Longer Treatment Regimens Research Articles

Incidence, types and predictors of adverse events and their impact on treatment outcomes in multidrug/rifampicin resistant tuberculosis patients receiving all oral treatment regimens.

Patients suffering from multidrug/rifampicin resistant tuberculosis (MDR/RR-TB) are treated for prolonged periods with a complex regimen comprised of relatively less effective and more toxic anti-TB drugs, consequently resulting in high incidence of adverse events (AEs). The current study evaluates the incidence, types, management and predictors of AEs, and their impact on treatment outcomes in MDR/RR-TB patients receiving all oral treatment regimens. A total of 242 eligible MDR/RR-TB patients treated at two different study sites from June 2019 to December 2021 were included in this study. Patients' sociodemographic, microbiological, clinical characteristics, reported AEs and treatment outcomes were retrospectively abstracted from their medical records. Chi-square, and Fisher exact tests (wherever applicable) were used to find the association between the variable and the occurrence of AEs. Majority of the patients were suffered from MDR-TB (71.9%) and were treated with longer treatment regimen (77.7%). Overall 206/242 patients (85%) experienced at least one AE during their treatment. Gastrointestinal disturbance was the most common AE (49.6%), followed by arthralgia (49.2%), psychiatric disturbances (39.3%), dermatological reactions (27.7%), body/headache (24.8%) and hyperuricemia (19%). Due to AEs, treatment modification was noted in 55 (22.72%) patients. Level of modification in the treatment regimen was higher in optic neuritis (100%) followed by neuropathies (80%) and myelosuppression (59%). Similarly, hepatotoxicity was the most serious AE in which the whole treatment regimen was terminated in 27% of patients. Furthermore, the results revealed that only patients' education status had statistically significant association with the incidence of AEs (p = 0.02). The treatment success rate was 80.6% whereas the ratio of died and LTFU patients were 15.3% and 4.1% respectively. Although patients who experienced AEs were more likely to develop successful treatment outcomes (82%) than their counterparts (72.2%), though this difference was not statistically significant. Although AEs were highly present in the current cohort, but they were successfully managed mostly by nonpharmacological interventions or symptomatic treatment. Besides, the incidence of AEs did not have a negative impact on treatment outcomes. High-risk patients for AEs must receive special attention and enhanced clinical management.

Effectiveness of bedaquiline containing all oral longer regimens in treating multidrug/rifampicin resistant tuberculosis in Pakistan

BackgroundDespite the introduction of bedaquiline (Bdq) containing all-oral regimens for treating patients with rifampicin resistant/multidrug resistant tuberculosis (MDR/RR-TB) in 2019, data on its effectiveness in Pakistan, which has the fifth highest MDR-TB burden, is lacking. This study evaluates treatment outcomes and identifies factors associated with unsuccessful outcomes among MDR/RR-TB patients treated with an all-oral longer treatment regimen (LTR). MethodsThis retrospective record review included all microbiologically confirmed pulmonary MDR/RR-TB patients treated with an all-oral LTR between August 2019 and February 2021 across nine PMDT centres in Pakistan. Sociodemographic and clinical data were retrieved from the Electronic Nominal Recording and Reporting System. Treatment outcomes, defined by WHO criteria, were analysed using SPSS and multivariate binary logistic regression to identify factors associated with unsuccessful outcomes. A p-value < 0.05 was considered statistically significant. ResultsThe final analysis included 644 MDR/RR-TB patients (mean age 37.9 ± 17.6 years), mostly male (53.0 %), underweight (68.0 %), with TB treatment history (66.1 %), MDR-TB (84.9 %), lung cavitation (71.0 %), and no comorbidities (86.4 %). Fluoroquinolone resistance was found in 41.9 %, 16 % had used second-line drugs, and 9.8 % had previous MDR-TB treatment. A total of 400 (62.1 %) patients were declared cured, 53 (8.2 %) treatment completed, 117 (18.2 %) died, 37 (5.7 %) lost to follow-up (LTFU), and 37 (5.7 %) treatment failures. Overall treatment success rate was 70.3 % (n = 453). In multivariate analysis, history of TB treatment (OR:1.63, 95 %CI:1.09–2.64, p = 0.023), previous SLD use (OR:2.09, 95 %CI: 1.20–3.37, p = 0.012), resistance to Z (OR:0.43, 95 %CI: 0.20–0.81, p = 0.023), and resistance to > 5 drugs (OR:3.12, 95 %CI:1.36–11.64, p = 0.013) were significantly associated with death and treatment failure. Whereas, lung cavitation had statistically significant association with LTFU (OR:2.66, 95 %CI:1.10–7.32, p = 0.045). ConclusionTreatment success rate (70.3 %) in this study fell below the WHO recommended target success rate (>90 %). Enhanced clinical management, coupled with special attention to patients exhibiting identified risk factors could improve treatment outcomes.

