Effect of the relationship between anaemia and systemic inflammation on the risk of incident tuberculosis and death in people with advanced HIV: a sub-analysis of the REMEMBER trial.

Background: Tuberculosis (TB) is an infectious morbidity that commonly occurs in people living with HIV (PWH) and increases the progression of HIV disease, as well as the risk of death. Simple markers of progression are much needed to identify those at highest risk for poor outcome. This study aimed to assess how baseline severity of anaemia and associated inflammatory profiles impact death and the incidence of TB in a cohort of PWH who received TB preventive therapy (TPT). Methods: This study is a secondary posthoc analysis of the AIDS Clinical Trials Group A5274 REMEMBER clinical trial (NCT0138008), an open-label randomised clinical trial of antiretroviral-naïve PWH with CD4 <50 cells/µL, performed from October 31, 2011 to June 9, 2014, from 18 outpatient research clinics in 10 low- and middle-income countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda) who initiated antiretroviral therapy and either isoniazid TPT or 4-drug empiric TB therapy. Plasma concentrations of several soluble inflammatory biomarkers were measured prior to the commencement of antiretroviral and anti-TB therapies, and participants were followed up for at least 48 weeks. Incident TB or death during this period were primary outcomes. We performed multidimensional analyses, logistic regression analyses, survival curves, and Bayesian network analyses to delineate associations between anaemia, laboratory parameters, and clinical outcomes. Findings: Of all 269 participants, 76.2% (n = 205) were anaemic, and 31.2% (n = 84) had severe anaemia. PWH with moderate/severe anaemia exhibited a pronounced systemic pro-inflammatory profile compared to those with mild or without anaemia, hallmarked by a substantial increase in IL-6 plasma concentrations. Moderate/severe anaemia was also associated with incident TB incidence (aOR: 3.59, 95% CI: 1.32-9.76, p = 0.012) and death (aOR: 3.63, 95% CI: 1.07-12.33, p = 0.039). Interpretation: Our findings suggest that PWH with moderate/severe anaemia display a distinct pro-inflammatory profile. The presence of moderate/severe anaemia pre-ART was independently associated with the development of TB and death. PWH with anaemia should be monitored closely to minimise the occurrence of unfavourable outcomes. Funding: National Institutes of Health.

A Metastatic Well-differentiated Squamous Cell Carcinoma in a Patient with an Arteriovenous Fistula.

Patients receiving hemodialysis have an increased risk of developing nonmelanoma skin cancers, such as cutaneous squamous cell carcinoma (SCC). Management of SCC usually relies on complete surgical excision of the primary tumor and may require regional lymph node dissection due to lymphatic spread. An 81-year-old man with an arteriovenous fistula (AVF) presented with an unusually aggressive metastatic well-differentiated SCC, necessitating an axillary dissection for lymph node metastasis. He had been referred for radiotherapy to complete his oncological treatment following excision of the primary SCC on his forearm. An AVF site is subjected to significant changes in circulatory pressure, leading to reduced lymphatic drainage and likely focal immunosuppression. Increased lymphatic burden, combined with repeated trauma to the fistula in an immunosuppressed patient, potentially precipitated the development of an SCC on the affected limb. The individual risk factors for SCC such as sites of chronic inflammation and repeated trauma, host immunosuppression, and renal disease are well established. This patient demonstrates the perfect storm of all these risk factors, leading to a highly malignant metastatic SCC. As the standards of renal care improve and the number of patients with AVF increases, we must remain vigilant in the management of SCCs in these patients.

Rapid redesign and effect on clinical workload of a supra-regional burns and plastic surgery service during the COVID-19 pandemic.

INTRODUCTION: In March 2020, South Wales experienced the most significant COVID-19 outbreak in the UK outside of London. We share our experience of the rapid redesign and subsequent change in activity in one of the busiest supra-regional burns and plastic surgery services in the UK. METHODS: A time-matched retrospective service evaluation was completed for a 7-week "COVID-19" study period and the equivalent weeks in 2018 and 2019. The primary aim of this study was to evaluate plastic surgery theatre use and the impact of service redesign. Comparison between study periods was tested for statistical significance using two-tailed t-tests. RESULTS: Operation numbers reduced by 64% and total operating time by 70%. General anaesthetic cases reduced from 41% to 7% (p<0.0001), and surgery was mainly carried out in ringfenced daycase theatres. Emergency surgery decreased by 84% and elective surgery by 46%. Cancer surgery as a proportion of total elective operating increased from 51% to 96% (p<0.0001). The absolute number of cancer-related surgeries undertaken was maintained despite the pandemic. CONCLUSION: Rapid development of COVID-19 SOPs minimised inpatient admissions. There was a significant decrease in operating while maintaining emergency and cancer surgery. Our ringfenced local anaesthetic Plastic Surgery Treatment Centre was essential in delivering a service. COVID-19 acted as a catalyst for service innovations and the uptake of activities such as telemedicine, virtual MDTs, and online webinars. Our experiences support the need for a core burns and plastic service during a pandemic, and show that the service can be effectively redesigned at speed.

