Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Clinical utility of target-based next-generation sequencing for drug-resistant TB.

BACKGROUND: In high TB burden countries, access to drug susceptibility testing is a major bottleneck. Targeted next-generation sequencing (tNGS) is a promising technology for rapid resistance detection. This study assessed the role of tNGS for the diagnosis of drug-resistant TB (DR-TB).METHODS: A total of 161 samples from bacteriologically confirmed TB cases were subjected to tNGS using the Deeplex® Myc-TB kit and sequenced using the MiSeq platform. These samples were also processed for conventional phenotypic DST (pDST) using 13 drugs on Mycobacteria Growth Indicator Tube and line-probe assays (MTBDRplus and MTBDRsl).RESULTS: There were 146 DR-TB and 15 drug-susceptible TB (DS-TB) samples. About 70% of patients with DR-TB had no previous TB treatment history. Overall, 88.2% had rifampicin-resistant/multidrug-resistant TB (RR/MDR-TB), 58.5% pre-extensively drug-resistant TB (pre-XDR-TB) and 9.2% had XDR-TB as defined by the WHO (2020). Around 8% (n = 13) of samples were non-culturable; however, identified 8 were resistant to first and second-line drugs using tNGS. Resistance frequency was similar across methods, with discordance in drugs less reliable using pDST or with limited mutational representation within databases. Sensitivities were aligned with literature reports for most drugs. We observed 10% heteroresistance, while 75% of strains were of Lineages 2 and 3.CONCLUSIONS: Programme data supported tNGS in the diagnosis of DR-TB for early treatment using individualised regimens.

Isolation and molecular characterization of infectious bursal disease virus circulating in western and central India.

Background: Infectious bursal disease (IBD) caused substantial economic loss in central and western India during 2020 and 2021. Aims: The study was conducted to characterize IBD virus (IBDV) from field outbreaks. Methods: The study was conducted on 360 samples from 42 poultry flocks. The samples were subjected to histopathology and molecular detection, followed by phylogenetic typing of the partial VP2 gene. Results: The mortality ranged from 15.25 to 60.18%. The necropsy showed hemorrhages on thigh muscles, mottled spleen, swelling of kidneys and bursae with hemorrhages, and cheesy exudate. Histopathology revealed extensive necrosis and depletion of follicular lymphoid cells within the cortex and medulla, along with widespread hemorrhages, edema, and cystic cavities in the bursa. The field isolates showed cytopathic effects in the seventh passage. The cytopathic effects included swelling, rounding, granulation of cytoplasm around the nucleus, fragmentation of the infected cells, and detachment. The reverse transcription-polymerase chain reaction amplified 664 bp partial VP2 gene. The phylogenetic analysis identified 19 field isolates as very virulent IBDVs (vvIBDVs) and three as classical strains. Conclusion: The results indicated that different vvIBDV strains are involved in disease outbreaks in central and western India.

Human leukocyte antigen (HLA)-C and its association with HIV-1 transmission in discordant couple and mother-to-child cohorts.

Human leukocyte antigen (HLA) molecules play a key role in regulating the immune response towards infectious agents like human immunodeficiency virus type-1 (HIV-1). They have been shown to influence transmission as well as the progression of HIV-1 towards acquired immune deficiency syndrome (AIDS). Roles of HLA-A and HLA-B have been documented extensively; however, HLA-C has been poorly studied. In the present study, we have evaluated the role of HLA-C in discordant couple and mother-to-child cohorts. HLA-C*07 was higher both in HIV-1-infected spouses and infants as compared to exposed uninfected spouses and infants. However, this was not significant. HLA-C*15 was significantly higher in HIV-1-exposed uninfected babies as compared to infected babies. Lack of treatment in mothers and breastfeeding were significantly associated with HIV-1 transmission. HLA-C*07 may be a susceptible allele in HIV-1 transmission, whereas HLA-C*15 may be a protective allele in mother-to-child cohorts, independent of feeding options and treatment. These findings could be important in targeting immune responses via population-specific vaccine strategies against HIV-1.

