Phytochemical screening, antioxidant analyses, and in vitro and in vivo antimalarial activities of herbal medicinal plant - Rotheca serrata (L.) Steane & Mabb.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria is a major global health concern that is presently challenged by the emergence of Plasmodium falciparum (Pf) resistance to mainstay artemisinin-based combination therapies (ACTs). Hence, the discovery of novel and effective antimalarial drugs is pivotal to treating and controlling malaria. For many years, traditional plant-based herbal medicines have been employed in the treatment of various illnesses. Rotheca serrata (L.) Steane & Mabb. belongs to the Lamiaceae family that has been traditionally used to treat, cure, and prevent numerous diseases including malaria. AIM: The present investigation sought to assess the phytoconstituents, antioxidant, cytotoxicity, antimalarial activities of Rotheca serrata extract and its fractions. The in vitro antiplasmodial activity was assessed in chloroquine-sensitive Pf3D7 and artemisinin-resistant PfCam3.IR539T cultures, and the in vivo antimalarial activity was analyzed in Plasmodium berghei (Pb) ANKA strain-infected BALB/c mouse model. MATERIALS AND METHODS: The fresh leaves of Rotheca serrata were extracted in methanol (RsMeOH crude leaf extract). A portion of the extract was used to prepare successive solvent fractions using ethyl acetate (RsEA) and hexane (RsHex). The in vitro antiplasmodial activity was evaluated using [3H]-hypoxanthine incorporation assays against Pf3D7 and PfCam3.IR539T cultures. In vitro cytotoxicity study on HeLa, HEK-293T, and MCF-7 cell lines was carried out using MTT assay. The human red blood cells (RBCs) were used to perform the hemolysis assays. In vitro antioxidant studies and detailed phytochemical analysis were performed using GC-MS and FTIR. The four-day Rane's test was performed to evaluate the in vivo antimalarial activity against Pb ANKA strain-infected mice. RESULTS: Phytochemical quantification of Rotheca serrata extract (RsMeOH) and its fractions (RsEA and RsHex) revealed that RsMeOH crude extract and RsEA fraction had higher contents of total phenol and flavonoid than RsHex fraction. The RsEA fraction showed potent in vitro antiplasmodial activity against Pf3D7 and PfCam3.IR539T with IC50 values of 9.24 ± 0.52 µg/mL and 17.41 ± 0.43 µg/mL, respectively. The RsMeOH crude extract exhibited moderate antiplasmodial activity while the RsHex fraction showed the least antiplasmodial activity. The GC-MS and FTIR analysis of RsMeOH and RsEA revealed the presence of triterpenes, phenols, and hydrocarbons as major constituents. The RsMeOH crude extract was non-hemolytic and non-cytotoxic to HeLa, HEK-293T, and MCF-7 cell lines. The in vivo studies showed that a 1200 mg/kg dose of RsMeOH crude extract could significantly suppress parasitemia by ∼63% and prolong the survival of treated mice by ∼10 days. The in vivo antiplasmodial activity of RsMeOH was better than the RsEA fraction. CONCLUSION: The findings of this study demonstrated that traditionally used herbal medicinal plants like R. serrata provide a platform for the identification and isolation of potent bioactive phytochemicals that in turn can promote the antimalarial drug research. RsMeOH crude extract and RsEA fraction showed antiplasmodial, antimalarial and antioxidant activities. Chemical fingerprinting analysis suggested the presence of bioactive phytocompounds that are known for their antimalarial effects. Further detailed investigations on RsMeOH crude extract and RsEA fraction would be needed for the identification of the entire repertoire of the active antimalarial components with potent pharmaceutical and therapeutic values.

Antimalarial activity of Toona ciliata MJ Roem aqueous methanolic leaf extract and its antioxidant and phytochemical properties.