EFFECTIVENESS OF FDA VITAL STAINING IN FOLLOW UP OF DR PTB PATIENTS ON LONGER TREATMENT REGIMEN UNDER NTEP

EFFECTIVENESS OF FDA VITAL STAINING IN FOLLOW UP OF DR PTB PATIENTS ON LONGER TREATMENT REGIMEN UNDER NTEP

Five-Fraction Accelerated Partial Breast Irradiation [APBI] may Reduce Health Care Disparity in Patients Receiving Adjuvant Radiation Therapy for Breast Cancer by Overcoming Treatment Barriers of Distance to Treatment Center, Age, and Ethnicity

Although changing, breast irradiation is still standard of care in many patients after breast conservation therapy (lumpectomy). Distance from radiation treatment center, Age, and Ethnicity have been shown to be barriers to completing needed adjuvant radiation therapy in breast and other cancers. In this retrospective review, it was hypothesized that the Meattini five-fraction partial breast treatment (APBI) would reduce these barriers to care, and more patients would complete treatment. Data from the radiation planning system was utilized to identify all patients treated with APBI at a single community cancer center from 3/6/2020 to 10/14/2022. The Electronic Medical Record (EMR) was used to identify home addresses and then online navigation software measured patient round trip driving distance to the treatment center. Records in EMR were reviewed to see if each patient completed treatment. Patients were divided into 2 groups for three variables: 1. Distance from clinic- <40 miles round trip vs. >40 miles round trip, 2. Age- 65 and older or less than 65, 3. Ethnicity- Hispanic or Non-Hispanic. Each variable consisting of 2 groups were then evaluated statistically using two proportion Z test. Eighty-one patients were identified who underwent APBI. There were 50 patients living <40 miles round trip and 31 living >40 miles from cancer treatment center. There were 48 patients age 65 and older and 33 patients under 65. Patients self- identified their ethnicity as: Hispanic (26 patients, 32.1%), non-Hispanic (55 patients, 67.9%: European Descent-52 patients, Native American- 2 patients, Asian American- 1 patient). 80/81 APBI patients completed the planned treatment. Using the two proportion Z-test, there was no statistical difference between patients with distance to treatment center less than 40 mi round trip commute vs greater than 40 miles round trip commute (Z score 1.28, p = .20), no statistical difference by age 65 or older vs under 65 (Z score = -.83, p = 0.40), and no statistical difference between ethnicity of Hispanic vs non-Hispanic patients (Z score 0.69, p = 0.49). Shorter course radiation therapy regimens for many reasons are easier to complete than longer treatment regimens. In this single-institution retrospective review, all but one short course five-fraction APBI patient (80/81) completed treatment. APBI short course five-fraction treatment (compared to traditional longer breast radiation therapy regimens) may help increase completion of adjuvant radiotherapy and reduce healthcare disparity in breast cancer patients and may overcome barriers to treatment such as Distance to treatment center, Age, and Ethnicity.

Pediatric multi-drug-resistant tuberculosis in Germany – diagnostic and therapeutic challenges of an “orphan disease”

Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case–control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss).Conclusions: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects.Trial Registration: Deutsches Register Klinischer Studien (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817), DRKS00023817, 2020–09-08.What is Known:•Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease).•Choice of treatment regimen and monitoring of side effects.What is New:•Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country.•The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.

