Autism-related KLHL17 and SYNPO act in concert to control activity-dependent dendritic spine enlargement and the spine apparatus.

Dendritic spines, the tiny and actin-rich protrusions emerging from dendrites, are the subcellular locations of excitatory synapses in the mammalian brain that control synaptic activity and plasticity. Dendritic spines contain a specialized form of endoplasmic reticulum (ER), i.e., the spine apparatus, required for local calcium signaling and that is involved in regulating dendritic spine enlargement and synaptic plasticity. Many autism-linked genes have been shown to play critical roles in synaptic formation and plasticity. Among them, KLHL17 is known to control dendritic spine enlargement during development. As a brain-specific disease-associated gene, KLHL17 is expected to play a critical role in the brain, but it has not yet been well characterized. In this study, we report that KLHL17 expression in mice is strongly regulated by neuronal activity and KLHL17 modulates the synaptic distribution of synaptopodin (SYNPO), a marker of the spine apparatus. Both KLHL17 and SYNPO are F-actin-binding proteins linked to autism. SYNPO is known to maintain the structure of the spine apparatus in mature spines and contributes to synaptic plasticity. Our super-resolution imaging using expansion microscopy demonstrates that SYNPO is indeed embedded into the ER network of dendritic spines and that KLHL17 is closely adjacent to the ER/SYNPO complex. Using mouse genetic models, we further show that Klhl17 haploinsufficiency and knockout result in fewer dendritic spines containing ER clusters and an alteration of calcium events at dendritic spines. Accordingly, activity-dependent dendritic spine enlargement and neuronal activation (reflected by extracellular signal-regulated kinase (ERK) phosphorylation and C-FOS expression) are impaired. In addition, we show that the effect of disrupting the KLHL17 and SYNPO association is similar to the results of Klhl17 haploinsufficiency and knockout, further strengthening the evidence that KLHL17 and SYNPO act together to regulate synaptic plasticity. In conclusion, our findings unravel a role for KLHL17 in controlling synaptic plasticity via its regulation of SYNPO and synaptic ER clustering and imply that impaired synaptic plasticity contributes to the etiology of KLHL17-related disorders.

E2F7 drives autotaxin/Enpp2 transcription via chromosome looping: Repression by p53 in murine but not in human carcinomas.

Dysregulation of the autotaxin (ATX, Enpp2)-lysophosphatidic acid (LPA) signaling in cancerous cells contributes to tumorigenesis and therapy resistance. We previously found that ATX activity was elevated in p53-KO mice compared to wild-type (WT) mice. Here, we report that ATX expression was upregulated in mouse embryonic fibroblasts from p53-KO and p53R172H mutant mice. ATX promoter analysis combined with yeast one-hybrid testing revealed that WT p53 directly inhibits ATX expression via E2F7. Knockdown of E2F7 reduced ATX expression and chromosome immunoprecipitation showed that E2F7 promotes Enpp2 transcription through cooperative binding to two E2F7 sites (promoter region -1393 bp and second intron 996 bp). Using chromosome conformation capture, we found that chromosome looping brings together the two E2F7 binding sites. We discovered a p53 binding site in the first intron of murine Enpp2, but not in human ENPP2. Binding of p53 disrupted the E2F7-mediated chromosomal looping and repressed Enpp2 transcription in murine cells. In contrast, we found no disruption of E2F7-mediated ENPP2 transcription via direct p53 binding in human carcinoma cells. In summary, E2F7 is a common transcription factor that upregulates ATX in human and mouse cells but is subject to steric interference by direct intronic p53 binding only in mice.

Hippocampal integration and separation processes with different temporal and spatial dynamics during learning for associative memory.

The hippocampus is known to be critically involved in associative memory formation. However, the role of the hippocampus during the learning of associative memory is still controversial; while the hippocampus is considered to play a critical role in the integration of related stimuli, numerous studies also suggest a role of the hippocampus in the separation of different memory traces for rapid learning. Here, we employed an associative learning paradigm consisting of repeated learning cycles. By tracking the changes in the hippocampal representations of associated stimuli on a cycle-by-cycle basis as learning progressed, we show that both integration and separation processes occur in the hippocampus with different temporal dynamics. We found that the degree of shared representations for associated stimuli decreased significantly during the early phase of learning, whereas it increased during the later phase of learning. Remarkably, these dynamic temporal changes were observed only for stimulus pairs remembered 1 day or 4 weeks after learning, but not for forgotten pairs. Further, the integration process during learning was prominent in the anterior hippocampus, while the separation process was obvious in the posterior hippocampus. These results demonstrate temporally and spatially dynamic hippocampal processing during learning that can lead to the maintenance of associative memory.

