Adverse effects and duration of treatment of TB in Canterbury, New Zealand.

BACKGROUND Treatment of TB is often extended beyond the recommended duration. The aim of this study was to assess prevalence of extended treatment and to identify associated risk factors. We also aimed to determine the frequency and type of adverse drug reactions (ADR) experienced by this study population.METHODS We performed a retrospective cohort study of all patients treated for active TB at Christchurch Hospital, Christchurch, New Zealand, between 1 March 2012 and 31 December 2018. Data for 192 patients were collected on patient demographics, disease characteristics and treatment characteristics, including planned and actual duration of treatment and ADRs.RESULTS Of 192 patients, 35 (18.2%) had treatment extended, and 85 (46.5%) of 183 with fully drug-susceptible TB received ≥9 months treatment. The most common reasons for extension were persistent or extensive disease and ADR. Extended treatment duration was not associated with any patient or disease characteristics. We found 35 (18.2%) patients experienced at least one ADR. The most common ADRs were hepatitis, rash and peripheral neuropathy.CONCLUSION TB treatment extension beyond WHO guidelines is common. Further research is needed to guide management of those with slow response to treatment. Methods for early detection of ADR, systems to improve adherence and therapeutic drug monitoring are potentially useful strategies.

Neuroinflammation is a putative target for the prevention and treatment of perioperative neurocognitive disorders.

INTRODUCTION: The demographics of aging of the surgical population has increased the risk for perioperative neurocognitive disorders in which trauma-induced neuroinflammation plays a pivotal role. SOURCES OF DATA: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. AREAS OF AGREEMENT: Neuroinflammation is a sine qua non for development of perioperative neurocognitive disorders. AREAS OF CONTROVERSY: What is the best method for ameliorating trauma-induced neuroinflammation while preserving inflammation-based wound healing. GROWING POINTS: This review considers how to prepare for and manage the vulnerable elderly surgical patient through the entire spectrum, from preoperative assessment to postoperative period. AREAS TIMELY FOR DEVELOPING RESEARCH: What are the most effective and safest interventions for preventing and/or reversing Perioperative Neurocognitive Disorders.

Diagnostic accuracy of leptospirosis whole-cell lateral flow assays: a systematic review and meta-analysis.

BACKGROUND: Leptospirosis is under-diagnosed by clinicians in many high-incidence countries, because reference diagnostic tests are largely unavailable. Lateral flow assays (LFA) that use antigen derived from heat-treated whole cell Leptospira biflexa serovar Patoc have the potential to improve leptospirosis diagnosis in resource-limited settings. OBJECTIVES: We sought to summarize estimates of sensitivity and specificity of LFA by conducting a systematic review and meta-analysis of evaluations of the accuracy of LFA to diagnose human leptospirosis. DATA SOURCES: On 4 July 2017 we searched three medical databases. Study eligibility criteriaArticles were included if they were a study of LFA sensitivity and specificity. PARTICIPANTS: Patients with suspected leptospirosis. INTERVENTIONS: Nil. METHODS: For included articles, we assessed study quality, characteristics of participants and diagnostic testing methods. We estimated sensitivity and specificity for each study against the study-defined case definition as the reference standard, and performed a meta-analysis using a random-effects bivariate model. RESULTS: Our search identified 225 unique reports, of which we included nine (4%) published reports containing 11 studies. We classified one (9%) study as high quality. Nine (82%) studies used reference tests with considerable risk of misclassification. Our pooled estimates of sensitivity and specificity were 79% (95% CI 70%-86%) and 92% (95% CI 85%-96%), respectively. CONCLUSIONS: As the evidence base for determining the accuracy of LFA is small and at risk of bias, pooled estimates of sensitivity and specificity should be interpreted with caution. Further studies should use either reference tests with high sensitivity and specificity or statistical techniques that account for an imperfect reference standard.

Past, present, and future of nitrous oxide.