Fecal microbial transplantation as a novel therapeutic for autism spectrum disorders: a review of the current literature

BackgroundAutism spectrum disorders (ASDs) are complex neurobiological conditions with poor long-term outcomes and limited treatment options. The microbiota–gut–brain axis indicates a pathway by which the gut microbiota links to ASDs. Fecal microbial transplantation (FMT), whereby the gut microbiota is replaced with that of a healthy individual, shows promise for the treatment of neurobiological conditions. This review examines the current evidence for the use of FMT as a therapeutic for ASD.DiscussionASDs and their associated gastrointestinal symptoms are improved with FMT, potentially due to the engraftment of features of a healthy gut. Longer treatment regimens that include daily maintenance doses appear to be the most effective long-term therapeutic option, with benefits persisting 2 years post-intervention. Evidence is mixed regarding the use of preparatory treatments. Considering the sex bias in ASD research, small sample sizes and the lack of placebo control arms, randomized controlled trials would be of benefit to the evidence base regarding the use of FMT as a therapeutic option for ASD.ConclusionFMT is a promising new therapeutic for ASD, but the evidence base is in its infancy.

Phenotypic Evaluation of Nucleoside Analogues against Trypanosoma cruzi Infection: In Vitro and In Vivo Approaches.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is a serious public health problem. Current treatment is restricted to two drugs, benznidazole and nifurtimox, displaying serious efficacy and safety drawbacks. Nucleoside analogues represent a promising alternative as protozoans do not biosynthesize purines and rely on purine salvage from the hosts. Protozoan transporters often present different substrate specificities from mammalian transporters, justifying the exploration of nucleoside analogues as therapeutic agents. Previous reports identified nucleosides with potent trypanocidal activity; therefore, two 7-derivatized tubercidins (FH11706, FH10714) and a 3'-deoxytubercidin (FH8513) were assayed against T. cruzi. They were highly potent and selective, and the uptake of the tubercidin analogues appeared to be mediated by the nucleoside transporter TcrNT2. At 10 μM, the analogues reduced parasitemia &gt;90% in 2D and 3D cardiac cultures. The washout assays showed that FH10714 sterilized the infected cultures. Given orally, the compounds did not induce noticeable mouse toxicity (50 mg/kg), suppressed the parasitemia of T. cruzi-infected Swiss mice (25 mg/kg, 5 days) and presented DNA amplification below the limit of detection. These findings justify further studies with longer treatment regimens, as well as evaluations in combination with nitro drugs, aiming to identify more effective and safer therapies for Chagas disease.

Predictors of slow clinical response and extended treatment in patients with extra-pulmonary tuberculosis in Pakistan, A hospital-based prospective study.

The optimal duration of treatment in different forms of extrapulmonary tuberculosis (EPTB) is not clearly defined. This study aimed to identify predictors of slow clinical response and extended anti-TB treatment in EPTB patients. Socio-demographic, clinical, and microbiological characteristics of EPTB patients registered for anti-TB treatment at a tertiary care hospital, were analysed for identification of predictors of extended treatment. A total of 251 patients (137 lymphadenitis, and 114 pleuritis) were included in the analysis. Treatment was extended to more than 6 months in 58/251 (23%) patients. In the multivariate regression analysis, culture-positive EPTB (p = 0.007) [OR (95% CI) = 3.81 (1.43, 10.11)], history of diabetes (p = 0.014) [OR (95% CI) = 25.18 (1.94, 325.83)], smokeless tobacco use (p = 0.002) [OR (95% CI) = 17.69 (2.80, 111.72)], and slow regression of local signs and symptoms after 2 months of treatment (p < 0.001) [OR (95% CI) = 17.09 [(5.79, 50.39)] were seen to be significantly associated with treatment extension. Identification of predictors of extended treatment can help clinical decisions regarding optimal duration of treatment. Further studies are needed to identify subgroups of EPTB patients who can benefit from a shorter or longer treatment regimen.

