Impact of Undernutrition on Tuberculosis Treatment Outcomes in India: A Multicenter, Prospective, Cohort Analysis.

BACKGROUND: Undernutrition is the leading risk factor for tuberculosis (TB) globally. Its impact on treatment outcomes is poorly defined. METHODS: We conducted a prospective cohort analysis of adults with drug-sensitive pulmonary TB at 5 sites from 2015-2019. Using multivariable Poisson regression, we assessed associations between unfavorable outcomes and nutritional status based on body mass index (BMI) nutritional status at treatment initiation, BMI prior to TB disease, stunting, and stagnant or declining BMI after 2 months of TB treatment. Unfavorable outcome was defined as a composite of treatment failure, death, or relapse within 6 months of treatment completion. RESULTS: Severe undernutrition (BMI <16 kg/m2) at treatment initiation and severe undernutrition before the onset of TB disease were both associated with unfavorable outcomes (adjusted incidence rate ratio [aIRR], 2.05; 95% confidence interval [CI], 1.42-2.91 and aIRR, 2.20; 95% CI, 1.16-3.94, respectively). Additionally, lack of BMI increase after treatment initiation was associated with increased unfavorable outcomes (aIRR, 1.81; 95% CI, 1.27-2.61). Severe stunting (height-for-age z score <-3) was associated with unfavorable outcomes (aIRR, 1.52; 95% CI, 1.00-2.24). Severe undernutrition at treatment initiation and lack of BMI increase during treatment were associated with a 4- and 5-fold higher rate of death, respectively. CONCLUSIONS: Premorbid undernutrition, undernutrition at treatment initiation, lack of BMI increase after intensive therapy, and severe stunting are associated with unfavorable TB treatment outcomes. These data highlight the need to address this widely prevalent TB comorbidity. Nutritional assessment should be integrated into standard TB care.

Perioperative factors associated with acute kidney injury after partial nephrectomy.

BACKGROUND: Partial nephrectomy is performed with the aim to preserve renal function. But the occurrence of postoperative acute kidney injury (AKI) can interfere with this goal. Our primary aim was to evaluate associations between pre-specified modifiable factors and estimated glomerular filtration rate after partial nephrectomy. Our secondary aims were to evaluate associations between pre-specified modifiable factors and both serum creatinine concentration and type of nephrectomy. METHODS: The records of 1955 patients who underwent partial nephrectomy were collected. Postoperative estimated glomerular filtration rate (eGFR) was used as the primary outcome measure. Twenty modifiable risk factors were studied. A repeated-measures linear model with autoregressive within-subject correlation structure was used. The interaction between all the factors and type of nephrectomy was also studied. RESULTS: A total of 1187 (61%) patients had no kidney injury, 647 (33%) had stage I, 80 (4%) had stage II, and 41 (2%) had stage III injury. The mean eGFR increased an estimated 0.83 (99.76% CI 0.79-0.88) ml min(-1) 1.73 m(-2) for a unit increase in baseline eGFR. Mean eGFR was 2.65 (99.76% CI: 0.13, 5.18) ml min(-1) 1.73 m(-2) lower in patients with hypertension. Mean eGFR decreased 0.42 (99.76% CI: 0.22, 0.62) ml min(-1) 1.73 m(-2) for a 10-minute longer in duration of procedure and decreased 2.09 (99.76% CI: 1.39, 2.80) ml min(-1) 1.73 m(-2) for a 10-minute longer in ischemia time. It was 3.53 (99.76% CI: 0.83, 6.23) ml min(-1) 1.73 m(-2) lower for patients who received warm ischemia as compared to cold ischemia. CONCLUSION: Potentially modifiable factors associated with AKI in the postoperative period were identified as baseline renal function, preoperative hypertension, longer duration of surgical time and ischaemia time, and warm ischaemia.

Multivariate combination of magnetization transfer, T2* and B0 orientation to study the myelo-architecture of the in vivo human cortex.