Childhood adversities and mental disorders in first-year college students: results from the World Mental Health International College Student Initiative.

BACKGROUND: This study investigates associations of several dimensions of childhood adversities (CAs) with lifetime mental disorders, 12-month disorder persistence, and impairment among incoming college students. METHODS: Data come from the World Mental Health International College Student Initiative (WMH-ICS). Web-based surveys conducted in nine countries (n = 20 427) assessed lifetime and 12-month mental disorders, 12-month role impairment, and seven types of CAs occurring before the age of 18: parental psychopathology, emotional, physical, and sexual abuse, neglect, bullying victimization, and dating violence. Poisson regressions estimated associations using three dimensions of CA exposure: type, number, and frequency. RESULTS: Overall, 75.8% of students reported exposure to at least one CA. In multivariate regression models, lifetime onset and 12-month mood, anxiety, and substance use disorders were all associated with either the type, number, or frequency of CAs. In contrast, none of these associations was significant when predicting disorder persistence. Of the three CA dimensions examined, only frequency was associated with severe role impairment among students with 12-month disorders. Population-attributable risk simulations suggest that 18.7-57.5% of 12-month disorders and 16.3% of severe role impairment among those with disorders were associated with these CAs. CONCLUSION: CAs are associated with an elevated risk of onset and impairment among 12-month cases of diverse mental disorders but are not involved in disorder persistence. Future research on the associations of CAs with psychopathology should include fine-grained assessments of CA exposure and attempt to trace out modifiable intervention targets linked to mechanisms of associations with lifetime psychopathology and burden of 12-month mental disorders.

Cardiovascular concentration-effect relationships of amodiaquine and its metabolite desethylamodiaquine: Clinical and preclinical studies.

AIMS: Amodiaquine is a 4-aminoquinoline used extensively for the treatment and prevention of malaria. Orally administered amodiaquine is largely converted to the active metabolite desethylamodiaquine. Amodiaquine can cause bradycardia, hypotension, and electrocardiograph QT interval prolongation, but the relationship of these changes to drug concentrations is not well characterized. METHODS: We conducted a secondary analysis of a pharmacokinetic study of the cardiac safety of amodiaquine (10 mg base/kg/day over 3 days) in 54 Kenyan adults (≥18 years) with uncomplicated malaria. Nonlinear mixed effects modelling was used to assess amodiaquine and desethylamodiaquine concentration-effect relationships for vital sign (pulse rate, blood pressure) and electrocardiograph interval (QT, QRS, PR) outcomes. We also measured the spontaneous beating heart rate after cumulative dosing of amodiaquine and desethylamodiaquine in isolated mouse atrial preparations. RESULTS: Amodiaquine and desethylamodiaquine caused concentration-dependent mean decreases in pulse rate (1.9 beats/min per 100 nmol/L; 95% confidence interval: 1.5-2.4), supine systolic blood pressure (1.7 mmHg per 100 nmol/L; 1.2-2.1), erect systolic blood pressure (1.5 mmHg per 100 nmol/L; 1.0-2.0) and erect diastolic blood pressure (1.4 mmHg per 100 nmol/L; 1.0-1.7). The mean QT interval prolongation was 1.4 ms per 100 nmol/L irrespective of correction factor after adjustment for residual heart rate dependency. There was no significant effect of drug concentration on postural change in blood pressure or PR and QRS intervals. In mouse atria, the spontaneous beating rate was significantly reduced by amodiaquine (n = 6) and desethylamodiaquine (n = 8) at 3 µmol/L (amodiaquine: 10 ± 2%; desethylamodiaquine: 12 ± 3%) and 10 µmol/L (amodiaquine: 50 ± 7%; desethylamodiaquine: 46 ± 6%) concentrations with no significant difference in potency between the 2 compounds. CONCLUSION: Amodiaquine and desethylamodiaquine have concentration-dependent effects on heart rate, blood pressure, and ventricular repolarization.

Incidence and severity of cytomegalovirus infection in seropositive heart transplant recipients.