Introduction: For a drug that has been omnipresent for nearly 200 years, nitrous oxide's (N2O) future seems less certain than its illustrious past. Environmental concerns are coming to the fore and may yet outweigh important clinical benefits. Sources of data: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. Areas of agreement: The analgesic and anaesthetic advantages of N2O remain despite a plethora of newer agents. Areas of controversy: N2O greenhouse gas effect and its inhibition of key enzymes involved in protein and DNA synthesis have provided further fuel for those intent on eliminating its further clinical use. Growing points: The use of N2O for treatment-resistant depression has gained traction. Areas timely for developing research: Comparative studies for N2O role in combatting the prescription opioid analgesic epidemic may well provide further clinical impetus.

The epidemiology of febrile illness in sub-Saharan Africa: implications for diagnosis and management.

BACKGROUND: Fever is among the most common symptoms of people living in Africa, and clinicians are challenged by the similar clinical features of a wide spectrum of potential aetiologies. AIM: To summarize recent studies of fever aetiology in sub-Saharan Africa focusing on causes other than malaria. SOURCES: A narrative literature review by searching the MEDLINE database, and recent conference abstracts. CONTENT: Studies of multiple potential causes of fever are scarce, and for many participants the infecting organism remains unidentified, or multiple co-infecting microorganisms are identified, and establishing causation is challenging. Among ambulatory patients, self-limiting arboviral infections and viral upper respiratory infections are common, occurring in up to 60% of children attending health centres. Among hospitalized patients there is a high prevalence of potentially fatal infections requiring specific treatment. Bacterial bloodstream infection and bacterial zoonoses are major causes of fever. In recent years, the prevalence of antimicrobial resistance among bacterial isolates has increased, notably with spread of extended spectrum ß-lactamase-producing Enterobacteriaceae and fluoroquinolone-resistant Salmonella enterica. Among those with human immunodeficiency virus (HIV) infection, Mycobacterium tuberculosis bacteraemia has been confirmed in up to 34.8% of patients with sepsis, and fungal infections such as cryptococcosis and histoplasmosis remain important. IMPLICATIONS: Understanding the local epidemiology of fever aetiology, and the use of diagnostics including malaria and HIV rapid-diagnostic tests, guides healthcare workers in the management of patients with fever. Current challenges for clinicians include assessing which ambulatory patients require antibacterial drugs, and identifying hospitalized patients infected with organisms that are not susceptible to empiric antibacterial regimens.

Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice.

BACKGROUND: Perioperative neurocognitive disorders (PND) result in long-term morbidity and mortality with no effective interventions available. Because interleukin-6 (IL-6), a pro-inflammatory cytokine, is consistently up-regulated by trauma, including after surgery, we determined whether IL-6 is a putative therapeutic target for PND in a mouse model. METHODS: Following institutional approval, adult (12-14 weeks) male C57/Bl6 mice were pretreated with the IL-6 receptor (IL6R) blocking antibody tocilizumab prior to open tibia fracture with internal fixation under isoflurane anaesthesia. Inflammatory and behavioural responses in a trace fear conditioning (TFC) paradigm were assessed postoperatively. Separately, the effects of IL-6 administration or of depletion of bone marrow-derived monocytes (BM-DMs) with clodrolip on the inflammatory and behavioural responses were assessed. Blood brain barrier disruption, hippocampal microglial activation, and infiltration of BM-DMs were each assessed following IL-6 administration. RESULTS: The surgery-induced decrement in freezing time in the TFC assay, indicative of cognitive decline, was attenuated by tocilizumab (P<0.01). The surgery-induced increase in pro-inflammatory mediators was significantly reduced by tocilizumab. Exogenously administered IL-6 significantly impaired freezing behaviour (P<0.05) and up-regulated pro-inflammatory cytokines; both responses were prevented by depletion of BM-DMs. IL-6 disrupted the blood brain barrier, and increased hippocampal activation of microglia and infiltration of BM-DMs. CONCLUSIONS: IL-6 is both necessary and sufficient to produce cognitive decline. Following further preclinical testing of its perioperative safety, the IL6R blocker tocilizumab is a candidate for prevention and/or treatment of PND.

The hip fracture surgery in elderly patients (HIPELD) study to evaluate xenon anaesthesia for the prevention of postoperative delirium: a multicentre, randomized clinical trial.

