CBP/p300 activation promotes axon growth, sprouting, and synaptic plasticity in chronic experimental spinal cord injury with severe disability.

The interruption of spinal circuitry following spinal cord injury (SCI) disrupts neural activity and is followed by a failure to mount an effective regenerative response resulting in permanent neurological disability. Functional recovery requires the enhancement of axonal and synaptic plasticity of spared as well as injured fibres, which need to sprout and/or regenerate to form new connections. Here, we have investigated whether the epigenetic stimulation of the regenerative gene expression program can overcome the current inability to promote neurological recovery in chronic SCI with severe disability. We delivered the CBP/p300 activator CSP-TTK21 or vehicle CSP weekly between week 12 and 22 following a transection model of SCI in mice housed in an enriched environment. Data analysis showed that CSP-TTK21 enhanced classical regenerative signalling in dorsal root ganglia sensory but not cortical motor neurons, stimulated motor and sensory axon growth, sprouting, and synaptic plasticity, but failed to promote neurological sensorimotor recovery. This work provides direct evidence that clinically suitable pharmacological CBP/p300 activation can promote the expression of regeneration-associated genes and axonal growth in a chronic SCI with severe neurological disability.

Dysregulated expression of cholesterol biosynthetic genes in Alzheimer's disease alters epigenomic signatures of hippocampal neurons.

Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer's disease, with epigenome alterations as a contributing factor. Here, we compared transcriptomic/epigenomic changes in the hippocampus, modified by aging and by tauopathy, an AD-related feature. We show that the cholesterol biosynthesis pathway is severely impaired in hippocampal neurons of tauopathic but not of aged mice pointing to vulnerability of these neurons in the disease. At the epigenomic level, histone hyperacetylation was observed at neuronal enhancers associated with glutamatergic regulations only in the tauopathy. Lastly, a treatment of tau mice with the CSP-TTK21 epi-drug that restored expression of key cholesterol biosynthesis genes counteracted hyperacetylation at neuronal enhancers and restored object memory. As acetyl-CoA is the primary substrate of both pathways, these data suggest that the rate of the cholesterol biosynthesis in hippocampal neurons may trigger epigenetic-driven changes, that may compromise the functions of hippocampal neurons in pathological conditions.

Study of Glass Formation and Crystallization Kinetics in a 2D Metal Halide Perovskite Using Ultrafast Calorimetry.

While crystalline 2D metal halide perovskites (MHPs) represent a well-celebrated semiconductor class, supporting applications in the fields of photovoltaics, emitters, and sensors, the recent discovery of glass formation in an MHP opens many new opportunities associated with reversible glass-crystalline switching, with each state offering distinct optoelectronic properties. However, the previously reported [S-(-)-1-(1-naphthyl)ethylammonium]2PbBr4 perovskite is a strong glass former with sluggish glass-crystal transformation time scales, pointing to a need for glassy MHPs with a broader range of compositions and crystallization kinetics. Herein we report glass formation for low-melting-temperature 1-MeHa2PbI4 (1-MeHa = 1-methyl-hexylammonium) using ultrafast calorimetry, thereby extending the range of MHP glass formation across a broader range of organic (fused ring to branched aliphatic) and halide (bromide to iodide) compositions. The importance of a slight loss of organic and hydrogen iodide components from the MHP in stabilizing the glassy state is elucidated. Furthermore, the underlying kinetics of glass-crystal transformation, including activation energies, crystal growth rate, Angell plot, and fragility index, is studied using a combination of kinetic, thermodynamic, and rheological modeling techniques. An inferred fast crystal growth rate of 0.21 m/s for 1-MeHa2PbI4 shows promise toward suitability in extended application spaces, for example, in metamaterials, nonvolatile memory, and optical and neuromorphic computing devices.

HAT: haplotype assembly tool using short and error-prone long reads.

MOTIVATION: Haplotypes are the set of alleles co-occurring on a single chromosome and inherited together to the next generation. Because a monoploid reference genome loses this co-occurrence information, it has limited use in associating phenotypes with allelic combinations of genotypes. Therefore, methods to reconstruct the complete haplotypes from DNA sequencing data are crucial. Recently, several attempts have been made at haplotype reconstructions, but significant limitations remain. High-quality continuous haplotypes cannot be created reliably, particularly when there are few differences between the homologous chromosomes. RESULTS: Here, we introduce HAT, a haplotype assembly tool that exploits short and long reads along with a reference genome to reconstruct haplotypes. HAT tries to take advantage of the accuracy of short reads and the length of the long reads to reconstruct haplotypes. We tested HAT on the aneuploid yeast strain Saccharomyces pastorianus CBS1483 and multiple simulated polyploid datasets of the same strain, showing that it outperforms existing tools. AVAILABILITY AND IMPLEMENTATION: https://github.com/AbeelLab/hat/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Meltable Hybrid Antimony and Bismuth Iodide One-Dimensional Perovskites.