BACKGROUND: The frequency and significance of cytomegalovirus (CMV) infection in seropositive (R+) heart transplant recipients (HTR) is unclear, with preventative recommendations mostly extrapolated from other groups. We evaluated the incidence and severity of CMV infection in R+ HTR, to identify risk factors and describe outcomes. METHODS: R+ HTR from 2010 to 2019 were included. Antiviral prophylaxis was not routinely used, with clinically guided monitoring the local standard of care. The primary outcome was CMV infection within one-year post-transplant; secondary outcomes included other herpesvirus infections and mortality. RESULTS: CMV infection occurred in 27/155 (17%) R+ HTR. Patients with CMV had a longer hospitalization (27 vs. 20 days, unadjusted HR 1.02, 95% CI 1.00-1.02, p = .01), higher rate of intensive care readmission (26% vs. 9%, unadjusted HR 3.46, 1.46-8.20, p = .005), and increased mortality (33% vs. 8%, unadjusted HR 10.60, 4.52-24.88, p < .001). The association between CMV and death persisted after adjusting for multiple confounders (HR 24.19, 95% CI 7.47-78.30, p < .001). Valganciclovir prophylaxis was used in 35/155 (23%) and was protective against CMV (infection rate 4% vs. 27%, adjusted HR .07, .01-.72, p = .025), even though those receiving it were more likely to have received thymoglobulin (adjusted OR 10.5, 95% CI 2.01-55.0, p = .005). CONCLUSIONS: CMV infection is common in R+ HTR and is associated with a high burden of disease and increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection, despite being at higher risk. These findings support the routine use of antiviral prophylaxis following heart transplantation in all CMV R+ patients.

Quality of life in people living with HIV (the fourth 90) - are we there yet in Australia?

In 2014, UNAIDS outlined the 90-90-90 treatment targets. The "fourth 90" reflects the need to focus on optimising quality of life (HRQoL) in people living with HIV. Using a sample of non-heterosexual males in Melbourne, Australia, we aimed to assess HRQoL differences between HIV-positive and HIV-negative individuals, and identify factors that predict HRQoL both at baseline and after three years of follow up. Clinical information and patient-reported outcomes incorporating the Assessing Quality of Life-6D scale were collected at baseline and at three years. Sixty-two HIV-positive cases (antiretroviral therapy naïve at baseline) and 48 controls were enrolled. Results were compared between cases and controls at baseline, three-year follow-up, and between timepoints. HRQoL was significantly lower in cases compared to controls (83.5 (IQR 77.2-88.6) vs 87.3 (IQR 82.1-91.8), p = 0.022) at baseline, with increased depression and anxiety associated with reduced HRQoL in multivariate analysis. Mental health in cases improved between timepoints (75.0 (IQR 56.3-81.3) to 81.3 (IQR 62.5-81.3), p = 0.0428). No differences between the HRQoL of cases and controls were observed at three years. Increased mental health support may be required at commencement of antiretroviral therapy to enable similar levels of HRQoL between HIV-positive and HIV-negative individuals to be achieved.

Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis Associated With Mediastinal and Ovarian Teratomas: A Case Report.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common type of autoimmune encephalitis. Approximately 80% of patients with anti-NMDAR encephalitis are women. Tumors are detected in approximately 50% of female patients with anti-NMDAR encephalitis, of which 96% are ovarian teratomas. We describe the case of a 28-year-old woman diagnosed with anti-NMDAR encephalitis with mediastinal and bilateral ovarian teratomas in July 2019. The patient recovered following surgical management of the mediastinal mass and both ovarian teratomas, and immunotherapy. This case shows that teratomas can be found at multiple sites other than ovaries. Therefore, detecting teratomas using whole-body evaluation may be helpful for diagnosis and treatment.

Visual Aura in Non-Migraine Headaches: A Population Study.