26016 Combined modality therapies adjunctive to hedgehog inhibitors in the management of basal cell carcinoma: A systematic review and pooled-analysis

Importance: Surgical and radiation treatment modalities can have limited effectiveness in the management of patients with locally advanced basal cell carcinoma (laBCC) due to size, location, aggressive lesion morphologies and higher potential for metastasis. Hedgehog inhibitors show promise but have limitations due to low rates of complete response, undesirable adverse effects with longer treatment regimens and tumor recurrence after discontinuation.

Factors affecting outcome of longer regimen multidrug-resistant tuberculosis treatment in West Java Indonesia: A retrospective cohort study.

BackgroundMultidrug-resistant tuberculosis had high treatment failure and mortality. Success rate of treatment currently 56% at global level, 48% in Indonesia and 36% in West Java province, the most populated province and surround Jakarta, the capitol of Indonesia.ObjectiveThis study aimed to evaluate factors affecting success of multidrug-resistant tuberculosis treatment in patients using longer treatment regimen in West Java Indonesia.MethodsThis was a retrospective cohort study of multidrug-resistant tuberculosis patients treated with longer regimen at Hasan Sadikin General Hospital from January 2015 to December 2017. Potential risk factors associated with the treatment outcome were analyzed using multiple logistic regression.ResultsA total of 492 patients were enrolled during the study period. Fifty percents multidrug-resistant tuberculosis patients had successful treatment outcome. Age ≤45 years, male, normal body mass index, no previous tuberculosis treatment, culture conversion ≤2 months, acid fast bacilli sputum smear ≤+1 were independent factors associated with increased treatment success. Sputum culture conversion ≤2 months was the major factor affecting successful outcome (RR 2.79; 95% CI: 1.61–4.84; p-value<0.001). Human Immunodeficiency Virus infection, chronic kidney disease, and cavitary lesion were independent risk factors for unfavourable outcome.ConclusionAge, gender, body mass index, tuberculosis treatment history, time of sputum conversion, acid fast bacilli sputum smear, HIV infection, chronic kidney disease, and cavitary lesion can be used as predictors for longer multidrug-resistant tuberculosis treatment regimen outcome.

Combinatorial Administration of Pharmacological Inhibitors Targeting DNMT1 and KDM1A Produces Synergistic and Additive Increases in F Retiulocytes and γ-Globin Expression in Normal Baboons