Background and aim: Malaria is a global health issue causing substantial morbidity and mortality. Screening of various traditionally important medicinal plants is a key source for the discovery of new antimalarials. We evaluated the antimalarial and antioxidant activities, and performed detailed phytochemical analyses of Toona ciliata MJ Roem aqueous methanolic leaf extract (TcMLE). Experimental procedures: In vitro antiplasmodial studies in Plasmodium falciparum (Pf) 3D7 and PfCam3.IR539T strains were performed by [3H]-hypoxanthine uptake assays. In vitro cytotoxicity in HeLa and HEK293T cell lines was evaluated using MTT assays. Hemolysis assay was performed using RBCs. Phytochemical analysis by GC-MS and in vitro antioxidant studies by DPPH and ABTS assays were performed. In vivo antimalarial studies in Pb-infected mice were carried out using Rane's test and Peters' 4-day test. Results and conclusions: TcMLE showed significant in vitro antioxidant activity and had phytochemicals reported for antimalarial activity. In vitro studies showed prominent antiplasmodial activity against Pf3D7 strain (IC50 ∼22 µg/ml) and PfCam3. IR539Tstrain (IC50 value ∼43 µg/ml). In vitro cytotoxicity studies, in vitro hemolytic assays, and in vivo acute toxicity studies further suggested that TcMLE is nontoxic. In vivo antimalarial studies using Rane's test showed a significant decrease in parasitemia by ∼70% at 1200 mg/kg doses and delayed the mortality of mice by ∼10-14 days. Peters' 4-day test also showed a similar pattern. The present study demonstrated the antimalarial potential of TcMLE. These findings deliver a platform for further studies to identify the active components of TcMLE and discover new antimalarials.

Can we predict motion artifacts in clinical MRI before the scan completes?

Subject motion can cause artifacts in clinical MRI, frequently necessitating repeat scans. We propose to alleviate this inefficiency by predicting artifact scores from partial multi-shot multi-slice acquisitions, which may guide the operator in aborting corrupted scans early.

Clinical evaluation of k-space correlation informed motion artifact detection in segmented multi-slice MRI.

Motion artifacts can negatively impact diagnosis, patient experience, and radiology workflow especially when a patient recall is required. Detecting motion artifacts while the patient is still in the scanner could potentially improve workflow and reduce costs by enabling immediate corrective action. We demonstrate in a clinical k-space dataset that using cross-correlation between adjacent phase-encoding lines can detect motion artifacts directly from raw k-space in multi-shot multi-slice scans. We train a split-attention residual network to examine the performance in predicting motion artifact severity. The network is trained on simulated data and tested on real clinical data.

Significance of Plasmodium berghei Amino Acid Transporter 1 in Food Vacuole Functionality and Its Association with Cerebral Pathogenesis.

The food vacuole plays a central role in the blood stage of parasite development by digesting host hemoglobin acquired from red blood cells and detoxifying the host heme released during hemoglobin digestion into hemozoin. Blood-stage parasites undergo periodic schizont bursts, releasing food vacuoles containing hemozoin. Clinical studies in malaria-infected patients and in vivo animal studies have shown the association of hemozoin with disease pathogenesis and abnormal host immune responses in malaria. Here, we perform a detailed in vivo characterization of putative Plasmodium berghei amino acid transporter 1 localized in the food vacuole to understand its significance in the malaria parasite. We show that the targeted deletion of amino acid transporter 1 in Plasmodium berghei leads to a swollen food vacuole phenotype with the accumulation of host hemoglobin-derived peptides. Plasmodium berghei amino acid transporter 1-knockout parasites produce less hemozoin, and the hemozoin crystals display a thin morphology compared with wild-type parasites. The knockout parasites show reduced sensitivity to chloroquine and amodiaquine by showing recrudescence. More importantly, mice infected with the knockout parasites are protected from cerebral malaria and display reduced neuronal inflammation and cerebral complications. Genetic complementation of the knockout parasites restores the food vacuole morphology with hemozoin levels similar to that of wild-type parasites, causing cerebral malaria in the infected mice. The knockout parasites also show a significant delay in male gametocyte exflagellation. Our findings highlight the significance of amino acid transporter 1 in food vacuole functionality and its association with malaria pathogenesis and gametocyte development. IMPORTANCE Food vacuoles of the malaria parasite are involved in the degradation of red blood cell hemoglobin. The amino acids derived from hemoglobin degradation support parasite growth, and the heme released is detoxified into hemozoin. Antimalarials such as quinolines target hemozoin formation in the food vacuole. Food vacuole transporters transport hemoglobin-derived amino acids and peptides from the food vacuole to the parasite cytosol. Such transporters are also associated with drug resistance. Here, we show that the deletion of amino acid transporter 1 in Plasmodium berghei leads to swollen food vacuoles with the accumulation of hemoglobin-derived peptides. The transporter-deleted parasites generate less hemozoin with thin crystal morphology and show reduced sensitivity to quinolines. Mice infected with transporter-deleted parasites are protected from cerebral malaria. There is also a delay in male gametocyte exflagellation, affecting transmission. Our findings uncover the functional significance of amino acid transporter 1 in the life cycle of the malaria parasite.

