotrichosis caused by Sporothrix brasiliensis outside South America, and the first ever cases of cat-transmitted sporotrichosis in the United Kingdom. We outline the public health implications and outbreak response and encourage clinicians and veterinarians worldwide to be vigilant for sporotrichosis in cats and cat owners.

The clinical presentation of monkeypox: a retrospective case-control study of patients with possible or probable monkeypox in a West London cohort.

OBJECTIVES: Since May 2022, cases of human monkeypox virus (hMPXV) with human-to-human cross-transmission have significantly increased in nonendemic countries. Our aim was to characterize diagnostic features of patients with confirmed and possible monkeypox to guide future risk stratification and to describe a virtual care model. METHODS: We performed a retrospective case-control study of 140 patients assessed and screened for suspected monkeypox; on hMPXV polymerase chain reaction testing, 70 were confirmed positive, and 70 were negative. Data were compared to generate odds ratios of demographic and clinical features. RESULTS: Patients who tested positive were predominantly cis-male (99%) and self-identified as gay, bisexual, and other men who have sex with men (94%). Lymphadenopathy at presentation was associated with a higher likelihood of a positive result (odds ratio [OR] 7.69 [95% confidence interval (CI) 3.58, 16.51]). Patients who tested positive were more likely to have a rash affecting the genital (OR 5.38 [95% CI 2.57, 11.23]) or buttocks/perianal region (OR 3.79 [1.70, 8.45]) than negative controls. A total of 79% of patients were engaged with a virtual ward follow-up. CONCLUSION: These data can inform a risk-based approach to the management of suspected monkeypox in gay, bisexual, and other men who have sex with men populations. Lymphadenopathy at presentation and the location of the rash were more associated with a positive hMPXV result. Health authorities can consider a virtual ward approach in the hMPHXV outbreak.

Needle in a haystack: a case report of splenic foreign body-associated sepsis.

Instances of foreign bodies impacted in solid organs are rare, and rarer still are reports of objects in the spleen. A 42-year-old presented septic with abdominal pain, high inflammatory markers and haemodynamic instability. She was found to have a splenic haematoma and a 4-cm hyperdense foreign body within the spleen. Ultrasound-guided drainage of the haematoma isolated Streptococcus anginosus and conservative management with intravenous antibiotics avoided the need for emergency splenectomy. The bacterium isolated was the same cultured 9 months previously from the patient's empyema fluid. The origin of the foreign body was not identified, though is made of metal and pre-dates any hospital admissions. The case raised the question of how an object might penetrate the spleen without knowledge of the patient and highlighted the risks of foreign body-associated sepsis, the risks and benefits of emergency splenectomy and management of complex cases with paucity of evidence.

Investigating competencies needed by European-trained doctors in rural South African hospitals.

BACKGROUND: Many European-trained doctors (ETDs) recruited to work in rural district hospitals in South Africa have insufficient generalist competencies for the range of practice required. Africa Health Placements recruits ETDs to work in rural hospitals in Africa. Many of these doctors feel inadequately prepared. The Stellenbosch University Ukwanda Centre for Rural Health is launching a Postgraduate Diploma in Rural Medicine to help prepare doctors for such work. AIM: To determine the competencies gap for ETDs working in rural district hospitals in South Africa to inform the curriculum of the PG Dip (Rural Medicine). SETTING: Rural district hospitals in South Africa. METHODS: Nine hospitals in the Eastern Cape, KwaZulu-Natal and Mpumalanga were purposefully selected by Africa Health Placements as receiving ETDs. An online survey was developed asking about the most important competencies and weaknesses for ETDs when working rurally. The clinical manager and any ETDs currently working in each hospital were invited to complete the survey. RESULTS: Surveys were completed by 19 ETDs and five clinical managers. The top clinical competencies in relation to 10 specific domains were identified. The results also indicate broader competencies required, specific skills gaps, the strengths that ETDs bring to South Africa and how ETDs prepare themselves for working in this context. CONCLUSION: This study identifies the important competency gaps among ETDs and provides useful direction for the diploma and other future training initiatives. The diploma faculty must reflect on these findings and ensure the curriculum is aligned with these gaps.

Leptospirosis as an important differential of pulmonary haemorrhage on the intensive care unit: a case managed with VV-ECMO.