BACKGROUND: Postoperative delirium occurs frequently in elderly hip fracture surgery patients and is associated with poorer overall outcomes. Because xenon anaesthesia has neuroprotective properties, we evaluated its effect on the incidence of delirium and other outcomes after hip fracture surgery. METHODS: This was a phase II, multicentre, randomized, double-blind, parallel-group, controlled clinical trial conducted in hospitals in six European countries (September 2010 to October 2014). Elderly (≥75yr-old) and mentally functional hip fracture patients were randomly assigned 1:1 to receive either xenon- or sevoflurane-based general anaesthesia during surgery. The primary outcome was postoperative delirium diagnosed through postoperative day 4. Secondary outcomes were delirium diagnosed anytime after surgery, postoperative sequential organ failure assessment (SOFA) scores, and adverse events (AEs). RESULTS: Of 256 enrolled patients, 124 were treated with xenon and 132 with sevoflurane. The incidence of delirium with xenon (9.7% [95% CI: 4.5 -14.9]) or with sevoflurane (13.6% [95% CI: 7.8 -19.5]) were not significantly different (P=0.33). Overall SOFA scores were significantly lower with xenon (least-squares mean difference: -0.33 [95% CI: -0.60 to -0.06]; P=0.017). For xenon and sevoflurane, the incidence of serious AEs and fatal AEs was 8.0% vs 15.9% (P=0.05) and 0% vs 3.8% (P=0.06), respectively. CONCLUSIONS: Xenon anaesthesia did not significantly reduce the incidence of postoperative delirium after hip fracture surgery. Nevertheless, exploratory observations concerning postoperative SOFA-scores, serious AEs, and deaths warrant further study of the potential benefits of xenon anaesthesia in elderly hip fracture surgery patients. CLINICAL TRIAL REGISTRATION: EudraCT 2009-017153-35; ClinicalTrials.gov NCT01199276.

Perioperative management of the obese surgical patient.

INTRODUCTION: The escalation in the prevalence of obesity throughout the world has led to an upsurge in the number of obese surgical patients to whom perioperative care needs to be delivered. SOURCES OF DATA: After determining the scope of the review, the authors used PubMed with select phrases encompassing the words in the scope. Both preclinical and clinical reports were considered. AREAS OF AGREEMENT: There were no controversies regarding preoperative management and the intraoperative care of the obese surgical patient. AREAS OF CONTROVERSY: Is there a healthy obese state that gives rise to the obesity paradox regarding postoperative complications? GROWING POINTS: This review considers how to prepare for and manage the obese surgical patient through the entire spectrum, from preoperative assessment to possible postoperative intensive care. AREAS TIMELY FOR DEVELOPING RESEARCH: What results in an obese patient developing 'unhealthy' obesity?

Therapeutic drug monitoring of isoniazid and rifampicin during anti-tuberculosis treatment in Auckland, New Zealand.

SETTING: There is uncertainty as to the optimal therapeutic concentrations of anti-tuberculosis drugs to achieve cure. OBJECTIVE: To characterise the use of therapeutic drug monitoring (TDM), and identify risk factors and outcomes for those with concentrations below the drug interval. DESIGN: Patients treated for tuberculosis (TB) who had rifampicin (RMP) or isoniazid (INH) concentrations measured between 1 January 2005 and 31 December 2012 were studied retrospectively. Matched concentrations and drug dosing time were assessed according to contemporary regional drug intervals (RMP > 6 µmol/l, INH > 7.5 µmol/l) and current international recommendations (RMP > 10 µmol/l, INH > 22 µmol/l). Outcomes were assessed using World Health Organization criteria. RESULTS: Of 865 patients, 121 had concentrations of either or both medications. RMP concentrations were within the regional drug intervals in 106/114 (93%) and INH in 91/100 (91%). Concentrations were within international drug intervals for RMP in 76/114 (67%) and INH in 53/100 (53%). Low weight-based dose was the only statistically significant risk factor for concentrations below the drug interval. Of the 35 patients with low concentrations, 21 were cured, 9 completed treatment and 5 transferred out. There were no relapses during follow-up (mean 66.5 months). CONCLUSION: There were no clinically useful characteristics to guide use of TDM. Many patients had concentrations below international therapeutic intervals, but were successfully treated.