Sickle cell disease (SCD) is an inherited blood disorder that severely impacts the quality of life and reduces the life expectancy of approximately 100,000 patients in the U.S. and millions worldwide. Elevated levels of Fetal Hemoglobin (HbF; α2γ2) reduce the severity of symptoms and lengthen the life span of patients with sickle cell disease by inhibiting deoxy HbS polymerization. Hydroxyurea (HU), the only FDA-approved drug shown to increase HbF, is not effective in a subset of patientsand importantly, in the refractory individuals the increased HbFis heterogeneously distributed within the erythrocyte population resulting in a large fraction of erythrocytes lacking protective levels. Simian primates such as the baboon are widely acknowledged as the best animal models for testing the ability of new drugs to increase γ-globin expression because results in baboons are predictive of effects in man due to conservation of the structure and developmental stage-specific regulation of the β-like globin genes in simian primates. Our previous studies in baboons have shown that the most powerful drugs for reactivation of HbF are DNMT1 and KDM1A inhibitors targeting enzymes located within the co-repressor complexes that act to establish and maintain repressive epigenetic modifications at the γ-globin promoter to repress γ-globin expression. Treatment of baboons with either decitabine, an inhibitor of DNMT1, or RN-1, an inhibitor of KDM1A, strongly stimulates HbF. Dose-limiting effects of these drugs include neutropenia, thrombocytopenia, and/or thrombophilia. In this investigation we have explored the hypothesis that a treatment regimen comprised of both decitabine and RN-1 could achieve additive or synergistic effects on HbF while minimizing adverse hematological side effects. Three baboons (PA8695, PA8697, PA8698) were treated with two courses of different doses of RN-1 (0.25 and 0.125mg/kg/d) administered subcutaneously for 3 days to select an optimal RN-1 dose for each animal. The response to RN-1 varied between individual animals and was associated with pretreatment levels of γ-globin expression. Higher pretreatment levels of γ-globin expression were observed in PA8697 (0.08 γ/γ+β) compared to PA8695 (0.014+0.005 γ/γ+β) and PA8698 (0.004+0.0007 γ/γ+β) and the effect on γ-globin expression in PA8697 (0.24+0.5 γ/γ+β) at the 0.125mg/kg/d dose was greater than the effect of 0.25 mg/kg/d dose in PA8695 (0.17+0.05 γ/γ+β) and PA8698 (0.121+0.006 γ/γ+β). For combinatorial studies with decitabine, an RN-1 dose of 0.125mg/kg/d was chosen for PA8697 and 0.25mg/kg/d for PA8695 and 8698. Decitabine (0.3mg/kg/d; 2d), administered as a single agent subcutaneously for two days increased F retics nearly 3 fold (23.6+12.5%; p&amp;lt;0.02) compared to pretreatment levels (8.26+9.90%) but changes in γ-globin expression (0.066+0.076 γ/γ+β) compared to the pretreatment levels (0.03+0.042 γ/γ+β) were not significant. For combinatorial experiments, decitabine (0.3mg/kg/d) was administered for 2 days followed by administration of RN-1 (0.25mg/kg/d PA8695 and 8698; 0.125mg/kg/d PA8697) for 3 days. This staggered dose schedule was used to avoid any possible effects of RN-1 on cell cycle kinetics that could potentially reduce incorporation of decitabine during S phase. The decitabine/RN-1 combination produced significantly higher increases in F retics (63.0+23.6%; p&amp;lt;0.002) than either RN-1 (29.9+27.1%) or decitabine (23.6+12.5%) alone. The effect of the decitabine/RN-1 combination on F retics was greater than additive (p&amp;lt;0.01; Figure 1A) in the two low HbF animals, PA8695 and 8698, and additive for the high HbF animal PA8697 (Figure 1B). Although increased levels of γ-globin expression produced by the decitabine/RN-1 combination (0.22+0.08 γ/γ+β) were not significantly different overall from those induced by RN-1 alone (0.178+0.06 γ/γ+β), individual analysis of PA8697 revealed an additive effect (Figure 1C). Plt and ANC remained with the normal range. In conclusion, targeting separate components of the γ-globin co-repressor complex by combinatorial administration of decitabine and RN-1 generated synergistic and additive increases in F retics and γ-globin expression in the absence of hematological toxicity. Future experiments will explore different doses, alternative schedules, and the effect of longer term treatment regimens. Disclosures Saunthararajah: EpiDestiny: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties.

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease.

Introduction Mycobacterium abscessus is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary M. abscessus disease, and examined heterogeneity of response to NO in vitro.MethodsIn the compassionate-use treatment, a 24-year-old CF patient with pulmonary M. abscessus was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. In vitro susceptibility tests were performed against patient’s isolate and comparison clinical isolates and quantified by Hill’s slopes calculated from time–kill curves.Results M. abscessus lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. In vitro susceptibility tests showed a dose-dependent NO effect on M. abscessus susceptibility and significant heterogeneity in response between M. abscessus clinical isolates. The patient’s isolate was found to be the least susceptible strain in vitro.Conclusion These results demonstrate heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

Onychomycosis: a review.