Hybrid lead-halide perovskites have been studied extensively for their promising optoelectronic properties and prospective applications, including photovoltaics, solid-state lighting, and radiation detection. Research into these materials has also been aided by the simple and low-temperature synthetic conditions involved in solution-state deposition/crystallization or melt-processing techniques. However, concern over lead toxicity has plagued the field since its infancy. One of the most promising routes to mitigating toxicity in hybrid perovskite materials is substituting isoelectronic Bi(III) for Pb(II). Various methods have been developed to allow pnictide-based systems to capture properties of the Pb(II) analogues, but the ability to melt extended hybrid pnictide-halide materials has not been investigated. In this work, we prepare a series of one-dimensional antimony- and bismuth-iodide hybrid materials employing tetramethylpiperazinium (TMPZ)-related cations. We observe, for the first time, the ability to melt extended hybrid pnictide-halide materials for both the Sb(III) and Bi(III) systems. Additionally, we find that Sb(III) analogues melt at lower temperatures and attribute this observation to structural changes induced by the increased stereochemical activity of the Sb(III) lone pair coupled with the reduction in effective dimensionality due to steric interactions with the organic cations. Finally, we demonstrate the ability to melt process phase pure thin films of (S-MeTMPZ)SbI5.

Kinetically Controlled Structural Transitions in Layered Halide-Based Perovskites: An Approach to Modulate Spin Splitting.

Two-dimensional hybrid organic-inorganic perovskite (HOIP) semiconductors with pronounced spin splitting, mediated by strong spin-orbit coupling and inversion symmetry breaking, offer the potential for spin manipulation in future spintronic applications. However, HOIPs exhibiting significant conduction/valence band splitting are still relatively rare, given the generally observed preference for (near)centrosymmetric inorganic (especially lead-iodide-based) sublattices, and few approaches are available to control this symmetry breaking within a given HOIP. Here, we demonstrate, using (S-2-MeBA)2PbI4 (S-2-MeBA = (S)-(-)-2-methylbutylammonium) as an example, that a temperature-induced structural transition (at ∼180 K) serves to change the degree of chirality transfer to and inversion symmetry breaking within the inorganic layer, thereby enabling modulation of HOIP structural and electronic properties. The cooling rate is shown to dictate whether the structural transition occurs─i.e., slow cooling induces the transition while rapid quenching inhibits it. Ultrafast calorimetry indicates a minute-scale structural relaxation time at the transition temperature, while quenching to lower temperatures allows for effectively locking in the metastable room-temperature phase, thus enabling kinetic control over switching between distinct states with different degrees of structural distortions within the inorganic layers at these temperatures. Density functional theory further highlights that the low-temperature phase of (S-2-MeBA)2PbI4 shows more significant spin splitting relative to the room-temperature phase. Our work opens a new pathway to use kinetic control of crystal-to-crystal transitions and thermal cycling to modulate spin splitting in HOIPs for future spintronic applications, and further points to using such "sluggish" phase transitions for switching and control over other physical phenomena, particularly those relying on structural distortions and lattice symmetry.

Using plant data to estimate biodegradable COD fractions - case study kwaMashu WWTP.

A modelling study is under way in preparation for a planned upgrade of the capacity of the kwaMashu WWTP in eThekwini, South Africa, from 50 to 80 ML/d. When the configuration of an existing plant is to be changed, the most critical part of the model calibration is the influent wastewater fractionation. However, the constantly varying characteristics of wastewater make experimental determination of an adequately representative set of components difficult, time-consuming and expensive, which constitutes significant barriers to the adoption of modelling by many municipalities. Compliance and process monitoring generate large sets of influent measurements of chemical oxygen demand (COD), free and saline ammonia (FSA), total suspended solids (TSS), etc., but these are insufficient for modelling purposes. In particular, biodegradability is not routinely measured. However, since influent fractionation is designed to predict the fate of material in the wastewater treatment process, it should be possible to infer the fractionation from a combination of influent and plant measurements. This case study demonstrates the application of a pair of modelling tools, a probabilistic influent fractionator and a simplified steady­state plant­wide model, to estimate the influent fractionation, together with certain unmeasured or unreliable operational parameters.