[Elaboration of a national biobank for the study of gestational trophoblastic diseases]. / Création d'une biobanque nationale pour l'étude des maladies trophoblastiques gestationnelles.

AIM: To generate a national biobank made up of samples of the highest quality for the purpose of inciting basic research on gestational trophoblastic diseases (GTD). MATERIAL AND METHODS: Three priority axes of research were defined to optimize the nature, method of collection, and storage of the samples. These are: to enhance our understanding of GTD, develop new diagnostic tests, and identify new therapeutic targets. The protocol for patient inclusion and sample processing was determined after extensive literature review and collaboration with international experts in the field of GTD. RESULTS: For each patient with a GTD and for control patients (legally induced abortions), chorionic villi, decidua and tumor samples (fresh, immersed in RNA-protective solution and fixed in formaldehyde), blood (serum, plasma, RNA, and peripheral blood mononuclear cells), urine (supernatant), and cell cultures of villous cytotrophoblasts are prospectively collected. Associations are then made between the collected samples and numerous clinical and biological data, such as human chorionic gonadotropic plasma levels following curettage in the case of a hydatidiform mole. CONCLUSION: Such a collection of high quality samples and their associated data open up new perspectives for both national and international collaborative research projects.

Relation between acute and long-term cognitive decline after surgery: Influence of metabolic syndrome.

INTRODUCTION: The relationship between persistent postoperative cognitive decline and the more common acute variety remains unknown; using data acquired in preclinical studies of postoperative cognitive decline we attempted to characterize this relationship. METHODS: Low capacity runner (LCR) rats, which have all the features of the metabolic syndrome, were compared postoperatively with high capacity runner (HCR) rats for memory, assessed by trace fear conditioning (TFC) on the 7th postoperative day, and learning and memory (probe trial [PT]) assessed by the Morris water-maze (MWM) at 3 months postoperatively. Rate of learning (AL) data from the MWM test, were estimated by non-linear mixed effects modeling. The individual rat's TFC result at postoperative day (POD) 7 was correlated with its AL and PT from the MWM data sets at postoperative day POD 90. RESULTS: A single exponential decay model best described AL in the MWM with LCR and surgery (LCR-SURG) being the only significant covariates; first order AL rate constant was 0.07 s(-1) in LCR-SURG and 0.16s(-1) in the remaining groups (p<0.05). TFC was significantly correlated with both AL (R=0.74; p<0.0001) and PT (R=0.49; p<0.01). CONCLUSION: Severity of memory decline at 1 week after surgery presaged long-lasting deteriorations in learning and memory.

Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model.

BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 to 0.6 µg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 µg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 µg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.

Xenon treatment protects against cold ischemia associated delayed graft function and prolongs graft survival in rats.

Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival.

Outcomes of infected abdominal aortic grafts managed with antimicrobial therapy and graft retention in an unselected cohort.

OBJECTIVE: To document the treatment of all patients with infected aortic grafts at Christchurch Hospital between 1999 and 2010, focussing on the mortality and morbidity of those treated without graft explantation. METHODS: Cases of infected aortic grafts were reviewed. Cases required a compatible clinical syndrome, CT imaging and tissue/blood culture results. RESULTS: Eighteen patients were identified. Organisms isolated at diagnosis from blood or graft site were Staphylococcus aureus 6 (MRSA 1), beta haemolytic streptococci 2, enteric organisms 9.There was no isolate from 2. One case had graft explantation and brief antimicrobial therapy. Seventeen patients had the graft retained. Of these, 14 received intravenous antimicrobial therapy for 6 weeks and 14 lifelong oral therapy. None died during their initial admission or within 30 days. During a mean follow-up of 57 months, 10 (59%) relapsed (median time 31 months, range 0--98), 4 (24%) underwent graft explantation and 10 (59%) died (median 40 months, range 1e 198). Four of 10 who relapsed had organisms isolated (all enteric). CONCLUSION: Patients treated with lifelong antimicrobial therapy and graft retention survived a median of 41 months, with low early mortality although over half relapsed. Empiric therapy should cover skin organisms and enteric organisms, even for those outside the post-operative period.