Onychomycosis is a fungal infection of the nail, causing discoloration and thickening of the affected nail plate, and is the most common nail infection worldwide. Onychomycosis was initially thought to be predominantly caused by dermatophytes; however, new research has revealed that mixed infections and those caused by non-dermatophyte moulds (NDMs) are more prevalent than previously thought, especially in warmer climates. Microscopy and fungal culture are the gold standard techniques for onychomycosis diagnosis, but high false-negative rates have pushed for more accurate methods, such as histology and PCR. As NDMs are skin and laboratory contaminants, their presence as an infectious agent requires multiple confirmations and repeated sampling. There are several treatment options available, including oral antifungals, topicals and devices. Oral antifungals have higher cure rates and shorter treatment periods than topical treatments, but have adverse side effects such as hepatotoxicity and drug interactions. Terbinafine, itraconazole and fluconazole are most commonly used, with new oral antifungals such as fosravuconazole being evaluated. Topical treatments, such as efinaconazole, tavaborole, ciclopirox and amorolfine have less serious side effects, but also have generally lower cure rates and much longer treatment regimens. New topical formulations are being investigated as faster-acting alternatives to the currently available topical treatments. Devices such as lasers have shown promise in improving the cosmetic appearance of the nail, but due to a high variation of study methods and definitions of cure, their effectiveness for onychomycosis has yet to be sufficiently proven. Recurrence rates for onychomycosis are high; once infected, patients should seek medical treatment as soon as possible and sanitize their shoes and socks. Prophylactic application of topicals and avoiding walking barefoot in public places may help prevent recurrence.

Effect of Nutritional Support on Treatment of Multi-Drug Resistant Tuberculosis in Rajshahi Division, Bangladesh

Introduction: Multi-drug resistant tuberculosis (MDR-TB) is a public health crisis throughout the world including Bangladesh particularly due to its complexities in diagnosis, longer treatment regimen, and adverse drug reaction. Nutritional supplementation has significant impact on patient’s weigh gain and optimum weight gain is a biomarker of treatment response. The objective of this study was to measure body mass index (BMI) progress among MDR-TB patients in different phases of treatment. Methodology: A prospective observational study was conducted from March 2010 to July 2015 in Chest Disease Hospital (CDH), Rajshahi and different communities of Rajshahi Division, Bangladesh. A total of 233 confirmed MDR-TB patients were selected from CDH who received treatment and nutritional support from ongoing national TB control program (NTP). They received free diagnosis, follow up tests, treatment and nutritional support as regular diet as well as cash amount Bangladeshi taka (BDT.) 1000 per month in CDH. Along with treatment, they also received only cash amount BDT. 1500 per month as nutritional support at community level. Weight measurement was taken at regular interval from enrollment to completion of treatment. Chi-square, paired t-test and linear regression analysis were used in this study. Results: The baseline prevalence of undernourished (BMI 2) was 82.4%. After two months of treatment, 14.5% underweight patients gained weight and reverted to normal BMI. Regression analysis showed the decreasing tendency of BMI progress with increasing age which was significant among male patients (p 92%). Conclusion: Nutritional support has synergistic effect on treatment response. Adequate nutritional support with proper treatment would help to get better outcomes particularly at community level. Gender issue should also be addressed at household level.

The safety and efficacy of miltefosine in the long-term treatment of post-kala-azar dermal leishmaniasis in South Asia - A review and meta-analysis.

BackgroundMiltefosine (MF) is the only oral drug available for treatment of visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). Although the drug is effective and well tolerated in treatment of VL, the efficacy and safety of MF for longer treatment durations (>28 days) in PKDL remains unclear. This study provides an overview of the current knowledge about safety and efficacy of long treatment courses with MF in PKDL, as a strategy in the VL elimination in South Asia.Methodology/Principal findingsLiterature was searched systematically for articles investigating MF treatment in PKDL. A meta-analysis included eight studies (total 324 PKDL patients) to estimate the efficacy of MF in longer treatment regimens (range 6–16 weeks). We found a per-protocol (PP) initial cure rate of 95.2% (95%CI 89.6–100.8) and a PP definite cure rate of 90% (95%CI 81.6–96.3). Descriptive analysis showed that 20% of patients experienced adverse events, which mostly had an onset in the first week of treatment and were likely to get more severe after four weeks of treatment. Gastrointestinal (GI) side effects such as vomiting, nausea, diarrhoea, and abdominal pain were most common.Conclusions/SignificanceLonger treatment regimens with MF are effective in PKDL patients in India, however with the caveat that the efficacy has recently been observed to decline. GI side effects are frequent, although mostly mild or moderate. However, on the basis of limited data, we cannot conclude that longer MF treatment regimens are safe. Moreover, VL and PKDL pharmacovigilance studies indicate a risk for serious adverse events, questioning the safety of MF. The provision of safer treatment regimens for PKDL patients are therefore recommended. Until these regimens are identified, it should be considered to halt the use of MF monotherapy for PKDL in order to preserve the drug’s efficacy.