Multiple Cycles of Granulocyte Colony-Stimulating Factor Increase Survival Times of Patients With Decompensated Cirrhosis in a Randomized Trial.

BACKGROUND & AIMS: There is controversy regarding the inclusion of granulocyte colony stimulating factor (G-CSF) in the treatment of decompensated cirrhosis. Previous studies tested only a single cycle of G-CSF administration or were underpowered to detect changes in survival time. We performed an adequately powered study to determine whether multiple cycles of G-CSF increased the survival of patients 1 year after the start of therapy. METHODS: We conducted an open-label trial of 100 patients with decompensated cirrhosis without acute-on-chronic liver failure at a tertiary center from July 2016 through June 2018. The patients were assigned randomly to a group given 5 days of G-CSF every 3 months, with standard medical therapy, in 4 cycles (group A, n = 50), or standard medical therapy alone (group B, n = 50). The primary outcome was survival for 12 months after treatment began. Secondary outcomes were an increase in the number of CD34+ cells at day 6 compared with day 0, along with reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased control of ascites, reduced decompensation and episodes of infection, fewer hospitalizations, lower liver stiffness measurements, increased quality of life and nutrition, fulfilment of liver transplant criteria, and fewer adverse events at 12 months after the start of treatment. RESULTS: Groups A and B were comparable at baseline. Survival at 12 months after initiation of treatment was significantly higher in group A (74%) than in group B (42%) (P < .001). Blood samples from patients in group A had significantly more CD34+ cells on day 6 than on day 0 (P < .001); there was no significant change in group B. Compared with patients in group B, patients in group A had significant reductions in Child-Turcotte-Pugh and model for end-stage liver disease scores, increased ascites control, fewer infections and hospitalizations, lower liver stiffness measurements, an increased quality of life, and a lower number fulfilled the liver transplant criteria (P < .05). There was no improvement in nutrition in either group compared with baseline. G-CSF was safe and well tolerated. CONCLUSIONS: Administration of multiple cycles of G-CSF increases the numbers of hematopoietic stem cells and survival of patients with decompensated cirrhosis receiving standard medical treatment. The addition of G-CSF to medical treatment might provide a bridge to liver transplantation for these patients. ClincialTrials.gov no: NCT03415698.

Early clinical and radiographic outcomes of an augmented baseplate in reverse shoulder arthroplasty for glenohumeral arthritis with glenoid deformity.

BACKGROUND: Glenoid deformity is commonly encountered in patients undergoing reverse shoulder arthroplasty (RSA). Augmented baseplates can correct glenoid deformity while potentially avoiding certain complications encountered with structural bone graft. Limited evidence exists to support the use of metallic augmented baseplates in RSA. METHODS: We performed a retrospective review to identify all patients treated with an augmented baseplate during primary RSA with a minimum of 1 year of clinical and radiographic follow-up. Preoperative radiographs and advanced imaging were used to determine glenoid morphology and deformity. Postoperative radiographs were used to evaluate for deformity correction, radiographic complications, and early baseplate loosening or failure. Prospectively collected clinical data and patient-reported outcome scores were determined. RESULTS: Primary RSA was performed with an augmented baseplate in 44 patients (mean age, 72 ± 6 years; 15 half-wedge and 29 full-wedge augmentations). Glenoid retroversion was significantly improved for the entire cohort (P = .001). Among the 22 patients with either Walch type B2, B3, or C glenoid morphology, glenoid version improved from 28° ± 8° to 16° ± 8° (P = .001). Glenoid inclination, as determined by the ß angle, was significantly improved for the entire cohort (P < .001). Among the 18 patients with Favard type E2 or E3 glenoid morphology, glenoid inclination improved from 67° ± 7° to 81° ± 8° (P < .001). Postoperative range of motion and functional outcome scores including the American Shoulder and Elbow Surgeons score, Simple Shoulder Test score, Single Assessment Numeric Evaluation score, and visual analog scale score for pain significantly improved within the entire cohort (P < .05). No patients had evidence of baseplate loosening or failure of the glenoid component. Acromial stress fractures developed in 5 patients (11.4%), and 2 patients (4.5%) underwent a reoperation unrelated to the glenoid component. DISCUSSION AND CONCLUSION: Primary RSA with an augmented baseplate results in excellent short-term clinical outcomes and significant deformity correction in patients with advanced glenoid deformity. There were no complications related to the augmented baseplate or glenoid component. The rate of acromial stress fractures appears higher than typically reported and warrants further investigation.