Joint Frequency and Image Space Learning for MRI Reconstruction and Analysis.

We propose neural network layers that explicitly combine frequency and image feature representations and show that they can be used as a versatile building block for reconstruction from frequency space data. Our work is motivated by the challenges arising in MRI acquisition where the signal is a corrupted Fourier transform of the desired image. The proposed joint learning schemes enable both correction of artifacts native to the frequency space and manipulation of image space representations to reconstruct coherent image structures at every layer of the network. This is in contrast to most current deep learning approaches for image reconstruction that treat frequency and image space features separately and often operate exclusively in one of the two spaces. We demonstrate the advantages of joint convolutional learning for a variety of tasks, including motion correction, denoising, reconstruction from undersampled acquisitions, and combined undersampling and motion correction on simulated and real world multicoil MRI data. The joint models produce consistently high quality output images across all tasks and datasets. When integrated into a state of the art unrolled optimization network with physics-inspired data consistency constraints for undersampled reconstruction, the proposed architectures significantly improve the optimization landscape, which yields an order of magnitude reduction of training time. This result suggests that joint representations are particularly well suited for MRI signals in deep learning networks. Our code and pretrained models are publicly available at https://github.com/nalinimsingh/interlacer.

"I would watch her with awe as she swallowed the first handful": A qualitative study of pediatric multidrug-resistant tuberculosis experiences in Durban, South Africa.

BACKGROUND: There are limited data on the experiences of children being treated for drug-resistant tuberculosis (DR-TB), and most work in the area has been done with older children and adolescents. Comprehensive explorations of the caregiver experiences in this area are also lacking. OBJECTIVE: To describe the experiences of being treated for drug-resistant tuberculosis of children and their caregivers. METHODS: This was a qualitative study done using focus group discussions (FGDs) among three different groups of participants: 1) health care providers involved in the care of children being treated for DR-TB (including physicians, nurses, and pharmacists)-herein referred to as providers; 2) household caregivers of children being treated for DR-TB-herein referred to as caregivers; and 3) children who were being treated for DR-TB-herein referred to as children. The population was a convenience sample and included children hospitalized between January 1, 2018, and June 30, 2020, ages 0-14 years old, as well as their caregivers and providers. Focus group transcripts and notes were analysed using a thematic network analysis based in grounded theory The analysis was iterative and the coding system developed focused on "stressful experiences" as well as ways to address them along the diagnostic and treatment journey. This paper follows the COREQ guidelines. RESULTS: 16 children between the ages 7 and 14 years participated in 5 FGDs, 30 caregivers participated in 7 FGDs, and 12 providers participated in 3 FDGs. Data from the children and the caregivers were the focus of this analysis, although some themes were informed by the discussions with the providers as well. In general, it was reported that for a child diagnosed with DR-TB, there is a lived experience of stress that impacts their physical, mental, and social well-being. These pediatric patients and their families therefore develop strategies for coping with these disruptions to their lives. In general, there were major disruptive experiences that resulted from the process around receiving a diagnosis of DR-TB and second distinct set of stressful experiences that occurred during the treatment of DR-TB once the diagnosis had been made. These stresses occur in the physical, mental, and social realms, and families develop multiple strategies to cope with them, demonstrating resilience in the face of this disease. CONCLUSION: Addressing the stresses experienced by children and their caregivers through child-friendly DR-TB testing, treatment, and counseling is not only essential for ending TB but also for enacting a human-rights based approach to child health in general. Children with DR-TB are a vulnerable population, and they have often been the last to benefit from advances in general pediatric care and in DR-TB care more specifically.