BACKGROUND: Visual aura (VA) occurs mostly in migraine with aura (MA), but some case studies have reported aura in non-migraine headaches. Thus, information of VA in non-migraine headaches is scarce. Aim of this study was to investigate the prevalence and impact of VA in non-migraine headache and compare it with that of migraine headache. METHODS: This study was a nationwide population-based study. We used an internet-based headache diagnosis questionnaire to diagnose headache, and various modules to evaluate clinical features and comorbidities of participants with headache. We defined migraine headache as migraine and probable migraine (PM), whereas non-migraine headache was defined as a headache but not migraine or PM. VA was defined as a self-reporting VA rating scale score ≥ 3. RESULTS: Of the 3,030 participants, 1,431 (47.2%) and 507 (16.7%) had non-migraine headache and migraine headache, respectively. VA prevalence was much lower in the non-migraine headache group than in the migraine headache group (14.5% [207/1,431] vs. 26.0% [132/507], P < 0.001). In subjects with non-migraine headache, those with VA had a markedly higher number of headache days per 30 days (median [25th-75th percentiles]: 2.0 [1.0-5.0] vs. 2.0 [1.0-3.0], P < 0.001), and headache-related disability (6.0 [3.0-16.0] vs. 2.0 [0.0-7.0], P < 0.001) than those without VA. VA prevalence did not differ significantly according to age and sex. CONCLUSION: Non-migraine headache with VA patients had more severe symptoms than those without VA. These findings may improve the understanding of VA and the management of individuals with non-migraine headache.

Factors associated with the development of coronary artery disease in people with HIV.

BACKGROUND: People living with HIV (PLHIV) are at increased risk for coronary artery disease (CAD). This study aimed to describe the features associated with CAD in PLHIV. METHODS: A case ([n =160] PLHIV with CAD) control ([n =317] PLHIV matched by age and sex without CAD) study was performed at the Alfred Hospital, Melbourne, Australia (January 1996 and December 2018). Data collected included CAD risk factors, duration of HIV infection, nadir and at-event CD4+ T-cell counts, CD4:CD8 ratio, HIV viral load, and antiretroviral therapy exposure. RESULTS: Participants were predominantly male (n =465 [97.4%]), with a mean age of 53years. Traditional risk factors associated with CAD in univariate analysis included hypertension (OR 11.4 [95%CI 5.01, 26.33], P <0.001), current cigarette smoking (OR 2.5 [95% CI 1.22, 5.09], P =0.012), and lower high-density lipoprotein cholesterol (OR 0.14 [95%CI 0.05, 0.37], P <0.001). There was no association between duration of HIV infection, nadir or current CD4 cell count. However, current and ever exposure to abacavir (cases: 55 [34.4%]; controls: 79 [24.9%], P =0.023 and cases: 92 [57.5%]; controls: 154 [48.6%], P =0.048, respectively) was associated with CAD. In conditional logistic regression analysis, current abacavir use, current smoking, and hypertension remained significantly associated (aOR=1.87 [CI=1.14, 3.07], aOR=2.31 [1.32, 4.04], and aOR=10.30 [5.25, 20.20] respectively). CONCLUSION: Traditional cardiovascular risk factors and exposure to abacavir were associated with CAD in PLHIV. This study highlights that aggressive management of cardiovascular risk factors remains critical for reducing risk in PLHIV.

Revisiting frequencies of phonological sound classes in speech input: Change over time in child-directed speech.

The purpose of the current study was to revisit a controversial topic: whether frequencies of phonological consonant and vowel classes differ in speech directed to children and to adults. In addition, the current study investigated whether the frequency of phonological consonant and vowel classes changes with children's increasing chronological and/or developmental age. This study analyzed speech input from 44 adults to four different age groups of listeners (i.e., three groups of children at 6, 18, and 36 months of age and one group of adult listeners) in terms of frequency of occurrence of consonant and vowel classes. Results revealed that consonant stop, nasal, fricative and glide manner classes as well as all four consonant place classes were significantly different in speech directed to the four different age groups. A perspective is discussed to better understand the nature of frequency input of phonological sound classes.

Beta-Lactam Antibiotic Therapeutic Drug Monitoring in Critically Ill Patients: A Systematic Review and Meta-Analysis.

Therapeutic drug monitoring (TDM) of beta-lactam antibiotics is recommended to address the variability in exposure observed in critical illness. However, the impact of TDM-guided dosing on clinical outcomes remains unknown. We conducted a systematic review and meta-analysis on TDM-guided dosing and clinical outcomes (all-cause mortality, clinical cure, microbiological cure, treatment failure, hospital and intensive care unit length of stay, target attainment, antibiotic-related adverse events, and emergence of resistance) in critically ill patients with suspected or proven sepsis. Eleven studies (n = 1463 participants) were included. TDM-guided dosing was associated with improved clinical cure (relative risk, 1.17; 95% confidence interval [CI], 1.04 to 1.31), microbiological cure (RR, 1.14; 95% CI, 1.03 to 1.27), treatment failure (RR, 0.79; 95% CI, .66 to .94), and target attainment (RR, 1.85; 95% CI, 1.08 to 3.16). No associations with mortality and length of stay were found. TDM-guided dosing improved clinical and microbiological cure and treatment response. Larger, prospective, randomized trials are required to better assess the utility of beta-lactam TDM in critically ill patients.