Thermal Conductivity Enhancement in MoS_{2} under Extreme Strain.

Because of their weak interlayer bonding, van der Waals (vdW) solids are very sensitive to external stimuli such as strain. Experimental studies of strain tuning of thermal properties in vdW solids have not yet been reported. Under ∼9% cross-plane compressive strain created by hydrostatic pressure in a diamond anvil cell, we observed an increase of cross-plane thermal conductivity in bulk MoS_{2} from 3.5 to about 25 W m^{-1} K^{-1}, measured with a picosecond transient thermoreflectance technique. First-principles calculations and coherent phonon spectroscopy experiments reveal that this drastic change arises from the strain-enhanced interlayer interaction, heavily modified phonon dispersions, and decrease in phonon lifetimes due to the unbundling effect along the cross-plane direction. The contribution from the change of electronic thermal conductivity is negligible. Our results suggest possible parallel tuning of structural, thermal, and electrical properties of vdW solids with strain in multiphysics devices.

AC Conductivity Measurements of Ultradilute Colloidal Suspensions in HEPES Buffer.

Impedance spectroscopy was used to probe the AC conductivity of extremely dilute colloidal suspensions (2.5 × 10-5 ≤ Φw/v ≤ 4.0 × 10-2) comprising of polystyrene microspheres (PS; κa ≫ 1 and ζ = -65 mV), gold nanoparticles (Au NPs; κa > 1 and ζ = -26 mV), and Au-coated PS metallodielectric particles (Au-PS) in HEPES buffer. When AC electric fields of strength 10 mV and 1 MHz were applied via 100 µm gap interdigitated microelectrodes across 10 µL samples, a highly resistive (θcapacitive < 1°) and nonmonotonic response was obtained with particle concentrations at steady state. While the suspensions were less resistive (than the buffer) below a critical concentration, they became more resistive above it. More interestingly, particle-particle interactions took place in suspensions with concentrations as low as 0.005% w/v. We believe this unique behavior is linked to the ion size asymmetry in the HEPES molecule that provides an ideal microenvironment for counterionic polarization around the particles. The exact mechanism of polarization in HEPES, however, still remains elusive as the current theoretical models for simple electrolytes fail to explain our data.

Workplace violence against resident doctors: A multicentric study from government medical colleges of Uttar Pradesh.

According to the World Health Organization, between 8% and 38% of health workers suffer physical violence at some point in their careers. This multicentric study was conducted to find the prevalence, perceived risk factors, and measures to prevent workplace violence among doctors. The sample consisted of all 2nd- and 3rd-year resident doctors (n = 305) from three colleges in Uttar Pradesh. An anonymous, pretested in a similar setting, self-administered questionnaire was used. 69.5% of doctors reported to have experienced violence in one or other form in the past 1 year. In most incidents, relatives and attendants (69.3%) were involved in violence. No action was taken immediately in regard to violence in 35.3% of instances; 60.3% of study participants reported that they had repeated disturbing memories, thoughts, or images of the attack. Nonavailability of medicines (38.6%) and less staff (36.7%) were cited as top reasons behind violence.

Efficacy of Granulocyte Colony-Stimulating Factor and N-Acetylcysteine Therapies in Patients With Severe Alcoholic Hepatitis.