Phytochemical screening, cytotoxicity assessment and evaluation of in vitro antiplasmodial and in vivo antimalarial activities of Mentha spicata L. methanolic leaf extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria causes extensive morbidity and mortality, and the decreasing efficacy of artemisinin and its partner drugs has posed a serious concern. Therefore, it is important to identify new antimalarials, and the natural compounds from plants provide a promising platform. Mentha spicata L. representing the Lamiaceae family has been used in traditional medicine for various diseases including malaria. AIM OF THE STUDY: This study was aimed at evaluating the antiplasmodial activity of M. spicata methanolic leaf extract using Plasmodium falciparum (Pf) cultures (Pf3D7 and artemisinin (ART)-resistant PfCam3.IR539T strains) and antimalarial activity using Plasmodium berghei (Pb)-infected mice. Dry leaf powder and methanolic leaf extract were examined for in vivo antimalarial activity and the efficacy of oral versus parenteral administration was compared. MATERIALS AND METHODS: Leaves of M. spicata were collected and extracted using 70% methanol in water (v/v). [3H]-hypoxanthine incorporation assays and Giemsa-stained smears were used to assess the in vitro antiplasmodial activity of M. spicata methanolic extract against Pf3D7 and ART-resistant PfCam3.IR539T strains. Cytotoxicity was evaluated in HeLa and HEK-293T cell lines using MTT assays. Hemolysis assays were performed using red blood cells (RBCs). In vivo antimalarial activities of M. spicata dry leaf powder and methanolic leaf extract were examined in P. berghei-infected mice by Rane's curative test and Peters' 4-day suppressive test. RESULTS: Phytochemical screening of M. spicata methanolic leaf extract indicated the presence of reducing sugars, phenolic compounds, flavonoids, glycosides, sterols, saponins, alkaloids, coumarins, tannins, carbohydrates, and proteins. In vitro studies carried out using Pf cultures showed that M. spicata methanolic leaf extract had significant antiplasmodial activity against Pf3D7 cultures with a 50% inhibitory concentration (IC50) of 57.99 ± 2.82 µg/ml. The extract was also effective against ART-resistant PfCam3.IR539T strain with an IC50 of 71.23 ± 3.85 µg/ml. The extract did not show significant in vitro cytotoxicity, hemolysis, and in vivo toxicity. In vivo studies performed using Pb-infected mice treated with M. spicata dry leaf powder and methanolic leaf extract showed ∼50% inhibition in parasite growth at 1500 mg/kg and 1000 mg/kg doses, respectively. There was also a significant delay in the mortality of treated mice. Parenteral administration was found to be appropriate for the in vivo treatment. CONCLUSIONS: Our in vitro and in vivo findings from Pf and Pb parasites suggested the therapeutic potential of M. spicata leaf extract as an antimalarial. M. spicata leaf extract could also inhibit the growth of ART-resistant Pf strain. Further studies on fractionation and active component analysis of M. spicata leaf extract would be required to identify the bioactive phytochemicals having pharmaceutical and therapeutic values. Such efforts would help us in developing new antimalarials to combat malaria.

How Machine Learning is Powering Neuroimaging to Improve Brain Health.