Peripheral orthopaedic surgery down-regulates hippocampal brain-derived neurotrophic factor and impairs remote memory in mouse.

Peripheral orthopaedic surgery induces a profound inflammatory response. This includes a substantial increase in cytokines and, especially, in the level of interleukin (IL)-1ß in the hippocampus, which has been shown to impair hippocampal-dependent memory in mice. We have employed two tests of contextual remote memory to demonstrate that the inflammatory response to surgical insult in mice also results in impairment of remote memory associated with prefrontal cortex (PFC). We have also found that, under the conditions presented in the social interaction test, peripheral orthopaedic surgery does not increase anxiety-like behaviour in our animal model. Although such surgery induces an increase in the level of IL-1ß in the hippocampus, it fails to do so in the PFC. Peripheral orthopaedic surgery also results in a reduction in the level of hippocampal brain-derived neurotrophic factor (BDNF) and this may contribute, in part, to the memory impairment found after such surgery. Our data suggest that a reduction in the level of hippocampal BDNF and an increase in the level of hippocampal IL-1ß following surgery may affect the transference of fear memory in the mouse brain.

Nucleic Acid Amplification of the opa Gene for Detection of Neisseria gonorrhoeae: experience from a diagnostic laboratory.

We report results of Neisseria gonorrhoeae nucleic acid amplification testing (NAAT) with the Abbott m2000 PCR at a tertiary laboratory 6 months after its introduction. Of 5,475 specimens tested, 45 samples (0.82%) tested positive for N. gonorrhoeae. Eight were not cultured, but seven tested positive with a porA pseudogene NAAT.

The glutaminergic, GABAergic, dopaminergic but not cholinergic neurons are susceptible to anaesthesia-induced cell death in the rat developing brain.

Neuronal cell death induced by anaesthetics in the developing brain was evident in previous pre-clinical studies. However, the neuronal cell types involved in anaesthesia-induced neuronal cell death remains elusive. The aim of this study was to investigate glutamatergic, GABAergic, cholinergic and dopaminergic neuronal cell apoptosis induced by anaesthetic exposure in specific brain regions in rats. Separate cohorts of 7-day-old Sprague Dawley (SD) rat pups were randomly assigned to two groups: Naive and anaesthetics alone (70% nitrous oxide and 0.75% isoflurane exposure for 6 h). The brains were sectioned and the slices that contained the basal forebrain, substantia nigra, cornu ammonis area 1 (CA1) subarea of hippocampus or cingulate cortex were selected and subsequently subjected to double-labelled fluorescent immunohistochemistry for choline acetyltransferase, dopamine, vesicular glutamate transporter 1 (vGLUT1) or glutamic acid decarboxylase 67 (GAD67) together with caspase 3, respectively. Compared to the naive control, anaesthetic exposure significantly increased the number of caspase-3 positive cells in the CA1 subarea of hippocampus, cingulate cortex, and substantia nigra, but not in the basal forebrain. 54% and 14% of apoptotic cells in the CA1 subarea of hippocampus were GABAergic and glutamatergic neurons respectively. In the cingulate cortex, 30% and 37% of apoptotic cells were GABAergic and glutamatergic neurons respectively. In the substantia nigra, 22% of apoptotic cells were dopaminergic neurons. Our data suggests, anaesthetic exposure significantly increases neuroapoptosis of glutamatergic, GABAergic and dopaminergic neurons in the developing brain but not that of the cholinergic neurons in the basal forebrain.

Ochroconis gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis.

Ochroconis gallopava has rarely been isolated in immunosuppressed patients. We report the first case to our knowledge of O. gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis. A 58-year-old man who had undergone cardiac transplant 8 years earlier alerted his dialysis nurses to the presence of black material in his catheter lumen. Fungal hyphae were seen on direct microscopy of the black material and from the dialysate effluent, and O. gallopava was cultured from both after 1 day. He was treated successfully with a single dose of intravenous voriconazole, followed by 2 weeks of oral voriconazole.