BACKGROUND & AIMS: Patients with alcoholic hepatitis (AH) have high mortality, so new therapies are needed. Administration of granulocyte colony stimulating factor (G-CSF) increases survival times of patients with AH. It is not known whether addition of N-acetyl cysteine (NAC) to G-CSF could further increase survival time. We performed a randomized controlled pilot study to compare the efficacy of standard medical therapy with pentoxifylline to treatment with a combination of G-CSF and standard medical therapy as well as to the combination of NAC, G-CSF, and standard medical therapy in patients with severe AH. METHODS: We performed an open-label, single-center study of 57 patients with severe AH admitted to a Liver Intensive Care unit in India from October 2014 through March 2017. Patients were randomly assigned to groups that received standard medical therapy (with pentoxifylline) plus G-CSF for 5 days (G-CSF group; n = 18), standard medical therapy plus G-CSF and intravenous NAC for 5 days (combination group; n = 19), or standard medical therapy alone (n = 20). Clinical data and blood samples were collected at baseline; on day 6; and 1, 2, and 3 months after the study began. CD34+ cells were measured in blood samples collected on days 0 and 6. The primary outcome was proportion of patients surviving for 90 days. Secondary outcomes were mobilization of CD34+ cells at day 6, as well as Child Turcotte Pugh, model for end-stage liver disease, and modified discriminant function scores until day 90. RESULTS: Significantly higher proportions of patients in the G-CSF group (16/18) and the combination group (13/19) survived for 90 days than in the standard medical therapy group (6/20) (P = .0001 for G-CSF group and P = .037 and combination group). The GGSF and combination groups each had increased numbers of CD34+ cells from baseline until day 6, compared with the standard medical therapy group. The G-CSF group (but not the combination group) had significantly larger median reductions in modified discriminant function scores at study months 1 (reduction of 60.36%), 2 (reduction of 75.36%), and 3 (reduction of 88.73%) vs the standard medical therapy group (P = .02; P = .05; and P = .00, respectively). The G-CSF group had a significantly larger median reduction in model for end-stage liver disease score at 3 months (reduction of 55.77%; P = .01), but not in Child Turcotte Pugh score, compared with the standard medical therapy group. All groups had similar numbers of complications. CONCLUSION: In a pilot randomized controlled trial, we found administration of G-CSF to improve liver function and increase survival times in patients with severe AH, compared with standard therapy. We found no evidence for benefit of adding NAC to G-CSF. These findings require confirmation in larger trials. ClincialTrials.gov, number: NCT02971306.

Sofosbuvir with NS5A inhibitors in hepatitis C virus infection with severe renal insufficiency.

Treatment of Hepatitis C virus (HCV) in patients with severe renal insufficiency is cumbersome as sofosbuvir is mainly excreted by the kidneys. There is paucity of data on the use of sofosbuvir and NS5A inhibitors in these patients. We hereby report our experience of treating chronic hepatitis C in patients with severe renal insufficiency with full dose sofosbuvir and NS5A inhibitors. Forty-seven patients with severe renal insufficiency (on dialysis n = 39, predialysis n = 8) with HCV infection were treated between December 2015-August 2017 with full dose sofosbuvir with ledipasvir or daclatasvir for 12/24 weeks depending on the genotype and the presence or absence of cirrhosis. The distribution of HCV genotype was genotype 1 in 32 (68.1%), genotype 3 in 13 (27.7%) and 4 in 2 (4.3%) patients. Among 12 (25.5%) patients with cirrhosis, 7 (14.9%) were decompensated with ascites. All patients had end of treatment response, and sustained viral response at 12 weeks was achieved in 45 (95.7%) patients. There was significant improvement in liver stiffness at 3 months after treatment (8.8 (3.8-42) to 7.1 (3.3-24.1) kPa; (P = 0.047)). There was no change in haemoglobin and eGFR with treatment in predialysis group (haemoglobin- 10.2 ± 1.5 g/dL vs 9.6 ± 1.3 g/dL, P = 0.44; eGFR- 19.8 ± 9.4 mL/min vs 17.9 ± 8.5 mL/min, P = 0.67). Therapy was very well accepted. Full dose sofosbuvir with NS5A inhibitors is a well tolerated and effective therapy for HCV infection in severe renal insufficiency.

Epigenetic modulation by small molecule compounds for neurodegenerative disorders.

The accumulation of somatic and genetic mutations which altered the structure and coding information of the DNA are the major cause of neurological disorders. However, our recent understanding of molecular mechanisms of 'epigenetic' phenomenon reveals that the modifications of chromatin play a significant role in the development and severity of neurological disorders. These epigenetic processes are dynamic and reversible as compared to genetic ablations which are stable and irreversible. Therefore, targeting these epigenetic processes through small molecule modulators are of great therapeutic potential. To date, large number of small molecule modulators have been discovered which are capable of altering the brain pathology by targeting epigenetic enzymes. In this review, we shall put forward the key studies supporting the role of altered epigenetic processes in neurological disorders with especial emphasis on neurodegenerative disorders. A few small molecule modulators which have been shown to possess promising results in the animal model system of neurological disorders will also be discussed with future perspectives.

Midodrine and tolvaptan in patients with cirrhosis and refractory or recurrent ascites: a randomised pilot study.