BACKGROUND: Leptospirosis is a potentially fatal zoonosis. It can cause a wide range of symptoms, including diffuse alveolar haemorrhage which occurs in a minority of cases but carries a mortality of over 70%. These patients may present with severe acute respiratory failure. The differential diagnosis for diffuse alveolar haemorrhage is broad whereas prompt diagnosis and treatment can be lifesaving. CASE PRESENTATION: A 20-year-old previously fit and well trout farm worker presented with a 3-day history of malaise, fevers, diarrhoea, vomiting and jaundice. He developed haemoptysis, severe headaches, neck stiffness and photophobia on the day of emergency admission. He was anaemic and thrombocytopenic. Anuric acute kidney injury (urea 32, creat 507) required immediate haemofiltration. In view of progressive respiratory failure with four-quadrant lung infiltrates on imaging, he was given broad spectrum antibiotics and pulsed methylprednisolone empirically, in case of a vasculitic pulmonary-renal presentation. He was intubated within 48 h of admission. Despite attempted protective ventilatory management, he remained hypoxaemic and developed pneumomediastinum. He was retrieved to a specialist cardiorespiratory intensive care unit on femoro-femoral mobile VV-ECMO. Three days from admission, results showed positive Leptospira IgM and real-time PCR. Serial bronchoscopies showed old and fresh clots, but not the classical progressive late red tinge of the returned lavage fluid. After eight days, VV-ECMO was weaned, he was extubated three days later, and made a full recovery. At 9 months follow-up, he was clinically better, with resolution of the CT scan findings and near normal lung function, albeit with low normal gas transfer. CONCLUSIONS: Leptospirosis is a rare but important differential to be considered in diffuse alveolar haemorrhage presenting to the ICU, especially in young males. A thorough history for occupational or recreational risk factors may offer the diagnostic clue. Most patients recover fully with antibiotics. However, resulting acute severe respiratory failure can ensue. In this situation, early consideration for respiratory ECMO support offers time for clearance of endobronchial clot, parenchymal recovery, and prevention of ventilator-induced lung injury. Steroids have no clear evidence but may be used to avoid delay in treating suspected vasculitic or autoimmune causes of diffuse alveolar haemorrhage.

Cytomegalovirus Retinitis Screening and Treatment in Human Immunodeficiency Virus Patients in Malawi: A Feasibility Study.

BACKGROUND: Cytomegalovirus retinitis is a treatable cause of blindness in people with human immunodeficiency virus (HIV) typically with CD4 counts <50 cells/mm3. Diagnosis is with indirect fundoscopy, and treatment is with intravitreal ganciclovir injections or systemic therapy. However, diagnosis and treatment are not widely available in Malawi, which has an adult HIV prevalence estimated at 10.6%. This study aimed to establish the prevalence of cytomegalovirus retinitis among people with HIV in Malawi and the feasibility of screening. METHODS: Patients with CD4 counts <200 cells/mm3 were examined from 2 HIV clinics in Lilongwe and the main government hospital. Data were collected on antiretroviral therapy, ocular symptoms, and visual acuity. Fundoscopy was performed to investigate for features of cytomegalovirus retinitis. Retinal photographs were reviewed by an ophthalmologist. Patients diagnosed with cytomegalovirus retinitis were offered weekly ganciclovir injections, because systemic treatment was not available. RESULTS: Five of the 102 people with HIV screened had cytomegalovirus retinitis (4.9%). All affected patients had CD4 counts <50 cells/mm3 (mean, 15 cells/mm3; range, 3-22 cells/mm3). Visual acuity was unhelpful in identifying those with cytomegalovirus retinitis. Symptomatically, only blurred vision was useful. Two patients consented to treatment, 1 of which improved but relapsed after defaulting. CONCLUSIONS: Cytomegalovirus retinitis screening based on CD4 count is essential to early recognition because visual acuity and symptoms are unreliable. Cytomegalovirus retinitis is a significant yet neglected public health issue in Malawi. Oral valganciclovir is essential to reduce blindness and mortality in those diagnosed but is not yet available. Further screening and advocacy are needed.

Excess cost and inpatient stay of treating deep spinal surgical site infections.

AIM: To determine the excess cost and hospitalisation associated with surgical site infections (SSI) following spinal operations in a New Zealand setting. METHODS: We identified inpatients treated for deep SSI following primary or revision spinal surgery at a regional tertiary spinal centre between 2009 and 2016. Excess cost and excess length of stay (LOS) were calculated via a clinical costing system using procedure-matched controls. RESULTS: Twenty-eight patients were identified. Twenty-five had metalware following spinal fusion surgery, while three had non-instrumented decompression and/or discectomy. Five were diagnosed during their index hospitalisation and 23 (82%) were re-admitted. The average excess SSI cost was NZ$51,434 (range $1,398-$262,206.16) and LOS 37.1 days (range 7-275 days). Infections following metalware procedures had a greater excess cost (average $56,258.90 vs. $11,228.61) and LOS (average 40.4 days vs. 9.7 days) than procedures without metalware. CONCLUSION: The costs associated with spinal SSI are significant and comparable to a previous New Zealand study of hip and knee prosthesis SSI. More awareness of the high costs involved should encourage research and implementation of infection prevention strategies.

Small molecule inhibition of p38 MAP kinase extends the replicative life span of human ATR-Seckel syndrome fibroblasts.

Ataxia-telangiectasia and rad3 (ATR)-related Seckel syndrome is associated with growth retardation and premature aging features. ATR-Seckel fibroblasts have a reduced replicative capacity in vitro and an aged morphology that is associated with activation of stress-associated p38 mitogen-activated protein kinase and phosphorylated HSP27. These phenotypes are prevented using p38 inhibitors, with replicative capacity restored to the normal range. However, this stressed phenotype is retained in telomerase-immortalized ATR-Seckel fibroblasts, indicating that it is independent of telomere erosion. As with normal fibroblasts, senescence in ATR-Seckel is bypassed by p53 abrogation. Young ATR-Seckel fibroblasts show elevated levels of p21(WAF1), p16(INK4A), phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16(INK4A) and caveolin-1 phosphorylation. In conclusion, ATR-Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p38 activation that may underlie certain clinical features of Seckel syndrome, and our data suggest a novel target for pharmacological intervention in this human syndrome.