Six months therapy for tuberculous meningitis.

Tuberculous meningitis (TBM) is the main form of tuberculosis that affects the central nervous system and is associated with high rates of death and disability. Most international guidelines recommend longer antituberculous treatment (ATT) regimens for TBM than for pulmonary tuberculosis disease to prevent relapse. However, longer regimens are associated with poor adherence, which could contribute to increased relapse, development of drug resistance, and increased costs to patients and healthcare systems. To compare the effects of short-course (six months) regimens versus prolonged-course regimens for people with tuberculous meningitis (TBM). We searched the following databases up to 31 March 2016: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; EMBASE; LILACS; INDMED; and the South Asian Database of Controlled Clinical Trials. We searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov for ongoing trials. We also checked article reference lists and contacted researchers in the field. We included randomized controlled trials (RCTs) and prospective cohort studies of adults and children with TBM treated with antituberculous regimens that included rifampicin for six months or longer than six months. The primary outcome was relapse, and included studies required a minimum of six months follow-up after completion of treatment. Two review authors (SJ and HR) independently assessed the literature search results for eligibility, and performed data extraction and 'Risk of bias' assessments of the included studies. We contacted study authors for additional information when necessary. Most data came from single arm cohort studies without a direct comparison so we pooled the findings for each group of cohorts and presented them separately using a complete-case analysis. We assessed the quality of the evidence narratively, as using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was inappropriate with no direct comparisons between short- and prolonged-course regimens. Four RCTs and 12 prospective cohort studies met our inclusion criteria, and included a total of 1881 participants with TBM. None of the included RCTs directly compared six months versus longer regimens, so we analysed all data as individual cohorts to obtain relapse rates in each set of cohorts.We included seven cohorts of participants treated for six months, with a total of 458 participants. Three studies were conducted in Thailand, two in South Africa, and one each in Ecuador and Papua New Guinea between the 1980s and 2009. We included 12 cohorts of participants treated for longer than six months (ranging from eight to 16 months), with a total of 1423 participants. Four studies were conducted in India, three in Thailand and one each in China, South Africa, Romania, Turkey and Vietnam, between the late 1970s and 2011.The proportion of participants classified as having stage III disease (severe) was higher in the cohorts treated for six months (33.2% versus 16.9%), but the proportion with known concurrent HIV was higher in the cohorts treated for longer (0/458 versus 122/1423). Although there were variations in the treatment regimens, most cohorts received isoniazid, rifampicin, and pyrazinamide during the intensive phase.Investigators achieved follow-up beyond 18 months after completing treatment in three out of the seven cohorts treated for six months, and five out of the 12 cohorts treated for eight to 16 months. All studies had potential sources of bias in their estimation of the relapse rate, and comparisons between the cohorts could be confounded.Relapse was an uncommon event across both groups of cohorts (3/369 (0.8%) with six months treatment versus 7/915 (0.8%) with longer), with only one death attributed to relapse in each group.Overall, the proportion of participants who died was higher in the cohorts treated for longer than six months (447/1423 (31.4%) versus 58/458 (12.7%)). However, most deaths occurred during the first six months in both treatment cohorts, which suggested that the difference in death rate was not directly related to duration of ATT but was due to confounding. Clinical cure was higher in the group of cohorts treated for six months (408/458 (89.1%) versus longer than six months (984/1336 (73.7%)), consistent with the observations for deaths.Few participants defaulted from treatment with six months treatment (4/370 (1.1%)) versus longer treatment (8/355 (2.3%)), and adherence was not well reported. In all cohorts most deaths occurred in the first six months; and relapse was uncommon in all participants irrespective of the regimen. Further inferences are probably inappropriate given this is observational data and confounding is likely. These data are almost all from participants who are HIV-negative, and thus the inferences will not apply to the efficacy and safety of the six months regimens in HIV-positive people. Well-designed RCTs, or large prospective cohort studies, comparing six months with longer treatment regimens with long follow-up periods established at initiation of ATT are needed to resolve the uncertainty regarding the safety and efficacy of six months regimens for TBM.