BACKGROUND: Splanchnic arterial vasodilatation and subsequent sodium and water retention play an important role in cirrhotic ascites. Midodrine and tolvaptan have been used separately in these patients. However, there are no reports on the use of combination of midodrine and tolvaptan in the control of ascites. The aim of this study was to evaluate the safety and efficacy of midodrine, tolvaptan and their combination in control of refractory or recurrent ascites in cirrhotics. METHODS: Fifty cirrhotic patients with refractory or recurrent ascites were randomised to receive midodrine (n=13), tolvaptan (n=12) or both (n=13) plus standard medical therapy (SMT) or SMT alone (n=12). RESULTS: A significant increase in urinary volume and urinary sodium at 1 and 3 months (P<.05) was observed in all groups except SMT. There was no worsening of renal or hepatic function in any group. There was deterioration of model for end-stage liver disease (MELD) in SMT. Midodrine as well as combination of midodrine and tolvaptan but not tolvaptan alone was superior to SMT in control of ascites at 3 months (P<.05). The combination therapy was also superior to midodrine in the control of ascites at 1 month. The morbidity and mortality were similar in all the groups except SMT. CONCLUSIONS: The results of this pilot study suggest that midodrine and combination with tolvaptan better controls ascites without any renal or hepatic dysfunction. The combination therapy rapidly controls ascites as compared to midodrine or tolvaptan alone.

High pre-diagnosis attrition among patients with presumptive MDR-TB: an operational research from Bhopal district, India.

BACKGROUND: Pre-diagnosis attrition needs to be addressed urgently if we are to make progress in improving MDR-TB case detection and achieve universal access to MDR-TB care. We report the pre-diagnosis attrition, along with factors associated, and turnaround times related to the diagnostic pathway among patient with presumptive MDR-TB in Bhopal district, central India (2014). METHODS: Study was conducted under the Revised National Tuberculosis Control Programme setting. It was a retrospective cohort study involving record review of all registered TB cases in Bhopal district that met the presumptive MDR-TB criteria (eligible for DST) in 2014. In quarter 1, Line Probe Assay (LPA) was used if sample was smear/culture positive. Quarter 2 onwards, LPA and Cartridge-based Nucleic Acid Amplification Test (CbNAAT) was used for smear positive and smear negative samples respectively. Pre-diagnosis attrition was defined as failure to undergo DST among patients with presumptive MDR-TB (as defined by the programme). RESULTS: Of 770 patients eligible for DST, 311 underwent DST and 20 patients were diagnosed as having MDR-TB. Pre-diagnosis attrition was 60% (459/770). Among those with pre-diagnosis attrition, 91% (417/459) were not identified as 'presumptive MDR-TB' by the programme. TAT [median (IQR)] to undergo DST after eligibility was 4 (0, 10) days. Attrition was more than 40% across all subgroups. Age more than 64 years; those from a medical college; those eligible in quarter 1; patients with presumptive criteria 'previously treated - recurrent TB', 'treatment after loss-to-follow-up' and 'previously treated-others'; and patients with extra-pulmonary TB were independent risk factors for not undergoing DST. CONCLUSION: High pre-diagnosis attrition was contributed by failure to identify and refer patients. Attrition reduced modestly with time and one factor that might have contributed to this was introduction of CbNAAT in quarter 2 of 2014. General health system strengthening which includes improvement in identification/referral and patient tracking with focus on those with higher risk for not undergoing DST is urgently required.

Isoniazid Preventive Therapy among Children Living with Tuberculosis Patients: Is It Working? A Mixed-Method Study from Bhopal, India.

Objective: We assessed uptake of isoniazid preventive therapy (IPT) among child contacts of smear-positive tuberculosis (TB) patients and its implementation challenges from healthcare providers' and parents' perspectives in Bhopal, India. Methods: A mixed-method study design: quantitative phase (review of programme records and house-to-house survey of smear-positive TB patients) followed by qualitative phase (interviews of healthcare providers and parents). Results: Of 59 child contacts (<6 years) of 129 index patients, 51 were contacted. Among them, 19 of 51 (37%) were screened for TB and one had TB. Only 11 of 50 (22%) children were started and 10 of 50 (20%) completed IPT. Content analysis of interviews revealed lack of awareness, risk perception among parents, cumbersome screening process, isoniazid stock-outs, inadequate knowledge among healthcare providers and poor programmatic monitoring as main barriers to IPT implementation. Conclusion: National TB programme should counsel parents, train healthcare providers, simplify screening procedures, ensure regular drug supply and introduce an indicator to strengthen monitoring and uptake of IPT.