Current scenario of opportunistic and co-infections in HIV-infected individuals at a tertiary care hospital in Mumbai, India.

PURPOSE: An update on opportunistic infections/co-infections (OIs/CIs) is essential to understand the success of highly active antiretroviral therapy offered by the government agencies in reducing AIDS-related OIs/CIs. Hence, the present study aimed to evaluate the frequency of OIs/CIs in HIV-positive individuals at a tertiary care hospital in Mumbai. Its' association with CD4 counts, anti-retroviral treatment and on HIV transmission was also determined. MATERIALS AND METHODS: An observational study was designed to evaluate different OIs/CIs in individuals, who tested positive for HIV infection at the ICTC/Shakti Clinic of Seth G.S. Medical College and KEM Hospital, Mumbai. Data analysis was done with the use of SPSS software (version 19.0, SPSS, Chicago, IL, USA). P value was considered significant if it is < 0.05. RESULTS: Heterosexual contact was the major route of transmission among the enrolled 185 individuals. Ninety (48.06%) HIV-infected individuals were with OIs/CIs. Tuberculosis (TB) was the most common OI (68.8%). Other CIs noted were Herpes zoster, syphilis, hepatitis C and B, malaria, typhoid and dengue. The median CD4 count in HIV-positive individuals with TB was 337 ± 248 cells/µl, and 67.7% of individuals with OIs/CIs had low CD4 counts (<400 cells/µl). Individuals in 31-40 years of age group had significantly (P = 0.01) more OIs/CIs. More (53.7%) spouse/children of HIV-positive individuals without OIs/CIs were HIV-1 positive. Low proportions of individuals with or without OIs/CIs were on ART. CONCLUSION: Nearly half of HIV-infected individuals were with OIs/CIs. Initiation of free ART programme since 2004 possibly associated with the type and rate of OIs/CIs. Tuberculosis and multiple OIs/CIs were associated with low CD4 counts. Infection was high in 31-40 years age group. Most of the spouses of individuals without OIs/CIs were HIV positive, indirectly indicates lack of condom use or lack of awareness of condom use.

Antiretroviral treatment, viral load of mothers & perinatal HIV transmission in Mumbai, India.

BACKGROUND & OBJECTIVES: Mother-to-child transmission (MTCT) is the most significant route of HIV transmission in children below the age of 15 yr. In India, perinatal HIV transmission, even after treatment, accounts for 5.4 per cent of HIV cases. The present study was conducted to evaluate the efficacy of anti-retro viral therapy (ART) or prophylactic treatment (PT) to control maternal viral load in HIV positive women, and its effect on vertical HIV transmission to their infants. METHODS: A total of 58 HIV positive women were enrolled at the time of delivery and their plasma samples were obtained within 24 h of delivery for estimation of viral load. Viral load analysis was completed in 38 women. Infants received single dose nevirapine within 2 h of birth and zidovudine for 6 wk. At the end of 18 month follow up, HIV positive or negative status was available in 28 infants. RESULTS: Results revealed undetectable levels of viral load in 58.3 per cent of women with ART compared to 30.7 per cent of women with PT. No women on ART had viral load more than 10,000 copies/ml, whereas seven (26.9%, P=0.07) women receiving PT had this viral load. Median CD4 count of women on PT (483 cells/µl) was high compared to the women on ART (289 cells/ µl). At the end of 18 months follow up, only two children were HIV positive, whose mothers were on PT. One had in utero transmission; infection detected within 48 h of delivery, while the other child was infected post partum as HIV was detected at six months follow up. INTERPRETATION & CONCLUSIONS: Women who received a single dose of nevirapine during delivery had higher levels of viral load than women on ART. Combination drug therapy for pregnant women is now a standard of care in most of the western countries; use of nevirapine monotherapy at the time of delivery in our settings is not effective in controlling viral load. This highlights initiation of ART in pregnant women to control their viral load and thus to inhibit mother to child HIV transmission.