Complex effect of continuous curcumin exposure on human bone marrow-derived mesenchymal stem cell regenerative properties through matrix metalloproteinase regulation.

Curcumin has been reported to be beneficial for cancers, cardiovascular and neurodegenerative diseases, based on its anti-oxidative, anti-inflammation, anti-tumorigenic and neuroprotective properties. With its high-dose application, curcumin toxicity to systemic tissues is a reasonable concern. Here, we report the responses of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) to continuous curcumin exposure. hBM-MSCs were treated with 0.01-100 µmol/L curcumin continuously in vitro for 7 days. 25 µmol/L curcumin or above significantly attenuated hBM-MSC maintenance, whereas 10 µmol/L curcumin reduced hBM-MSC proliferation and hindered their migration with increasing cell apoptosis. Besides, 5 µmol/L curcumin treatment inhibited hBM-MSC adipogenic differentiation, but enhanced osteogenic differentiation, which depended on matrix metalloproteinase (MMP)-13 expression and activity. Furthermore, curcumin treatment reduced MMP1 expression but up-regulated the immunomodulatory gene IDO1 expression. In summary, this study revealed the complex effects of continuous curcumin exposure on hBM-MSC maintenance and regenerative properties through MMP regulation. Given the complex effects of curcumin, its use for biomedical purposes should be carefully considered in treatment length and dosage.

Cross-validation of existing signatures and derivation of a novel 29-gene transcriptomic signature predictive of progression to TB in a Brazilian cohort of household contacts of pulmonary TB.

The goal of this study was to identify individuals at risk of progression and reactivation among household contacts (HHC) of pulmonary TB cases in Vitoria, Brazil. We first evaluated the predictive performance of six published signatures on the transcriptional dataset obtained from peripheral blood mononuclear cell samples from HHC that either progressed to TB disease or not (non-progressors) during a five-year follow-up. The area under the curve (AUC) values for the six signatures ranged from 0.670 to 0.461, and the PPVs did not reach the WHO published target product profiles (TPPs). We therefore used as training cohort the earliest time-point samples from the African cohort of adolescents (GSE79362) and applied an ensemble feature selection pipeline to derive a novel 29-gene signature (PREDICT29). PREDICT29 was tested on 16 progressors and 21 non-progressors. PREDICT29 performed better in segregating progressors from non-progressors in the Brazil cohort with the area under the curve (AUC) value of 0.911 and PPV of 20%. This proof of concept study demonstrates that PREDICT29 can predict risk of progression/reactivation to clinical TB disease in recently exposed individuals at least 5 years prior to disease development. Upon validation in larger and geographically diverse cohorts, PREDICT29 can be used to risk-stratify recently infected for targeted therapy.

Long-term results after elective laparoscopic surgery for colorectal cancer in octogenarians.

BACKGROUND: The aim of this study was to investigate the short- and long-term outcomes after elective laparoscopic surgery (LPS) for colorectal cancer patients over 80 years of age. METHODS: This was a retrospective study of all patients of 80 and above, who underwent elective colorectal resection, between January 2007 and January 2016. Data were analysed from a prospectively collected cancer database and cross checked with patient records. Determinants of survival were analysed using log-rank test and Kaplan-Meier curves. RESULTS: We identified 293 patients; 110 underwent LPS. LPS had significantly better overall survival (p = 0.0065) and disease-free survival (DFS) (p = 0.006). The LPS group also had a shorter length of stay (LOS)-9 vs 11 days (p < 0.00001), 90-day mortality-5.5 vs 13.7% (p = 0.03) and required fewer blood transfusions 22.7 vs 40.4% (p = 0.002), when compared to open surgery (OPS). There was no difference in 30-day mortality 1.8 vs 4.9% (p = 0.22), anastomotic leakage 2.3 vs 6% (p = 0.20) or post-operative complication rates 44.5 vs 50.8% (p = 0.30). CONCLUSIONS: LPS for patients in their 80s is characterised by better overall and DFS compared to open procedures and is associated with shorter post-operative LOS, and significantly lower 90-day mortality. Patients operated on laparoscopically also required fewer post-operative blood transfusions.