This report presents an overview of how machine learning is rapidly advancing clinical translational imaging in ways that will aid in the early detection, prediction, and treatment of diseases that threaten brain health. Towards this goal, we aresharing the information presented at a symposium, "Neuroimaging Indicators of Brain Structure and Function - Closing the Gap Between Research and Clinical Application", co-hosted by the McCance Center for Brain Health at Mass General Hospital and the MIT HST Neuroimaging Training Program on February 12, 2021. The symposium focused on the potential for machine learning approaches, applied to increasingly large-scale neuroimaging datasets, to transform healthcare delivery and change the trajectory of brain health by addressing brain care earlier in the lifespan. While not exhaustive, this overview uniquely addresses many of the technical challenges from image formation, to analysis and visualization, to synthesis and incorporation into the clinical workflow. Some of the ethical challenges inherent to this work are also explored, as are some of the regulatory requirements for implementation. We seek to educate, motivate, and inspire graduate students, postdoctoral fellows, and early career investigators to contribute to a future where neuroimaging meaningfully contributes to the maintenance of brain health.

Adherence Measured Using Electronic Dose Monitoring is Associated with Emergent Antiretroviral Resistance and Poor Outcomes in People with Human Immunodeficiency Virus/AIDS and Multidrug-Resistant Tuberculosis.

BACKGROUND: Medication adherence is known to challenge treatment of human immunodeficiency virus (HIV)/AIDS and multidrug-resistant tuberculosis (MDR-TB). We hypothesized that adherence using electronic dose monitoring (EDM) would identify an antiretroviral therapy (ART) adherence threshold for emergent ART resistance and predict treatment outcomes in patients with MDR-TB and HIV on ART and bedaquiline-containing TB regimens. METHODS: A prospective cohort of adults with MDR-TB and HIV on ART and initiating MDR-TB treatment with bedaquiline were enrolled at a public hospital in KwaZulu-Natal, South Africa (PRAXIS Study). Participants received separate EDM devices that measure adherence to bedaquiline and ART (nevirapine or lopinavir/ritonavir). Adherence was calculated cumulatively over 6 months. Participants were followed through completion of MDR-TB treatment. HIV genome sequencing was performed at baseline and 2 and 6 months on samples with HIV RNA ≥1000 copies/mL. RESULTS: From November 2016 through February 2018, 198 persons with MDR-TB and HIV were enrolled and followed (median, 17.2 months; interquartile range, 12.2-19.6). Eleven percent had baseline ART resistance mutations, and 7.5% developed emergent ART resistance at 6 months. ART adherence was independently associated with ART resistance and mortality. Modeling identified a significant (P < .001), linear association between ART adherence and emergent resistance, suggesting a strong association without a specific threshold. CONCLUSIONS: Our findings highlight the need for ART resistance testing, especially in patients with MDR-TB and HIV, which is currently not the standard of care in resource-limited settings. Despite short follow-up duration, reduced ART adherence was significantly associated with emergent resistance and increased mortality. CLINICAL TRIALS REGISTRATION: NCT03162107.

A deep learning system for differential diagnosis of skin diseases.

Skin conditions affect 1.9 billion people. Because of a shortage of dermatologists, most cases are seen instead by general practitioners with lower diagnostic accuracy. We present a deep learning system (DLS) to provide a differential diagnosis of skin conditions using 16,114 de-identified cases (photographs and clinical data) from a teledermatology practice serving 17 sites. The DLS distinguishes between 26 common skin conditions, representing 80% of cases seen in primary care, while also providing a secondary prediction covering 419 skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was non-inferior to six other dermatologists and superior to six primary care physicians (PCPs) and six nurse practitioners (NPs) (top-1 accuracy: 0.66 DLS, 0.63 dermatologists, 0.44 PCPs and 0.40 NPs). These results highlight the potential of the DLS to assist general practitioners in diagnosing skin conditions.

Goats decrease hindlimb stiffness when walking over compliant surfaces.