Polymorphisms in major cytokine genes: a study among human immunodeficiency Virus-1 serodiscordant couples in Mumbai, India.

PURPOSE: Polymorphism in cytokine genes may affect its production, which play an important role in modulation of human immunodeficiency virus (HIV) infection. Evaluation of these polymorphisms might help to understand why some individuals remain uninfected in spite of several exposures to HIV infection, such as the negative spouses of discordant couples. The aim of this study was to evaluate the association of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and their receptors with HIV infection in serodiscordant couples, attending the Integrated Counselling and Testing Centre of a Municipality Hospital. MATERIALS AND METHODS: At the end of at least 2 years of follow up, 42 couples were confirmed as being serodiscordant. Genotyping was carried out in blood samples of these couples using the polymerase chain reaction-sequence-specific amplification method. RESULTS: Significantly high frequency of interleukin-1 receptor antagonist IL-1RA mspa 11100 CC (P=0.04), tumor necrosis factor-alpha TNF-α -238 AG (P=0.01) and IL-4 -33 TT (P=0.01) was observed in HIV seropositives (HSP) while frequency of TNF-α -238 GG (P=0.02) was significantly high among the exposed uninfected (EU). However, application of Bonferroni correction identified only two SNPs i.e., TNF-α -238 AG and IL-4 -33 TT to be significantly associated with the acquisition of HIV. In remaining cytokine genes, no significant association was observed. CONCLUSION: Our study highlighted possible association of certain specific polymorphisms with HIV transmission, whereas presence or absence of certain other polymorphism in EU individuals might be offering protection from HIV infection. These variations at the genetic level might help to explore new insights into treatment and HIV prevention strategies.

Regression of coronary atherosclerosis through healthy lifestyle in coronary artery disease patients--Mount Abu Open Heart Trial.

AIMS: To evaluate the efficacy of a unique healthy and happy lifestyle (HLS) program in regression of coronary atherosclerosis and reduction in cardiac events in an open trial. METHODS: One hundred and twenty three angiographically documented moderate to severe coronary artery disease (CAD) patients were administered HLS comprising of low-fat, high-fiber vegetarian diet, moderate aerobic exercise and stress-management through Rajyoga meditation. Its most salient feature was training in self-responsibility (heal+thy) and self-empowerment through inner-self consciousness (swasth; swa=innerself, sth=consciousness) approach using Rajyoga meditation. Following a seven day in-house sojourn, patients were invited for six month follow-up for reassessment and advanced training. At the end of two years, all patients were asked to undergo repeat angiography. RESULTS: Three hundred and sixty coronary lesions were analysed by two independent angiographers. In CAD patients with most adherence, percent diameter stenosis regressed by 18.23 +/- 12.04 absolute percentage points. 91% patients showed a trend towards regression and 51.4% lesions regressed by more than 10 absolute percentage points. The cardiac events in coronary artery disease patients were: 11 in most adherence, and 38 in least adherence over a follow-up period of 6.48 yrs. (risk ratio; most vs least adherence: 4.32; 95% CI: 1.69-11.705; P < 0.002). CONCLUSION: Overall healthy changes in cardiovascular, metabolic and psychological parameters, decline in absolute percent diameter coronary stenosis and cardiac events in patients of CAD were closely related to HLS adherence. However, more than 50% adherence is essential to achieve a significant change.

Transient quadriparesis after electric shock in a child: case report.

Electric shock injuries are commonly encountered by emergency physicians. Various systemic complications owing to electric shock injury have been described. It is important to maintain raised awareness of these different complications to ensure that they are recognised and treated early. We describe a rare case of transient quadriparesis following electric shock in a 10-year-old boy.

Staphylococcal toxic shock syndrome presenting as acute respiratory distress and cor pulmonale.

We describe a 7-year-old boy with staphylococcal toxic shock syndrome who presented with acute respiratory distress and cor pulmonale. We wish to highlight this unusual presentation as the diagnosis of toxic shock syndrome depends chiefly on a high degree of clinical suspicion. Early diagnosis and prompt institution of appropriate therapy will significantly reduce morbidity and mortality.