Prolonged Oral Administration of a Pan-Retinoic Acid Receptor Antagonist Inhibits Spermatogenesis in Mice With a Rapid Recovery and Changes in the Expression of Influx and Efflux Transporters.

We have previously shown that oral administration of a pan-retinoic acid receptor antagonist in mice daily at 2.5 mg/kg for 4 weeks reversibly inhibited spermatogenesis, with no detectable side effects. To elucidate the lowest dose and the longest dosing regimen that inhibits spermatogenesis but results in complete restoration of fertility upon cessation of administration of the drug, we examined the effects of daily doses as low as 1.0 mg/kg with dosing periods of 4, 8, and 16 weeks. We observed 100% sterility in all regimens, with restoration of fertility upon cessation of the drug treatment even for as long as 16 weeks. There was no change in testosterone levels in these males and the progeny examined from 2 of the recovered males were healthy and fertile, with normal testicular weight and testicular histology. Strikingly, a more rapid recovery, as assessed by mating studies, was observed at the lower dose and longer dosing periods. Insight into possible mechanisms underlying this rapid recovery was obtained at 2 levels. First, histological examination revealed that spermatogenesis was not as severely disrupted at the lower dose and with the longer treatment regimens. Second, gene expression analysis revealed that the more rapid recovery may involve the interplay of ATP-binding cassette efflux and solute carrier influx transporters in the testes.

Intravenous silibinin monotherapy shows significant antiviral activity in HCV-infected patients in the peri-transplantation period

Hepatitis C recurrence after liver transplantation (LT) is the main problem of most transplant programs. We aimed at assessing the antiviral activity and safety of intravenous silibinin (SIL) administered daily during the peri-transplant period. This was a single-centre, prospective, randomized, double-blind, placebo-controlled study including 14 HCV-infected patients awaiting LT. Eleven patients received SIL and 3 placebo, for a maximum of 21 days before LT and 7 days after LT. Among the patients who received more than 14 days of pre-LT treatment, the median decrease in viral load (VL) was 2.31 log(10) (range 0.6-4.2) in the SIL-treated group (n=9) versus 0.30 log(10) (0.1-0.6) in the placebo group (n=3) (p=0.016). During the post-LT treatment, HCV-RNA levels were consistently and significantly (p=0.002) lower in the SIL group compared to placebo and decreased below the limit of quantification in 2 patients and below the limit of detection in 2 additional patients (all in the SIL-treated group). Peri-transplant treatment with SIL was well tolerated. This proof-of-concept study in patients in the waiting list for LT indicates that daily intravenous silibinin has evident antiviral properties and is well tolerated in the peri-LT period. A longer treatment regimen with silibinin (alone or in combination with other agents) should be assessed in clinical trials for the prevention of hepatitis C recurrence.

Resistance to Anti-Infective Drugs and the Threat to Public Health

Increasing resistance of pathogens to anti-infective drugs is an urgent public health problem that must be addressed through more prudent use of these drugs in human medicine and in animal husbandry, agriculture, and aquaculture.

Short-course radiation therapy in the treatment of head and neck tumors.

A pilot study undertaken to evaluate short-course, high-increment radiation therapy. This type of treatment was tolerated well by the patients, with a surprisingly low level of acute reaction to the regimen and few late complications. Tumor regression seemed to be earlier than might be expected and involved more than 50% of the tumor in over 75% of the patients following the fourth course of treatment. Preliminary results show that long-range survival rates are at least equivalent to those obtained with the conventional longer treatment regimen. In general, this seems to be a more economical and efficient method of treatment which entails less patient discomfort than the conventional method.