Stronger memory representation after memory reinstatement during retrieval in the human hippocampus.

Memory retrieval allows us to reinstate previously encoded information but is also considered to contribute to memory enhancement. Retrieval-induced enhancement may involve processing to strengthen memory traces, but neural processing beyond reinstatement during retrieval remains elusive. Here, we show that hippocampal processing, different from memory reinstatement, exists during retrieval in the human brain. By tracking changes in the response patterns in the selected hippocampal and cortical regions over time during retrieval based on functional MRI, we found that the representation of associative memory in CA3/DG became stronger even after cortical memory reinstatement, while CA1 showed significant memory representation at retrieval onset with the cortical reinstatement, but not afterwards. This tendency was not observed in the condition without active retrieval. Moreover, subsequent long-term memory performance depended on the delayed CA3/DG representation during retrieval. These findings suggest that CA3/DG contributes to neural processing beyond memory reinstatement during retrieval, which may lead to memory enhancement.

False memory confidence depends on the prefrontal reinstatement of true memory.

For confidence of memory, a neural basis such as traces of stored memories should be required. However, because false memories have never been stored, the neural basis for false memory confidence remains unclear. Here we monitored the brain activity in participants while they viewed learned or novel objects, subsequently decided whether each presented object was learned and assessed their confidence levels. We found that when novel objects are presented, false memory confidence significantly depends on the shared representations with learned objects in the prefrontal cortex. However, such a tendency was not found in posterior regions including the visual cortex, which may be involved in the processing of perceptual gist. Furthermore, the confidence-dependent shared representations were not observed when participants correctly answered novel objects as non-learned objects. These results demonstrate that false memory confidence is critically based on the reinstatement of high-level semantic gist of stored memories in the prefrontal cortex.

Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial.

BACKGROUND: We aimed to examine cemiplimab, a programmed cell death 1 inhibitor, in the first-line treatment of advanced non-small-cell lung cancer with programmed cell death ligand 1 (PD-L1) of at least 50%. METHODS: In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing. FINDINGS: Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9-not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2-17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42-0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1-8·8) with cemiplimab versus 5·7 months (4·5-6·2) with chemotherapy (HR 0·54 [0·43-0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3-4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy. INTERPRETATION: Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Socio-demographic and trauma-related predictors of depression within eight weeks of motor vehicle collision in the AURORA study.

BACKGROUND: This is the first report on the association between trauma exposure and depression from the Advancing Understanding of RecOvery afteR traumA(AURORA) multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. METHODS: We focus on participants presenting at EDs after a motor vehicle collision (MVC), which characterizes most AURORA participants, and examine associations of participant socio-demographics and MVC characteristics with 8-week depression as mediated through peritraumatic symptoms and 2-week depression. RESULTS: Eight-week depression prevalence was relatively high (27.8%) and associated with several MVC characteristics (being passenger v. driver; injuries to other people). Peritraumatic distress was associated with 2-week but not 8-week depression. Most of these associations held when controlling for peritraumatic symptoms and, to a lesser degree, depressive symptoms at 2-weeks post-trauma. CONCLUSIONS: These observations, coupled with substantial variation in the relative strength of the mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated in more in-depth analyses of the rich and evolving AURORA database to find new targets for intervention and new tools for risk-based stratification following trauma exposure.

Prior histories of posttraumatic stress disorder and major depression and their onset and course in the three months after a motor vehicle collision in the AURORA study.