Callosal holes: an unusual imaging appearance in systemic lupus erythematosus. A case report.

Systemic lupus erythematosus (SLE) has diverse imaging features. However, focal lesions in the corpus callosum are extremely rare in SLE with only few cases mentioned in the literature, with no mention of callosal holes in SLE. Callosal holes have been described as a characteristic finding in Susac syndrome and have been mentioned in Nipah virus encephalitis, Marchiafava Bignami disease and periventricular leukomalacia. We describe a case of SLE with callosal holes. The demonstration of callosal holes in this case brings the imaging appearance of SLE a step closer to that of Susac syndrome which is considered a clinically and radiologically close condition. It also adds to the list of imaging appearances of central nervous system SLE.

Relationship between mammography breast density and bone mineral density.

Mammography breast density (MBD) is a well-established and strong predictive risk factor for breast cancer. Bone mineral density (BMD) is another predictor of breast cancer risk in women. Both MBD and BMD are linked to a common pathway, which involves estrogens, and are highly heritable. This study evaluated the relationship between MBD and hip and spine BMD in Kuwaiti women. Mammograms and BMD data of 248 women were studied. BMD was measured at total lumbar spine (L1-L4) and total left hip using dual-energy X-ray absorptiometry. The women were classified into 3 groups: normal, osteopenia, and osteoporosis by their BMD, using the World Health Organization criteria. They were divided into another 4 groups: fatty, fibroglandular, heterogeneously dense, and extremely dense breast according to their MBD and as defined by the Breast Imaging Reporting and Data System. All MBD and BMD data were analyzed statistically. Statistical analysis showed no significant difference or correlation between the MBD and BMD groups even after adjusting for obesity and menopausal status. However, a highly significant difference in body weight was found among the MBD groups (p<0.005). No correlation between MBD and BMD was observed in the group of Kuwaiti women who took part in the present study.

Bilateral subdural hemorrhage following lumbar puncture in a case of suspected meningitis. A case report.

Intracranial subdural hemorrhage is a rare complication of lumbar puncture. Caudal traction and tear of the subdural veins due to negative pressure caused by leakage of cerebrospinal fluid (CSF) following lumbar puncture (LP) is the mechanism. Prolonged headache or neurological symptoms following LP should warrant cross-sectional imaging to rule out subdural hemorrhage as it can be fatal. We report a case of subdural hemorrhage following LP in a patient with suspected meningitis and communicating hydrocephalus.

Pituitary apoplexy: a rare cause of cerebral infarction. A case report.

Pituitary apoplexy is usually the result of hemorrhagic infarction in pituitary adenoma. The clinical presentation of pituitary apoplexy varies widely and includes asymptomatic hemorrhage, classical pituitary apoplexy and even sudden death. Few cases of cerebral infarction associated with pituitary apoplexy have been reported in the literature. Pituitary apoplexy can cause narrowing of intracranial vessels by mechanical obstruction due to mass effect or by vasospasm resulting in cerebral ischemia. We report a case of pituitary apoplexy associated with cerebral infarction and the putative mechanisms.

Persistent trigeminal artery and associated vascular variations.

Persistent trigeminal artery (PTA) is the most frequent type of persistent primitive carotid-basilar artery anastomoses. Persistent trigeminal artery is usually associated with small or absent posterior communicating artery (Pcom). It may also be associated with hypoplastic vertebral and basilar arteries. Patients may present with symptoms related to hypo-perfusion of posterior circulation or microembolization from carotid artery to posterior circulation. We are presenting a 60-year-old who had recurrent episodes of vertigo and parasthesia, in whom MR angiography revealed a medial, Saltzman type 1 PTA on the left with absent ipsilateral Pcom, duplicated ipsilateral superior cerebellar artery, hypoplastic A1 segment of contralateral anterior cerebral artery (ACA), azygous ACA and hypoplastic ipsilateral vertebral artery.

Perirolandic sparing and pituitary apoplexy in adult brain with global hypoxia. A case report.