Leg stiffness, commonly estimated as the 'compression' of a defined leg element in response to a load, has long been used to characterize terrestrial locomotion. This study investigated how goats adjust the stiffness of their hindlimbs to accommodate surfaces of different stiffness. Goats provide a compelling animal model for studying leg stiffness modulation, because they skillfully ambulate over a range of substrates that vary in compliance. To investigate the adjustments that goats make when walking over such substrates, ground reaction forces and three-dimensional trajectories of hindlimb markers were recorded as goats walked on rigid, rubber and foam surfaces. Net joint moments, power and work at the hip, knee, ankle and metatarsophalangeal joints were estimated throughout stance via inverse dynamics. Hindlimb stiffness was estimated from plots of total leg force versus total leg length, and individual joint stiffness was estimated from plots of joint moment versus joint angle. Our results support the hypothesis that goats modulate hindlimb stiffness in response to surface stiffness; specifically, hindlimb stiffness decreased on the more compliant surfaces (P<0.002). Estimates of joint stiffness identified hip and ankle muscles as the primary drivers of these adjustments. When humans run on compliant surfaces, they generally increase leg stiffness to preserve their center-of-mass mechanics. We did not estimate center-of-mass mechanics in this study; nevertheless, our estimates of hindlimb stiffness suggest that goats exhibit a different behavior. This study offers new insight into mechanisms that allow quadrupeds to modulate their gait mechanics when walking on surfaces of variable compliance.

High treatment success rate for multidrug-resistant and extensively drug-resistant tuberculosis using a bedaquiline-containing treatment regimen.

South African patients with rifampicin-resistant tuberculosis (TB) and resistance to fluoroquinolones and/or injectable drugs (extensively drug-resistant (XDR) and preXDR-TB) were granted access to bedaquiline through a clinical access programme with strict inclusion and exclusion criteria.PreXDR-TB and XDR-TB patients were treated with 24 weeks of bedaquiline within an optimised, individualised background regimen that could include levofloxacin, linezolid and clofazimine as needed. 200 patients were enrolled: 87 (43.9%) had XDR-TB, 99 (49.3%) were female and the median age was 34 years (interquartile range (IQR) 27-42). 134 (67.0%) were living with HIV; the median CD4+ count was 281 cells·µL-1 (IQR 130-467) and all were on antiretroviral therapy.16 out of 200 patients (8.0%) did not complete 6 months of bedaquiline: eight were lost to follow-up, six died, one stopped owing to side effects and one was diagnosed with drug-sensitive TB. 146 out of 200 patients (73.0%) had favourable outcomes: 139 (69.5%) were cured and seven (3.5%) completed treatment. 25 patients (12.5%) died, 20 (10.0%) were lost from treatment and nine (4.5%) had treatment failure. 22 adverse events were attributed to bedaquiline, including a QT interval corrected using the Fridericia formula (QTcF) >500 ms (n=5), QTcF increase >50 ms from baseline (n=11) and paroxysmal atrial flutter (n=1).Bedaquiline added to an optimised background regimen was associated with a high rate of successful treatment outcomes for this preXDR-TB and XDR-TB cohort.

Molecular Docking for Prediction and Interpretation of Adverse Drug Reactions.

AIM AND OBJECTIVE: Adverse drug reactions (ADRs) present a major burden for patients and the healthcare industry. Various computational methods have been developed to predict ADRs for drug molecules. However, many of these methods require experimental or surveillance data and cannot be used when only structural information is available. MATERIALS AND METHODS: We collected 1,231 small molecule drugs and 600 human proteins and utilized molecular docking to generate binding features among them. We developed machine learning models that use these docking features to make predictions for 1,533 ADRs. RESULTS: These models obtain an overall area under the receiver operating characteristic curve (AUROC) of 0.843 and an overall area under the precision-recall curve (AUPR) of 0.395, outperforming seven structural fingerprint-based prediction models. Using the method, we predicted skin striae for fluticasone propionate, dermatitis acneiform for mometasone, and decreased libido for irinotecan, as demonstrations. Furthermore, we analyzed the top binding proteins associated with some of the ADRs, which can help to understand and/or generate hypotheses for underlying mechanisms of ADRs. CONCLUSION: Machine learning combined with molecular docking can help to predict ADRs for drug molecules and provide possible explanations for the ADR mechanisms.

Risk of Nephrotoxicity in Patients With Drug-Resistant Tuberculosis Treated With Kanamycin/Capreomycin With or Without Concomitant Use of Tenofovir-Containing Antiretroviral Therapy.