BACKGROUND: A better understanding of the extent to which prior occurrences of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) predict psychopathological reactions to subsequent traumas might be useful in targeting posttraumatic preventive interventions. METHODS: Data come from 1306 patients presenting to 29 U.S. emergency departments (EDs) after a motor vehicle collision (MVC) in the advancing understanding of recovery after trauma study. Patients completed self-reports in the ED and 2-weeks, 8-weeks, and 3-months post-MVC. Associations of pre-MVC probable PTSD and probable MDE histories with subsequent 3-months post-MVC probable PTSD and probable MDE were examined along with mediation through intervening peritraumatic, 2-, and 8-week disorders. RESULTS: 27.6% of patients had 3-month post-MVC probable PTSD and/or MDE. Pre-MVC lifetime histories of these disorders were not only significant (relative risk = 2.6-7.4) but were dominant (63.1% population attributable risk proportion [PARP]) predictors of this 3-month outcome, with 46.6% prevalence of the outcome among patients with pre-MVC disorder histories versus 9.9% among those without such histories. The associations of pre-MVC lifetime disorders with the 3-month outcome were mediated largely by 2- and 8-week probable PTSD and MDE (PARP decreasing to 22.8% with controls for these intervening disorders). Decomposition showed that pre-MVC lifetime histories predicted both onset and persistence of these intervening disorders as well as the higher conditional prevalence of the 3-month outcome in the presence of these intervening disorders. CONCLUSIONS: Assessments of pre-MVC PTSD and MDE histories and follow-ups at 2 and 8 weeks could help target early interventions for psychopathological reactions to MVCs.

Impact of delayed processing of positive blood cultures on organism detection: a prospective multi-centre study.

BACKGROUND: Blood cultures remain the gold standard investigation for the diagnosis of bloodstream infections. In many locations, quality-assured processing of positive blood cultures is not possible. One solution is to incubate blood cultures locally, and then transport bottles that flag positive to a central reference laboratory for organism identification and antimicrobial susceptibility testing. However, the impact of delay between the bottle flagging positive and subsequent sub-culture on the viability of the isolate has received little attention. METHODS: This study evaluated the impact of delays to sub-culture (22 h to seven days) in three different temperature conditions (2-8 °C, 22-27 °C and 35 ± 2 °C) for bottles that had flagged positive in automated detection systems using a mixture of spiked and routine clinical specimens. Ninety spiked samples for five common bacterial causes of sepsis (Escherichia coli, Haemophilus influenzae, Staphylococcus aureus, Streptococcus agalactiae and Streptococcus pneumoniae) and 125 consecutive positive clinical blood cultures were evaluated at four laboratories located in Cambodia, Lao PDR and Thailand. In addition, the utility of transport swabs for preserving organism viability was investigated. RESULTS: All organisms were recoverable from all sub-cultures in all temperature conditions with the exception of S. pneumoniae, which was less likely to be recoverable after longer delays (> 46-50 h), when stored in hotter temperatures (35 °C), and from BacT/ALERT when compared with BACTEC blood culture bottles. Storage of positive blood culture bottles in cooler temperatures (22-27 °C or below) and the use of Amies bacterial transport swabs helped preserve viability of S. pneumoniae. CONCLUSIONS: These results have practical implications for the optimal workflow for blood culture bottles that have flagged positive in automated detection systems located remotely from a central processing laboratory, particularly in tropical resource-constrained contexts.

Cassia alata, Coriandrum sativum, Curcuma longa and Azadirachta indica: Food Ingredients as Complementary and Alternative Therapies for Atopic Dermatitis-A Comprehensive Review.

Traditional medicine is critical in disease treatment and management. Herbs are gaining popularity for disease management and treatment. Therefore, they can be utilised as complementary and alternative treatment (CAT) ingredients. Atopic dermatitis (AD) is one of the common non-communicable diseases. It is characterised by chronic inflammatory skin disease with intense pruritus and eczematous lesions. AD is associated with oxidative stress, microbial infection, and upregulation of inflammatory cytokines. Both children and adults could be affected by this skin disorder. The prevalence of AD is increasing along with the country's level of development. This review revisited the literature on four medicinal herbs widely used as complementary medicine to manage AD. These therapeutic herbs are commonly eaten as food and used as spices in Asian cuisine. The four food herbs reviewed are Cassia alata, Coriandrum sativum, Curcuma longa Linn, and Azadirachta indica. Their traditional uses and phytochemical content will be covered. Four relevant pharmacological and biological activities of the plants crucial in AD management have been reviewed and discussed, including anti-inflammatory, anti-microbial, antioxidant, and wound recovery.

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis.

BACKGROUND: Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. METHODS AND FINDINGS: Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS: While caution is advised in the use of amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.