Global hypoxia in adult brain usually manifests as ischemic lesions in watershed territories. Acute profound hypoxia involves the cortex especially the perirolandic area, white matter and deep grey matter. Perirolandic sparing in adult global hypoxia is not described in literature. Few cases of perirolandic sparing are described in conditions like anoxia in term infants in the post-neonatal period and hepatic encephalopathy. We report a case of global hypoxia in adult brain with perirolandic sparing and unique association with pituitary apoplexy. It is well known that the "diving reflex" redistribution of cerebral blood flow to the high metabolically active regions occurs when the hypoxic insult is prolonged and partial. The perirolandic sparing in our case could be explained by this phenomenon, wherein the patient acutely developed hypoxia, which was profound and prolonged but not prolonged enough for deep grey matter sparing.

Intracranial complications of otitis media: In retrospect.

OBJECTIVE: Evaluating intracranial complications of otitis media. DESIGN: An Evaluative study of 106 cases of intracranial complications secondary to otitis media. INTERVENTION: Diagnosis is based on history, clinical exam (general, systemic and ENT), investigations hemogram, X-ray mastoid CT scan brain and mastoid. TREATMENT: Medical management:IV Higher Antibiotics.Surgery for complicating pathology:Pus (in Abscesses)-bram canula aspiration.Lateral sinus thrombosis (thrombus removal),Otitic hydrocephalus (epidural catheterization).Primary disease eradication:Exploration of mastoid. RESULTS: Fully recovered patients without residual neurodeficit (85%), Morbidity (6%) CSF otorrhoea secondary to otitic hydrocephalus (9%) Mortality: preoperative (3%) and postoperative (6%). CONCLUSION: Otological approaches for management of cases of intracranial complications of otitis media are equally comparable with results by neurosurgical approaches of management. Therefore, holding promise if applied in the rural and peripheral parts of India with limited resources even with absence of the expertise of Neurosurgical Department.

Effect of rise in simulated inspiratory flow rate and carrier particle size on powder emptying from dry powder inhalers.

The purpose of this study was to evaluate the effect of carrier particle size and simulated inspiratory flow increase rate on emptying from dry powder inhalers (DPIs). Several flow rate ramps were created using a computer-generated voltage signal linked to an electronic proportioning valve with a fast response time. Different linear ramps were programmed to reach 30, 60, 90, and 120 L/minute over 1, 2, or 3 seconds. At the lower flow rates, 100-ms and 500-ms ramps were also investigated. Three DPIs, Spinhaler, Rotahaler, and Turbuhaler, were used to test the effect of flow rate ramp on powder emptying. To test the effect of carrier particle size, anhydrous lactose was sieved into 3 particle sizes, and 20 mg of each was introduced into #2 and #3 hard gelatin capsules for Spinhaler and Rotahaler, respectively. Emptying tests were also carried out using the on/off solenoid valve described in the United States Pharmacopeia (USP) (resulting in no ramp generation). Powder emptying increased from 9% to 46% for Rotahaler and 69% to 86% for Spinhaler from the shallowest (3 seconds to reach peak flow) to the 100-ms ramp for the 53- to 75 microm lactose size range at 30 L/minute. Similar trends were observed for larger particle size fractions at the same flow rate. However, at higher airflow rates (60, 90, and 120 L/minute), there was no significant increase in percentage of emptying within the ramps for a particular particle size range. Trends observed were similar for placebo-filled Turbuhaler and commercially available Rotacaps used with Rotahaler, with the steepest ramp demonstrating more complete emptying. Percentage of powder emptying determined by the USP solenoid valve overestimated the emitted dose compared with the ramp method at 30 L/minute for all 3 devices. Results indicate that there is a significant difference in powder emptying at 30 L/minute from the shallowest to the steepest ramp within a particular size range. Within a particular particle size range, the USP method produced more complete emptying than even the steepest ramp, especially at the lower flow rates. Thus, when the USP device is used to estimate DPI emptying at lower flow rates, the results are likely to overestimate DPI performance significantly.