A Parsimonious Host Inflammatory Biomarker Signature Predicts Incident Tuberculosis and Mortality in Advanced Human Immunodeficiency Virus.

BACKGROUND: People with advanced human immunodeficiency virus (HIV) (CD4 < 50) remain at high risk of tuberculosis (TB) or death despite the initiation of antiretroviral therapy (ART). We aimed to identify immunological profiles that were most predictive of incident TB disease and death. METHODS: The REMEMBER randomized clinical trial enrolled 850 participants with HIV (CD4 < 50 cells/µL) at ART initiation to receive either empiric TB treatment or isoniazid preventive therapy (IPT). A case-cohort study (n = 257) stratified by country and treatment arm was performed. Cases were defined as incident TB or all-cause death within 48 weeks after ART initiation. Using multiplexed immunoassay panels and ELISA, 26 biomarkers were assessed in plasma. RESULTS: In total, 52 (6.1%) of 850 participants developed TB; 47 (5.5%) died (13 of whom had antecedent TB). Biomarkers associated with incident TB overlapped with those associated with death (interleukin [IL]-1ß, IL-6). Biomarker levels declined over time in individuals with incident TB while remaining persistently elevated in those who died. Dividing the cohort into development and validation sets, the final model of 6 biomarkers (CXCL10, IL-1ß, IL-10, sCD14, tumor necrosis factor [TNF]-α, and TNF-ß) achieved a sensitivity of 0.90 (95% confidence interval [CI]: .87-.94) and a specificity of 0.71(95% CI: .68-.75) with an area under the curve (AUC) of 0.81 (95% CI: .78-.83) for incident TB. CONCLUSION: Among people with advanced HIV, a parsimonious inflammatory biomarker signature predicted those at highest risk for developing TB despite initiation of ART and TB preventive therapies. The signature may be a promising stratification tool to select patients who may benefit from increased monitoring and novel interventions. CLINICAL TRIALS REGISTRATION: NCT01380080.

Existing blood transcriptional classifiers accurately discriminate active tuberculosis from latent infection in individuals from south India.

Several studies have identified blood transcriptomic signatures that can distinguish active from latent Tuberculosis (TB). The purpose of this study was to assess how well these existing gene profiles classify TB disease in a South Indian population. RNA sequencing was performed on whole blood PAXgene samples collected from 28 TB patients and 16 latently TB infected (LTBI) subjects enrolled as part of an ongoing household contact study. Differential gene expression and clustering analyses were performed and compared with explicit predictive testing of TB and LTBI individuals based on established gene signatures. We observed strong predictive performance of TB disease states based on expression of known gene sets (ROC AUC 0.9007-0.9879). Together, our findings indicate that previously reported classifiers generated from different ethnic populations can accurately discriminate active TB from LTBI in South Indian patients. Future work should focus on converting existing gene signatures into a universal TB gene signature for diagnosis, monitoring TB treatment, and evaluating new drug regimens.

A Single Centre Experience of Day Case Laparoscopic Cholecystectomy Outcomes by Body Mass Index Group.

AIM: The purpose of this study was to evaluate whether patients with a high BMI can undergo safe day case LC for cholecystitis compared to groups of patients with a lower BMI. SETTING: NHS District General Hospital, UK. METHODS: A retrospective review of 2391 patients who underwent an attempted day case LC between 1 January 2009 and 15 August 2015 was performed. Patients were divided into five groups depending on their BMI. Inclusion criteria were patients undergoing elective day case laparoscopic cholecystectomy with cholecystitis on histology. The endpoints were complication requiring readmission and postoperative length of stay (LOS). RESULTS: There were 2391 LCs performed in the time period of which 1646 were eligible for inclusion. These LCs were classified as 273 (16.9%), 608 (37.8%), 428 (26.6%), 208 (12.9%), and 91 (5.66%) patients in the groups with BMI values of 18.5-24.9, 25-29.9, 30-34.9, 35-39.9, and >40, respectively. Average BMI was 30.0 (±5.53, 19-51) with an average postoperative LOS of 0.86, and there was no difference between the BMI groups. Overall complication rate was 4.3%; there was no significance between BMI groups. CONCLUSIONS: Increased BMI was not associated with worse outcomes after day case LC.