BACKGROUND: The intersection of HIV and drug-resistant (DR) tuberculosis (TB) presents the challenge of managing convergent drug toxicities. METHODS: We conducted a retrospective study of adult patients with DR-TB treated with a kanamycin/capreomycin-based (KM) regimen, with or without concomitant antiretroviral therapy (ART). We estimated the incidence of nephrotoxicity (defined as an increase in serum creatinine greater than 26.5 µmol, or an increase in serum creatinine to 1.5 times the baseline value, or a decline in glomerular filtration rate to less than 60 mL/min/1.73 m), and evaluated the association between reported drug use and nephrotoxicity using Kaplan-Meier plots. RESULTS: A total of 215 patients with DR-TB were treated with a kanamycin/capreomycin-based regimen, with or without concomitant ART. The incidence rate of nephrotoxicity was 3.6 [95% confidence interval (CI): 1.4 to 7.3], 6.9 (95% CI: 5.2 to 9.0), and 12 (95% CI: 3.3 to 30.9) cases per 100 person-months of follow-up in the KM only group (n = 42), the KM + TDF (tenofovir disoproxil fumarate) group (n = 163), and the KM + Other ART group (n = 10), respectively. Using the KM only group as a reference, the hazard ratio was 2.06 (95% CI: 0.92 to 4.63) in the KM + TDF group, and 4.09 (95% CI: 1.17 to 14.25) in the KM + Other ART group. Advancing age was an independent predictor of nephrotoxicity (adjusted hazard ratio 1.29, 95% CI: 1.14 to 1.46). CONCLUSIONS: Our findings provide evidence of a significant risk of nephrotoxicity during treatment with a kanamycin/capreomycin-based DR-TB regimen, with or without concurrent treatment with ART. This study lends further support to calls for the substitution of TDF during the intensive phase of DR-TB treatment and for close monitoring of renal function during DR-TB treatment, especially in settings where the use of kanamycin/capreomycin is unavoidable.

National survey of infection control programmes in South Asian association for Regional Cooperation countries in the era of patient safety.

BACKGROUND: The implementation of hospital infection prevention and control (IPC) in south Asia is not well described. We aimed to assess IPC programmes in hospitals in this region and explore opportunities for improvement. METHODS: Attendees from hospitals in the South Asian Association for Regional Cooperation (SAARC) region who were at one of four National Initiative for Patient Safety workshops organised by All India Institute of Medical Sciences (New Delhi) from 2009 to 2012 were invited to complete a semi-structured questionnaire. The survey addressed six main components of IPC programmes. RESULTS: We received responses from 306 participants from 82 hospitals. Five key opportunities for improvement emerged: (1) lack of healthcare epidemiologists, (2) relative infrequency of antibiotic guidelines (53%) and prescribing audits (33%) (3) lack of awareness of needle stick injury rates (84%) (4) only 47% of hospitals were prepared for surge capacity for patients with infectious diseases, and (5) limited coordination of hospital infection control personnel with other support services (55%-66%). CONCLUSION: These results outline IPC challenges in the SAARC region and may be useful to guide future quality improvement initiatives.

Evaluation of diphenhydramine in talc induced type 2 diabetes mellitus in Wistar rats.

Evaluation of diphenhydramine in talc induced type 2 diabetes mellitus was done in Wistar rats. Oral administration of Talc (10mg/kg)carried out for 21days increased the levels of serum glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), serum creatinine, blood glucose, urea, uric acid and triglycerides (TGs), but when the animals were treated with diphenhydramine (DPH), the levels of the aforementioned biochemical parameters decreased significantly (p<0.0001). The level of serum cholesterol and high density lipoprotein (HDL) was found to be reduced in Diabetes Mellitus (DM) control and when it was treated with DPH control animals, these makers increased significantly. The study done on DM and Diphenhydramine suggests that Talc increases the blood glucose level at a dose of 10mg/kg (0.14gm) and Diphenhydramine (1mg/kg)reduces the increased blood glucose level. These finding simply that diphenhydramine may be useful in the management of talc induced diabetes.

Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis.

BACKGROUND: The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. METHODS: We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. FINDINGS: We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. INTERPRETATION: Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori. FUNDING: World Health Organization.