Recently, T2* imaging at 7Tesla (T) MRI was shown to reveal microstructural features of the cortical myeloarchitecture thanks to an increase in contrast-to-noise ratio. However, several confounds hamper the specificity of T2* measures (iron content, blood vessels, tissues orientation). Another metric, magnetization transfer ratio (MTR), is known to also be sensitive to myelin content and thus would be an excellent complementary measure because its underlying contrast mechanisms are different than that from T2*. The goal of this study was thus to combine MTR and T2* using multivariate statistics in order to gain insights into cortical myelin content. Seven healthy subjects were scanned at 7T and 3T to obtain T2* and MTR data, respectively. A multivariate myelin estimation model (MMEM) was developed, and consists in (i) normalizing T2* and MTR values and (ii) extracting their shared information using independent component analysis (ICA). B0 orientation dependence and cortical thickness were also computed and included in the model. Results showed high correlation between MTR and T2* in the whole cortex (r=0.76, p<10(-16)), suggesting that both metrics are partly driven by a common source of contrast, here assumed to be the myelin. Average MTR and T2* were respectively 31.0+/-0.3% and 32.1+/-1.4 ms. Results of the MMEM spatial distribution showed similar trends to that from histological work stained for myelin (r=0.77, p<0.01). Significant right-left differences were detected in the primary motor cortex (p<0.05), the posterior cingulate cortex (p<0.05) and the visual cortex (p<0.05). This study demonstrates that MTR and T2* are highly correlated in the cortex. The combination of MTR, T2*, CT and B0 orientation may be a useful means to study cortical myeloarchitecture with more specificity than using any of the individual methods. The MMEM framework is extendable to other contrasts such as T1 and diffusion MRI.

Development and Validation of a LC-MS/MS Method for the Profiling of Impurities Formed during Stress Study of Antifungal Agent-Efinaconazole.

Liquid chromatography interfaced with mass spectroscopy (LC-MS) is a sensitive and effective analytical method that combines high-resolution separation as well as specific mass detection of impurities in formulated products and as well as in active pharmaceutical ingredient (API). In this study, LC-MS/MS was used to determine impurities formed during the stability period of Efinaconazole (EFZ, a triazole antifungal agent). The method was validated for its assay parameters such as specificity, linearity, accuracy, precision and also for solution stability. The calibration curve was found to be linear for the concentration range from 0.5 µg/mL to 30 µg/mL. A thorough investigation was performed by exposing Efinaconazole (1 mg/mL) to various stress conditions such as hydrolysis (acid and alkaline), oxidation, photolysis and temperature at various time intervals to achieve 10% degradation. The impurities formed during forced degradation were separated using high-performance liquid chromatography later it was identified using LC-MS/MS technique. The obtained results showed that EFZ is prone to oxidation when exposed to a 3% aqueous medium of hydrogen peroxide solution and quite stable in all the remaining stress conditions for a longer period.

Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study.

BACKGROUND: Given the close correlation between smoking and alcohol intake in most epidemiologic studies, it is difficult to exclude the residual confounding effect of alcohol in the association between smoking and hepatocellular carcinoma (HCC). METHOD: We evaluated the association between smoking and risk of HCC in the Singapore Chinese Health Study, a prospective cohort with a low prevalence of alcohol intake. Information on cigarette smoking and alcohol consumption was obtained through in-person interviews conducted at enrolment. RESULTS: After a mean of 11.5 years of follow-up, there were 394 incident cases of HCC. Participants who consumed more than two alcoholic drinks per day showed an increased risk for HCC (hazard ratio (HR)=2.24; 95% confidence interval (CI)=1.46-3.41). After adjusting for alcohol consumption and other potential confounders, current vs never smokers had a statistically significant, increased risk of HCC (HR=1.63; 95% CI=1.27-2.10) that was dose-dependent (number of cigarettes per day, P for trend<0.001). The observed tobacco-HCC association also was duration-dependent (years of smoking in ever smokers, P for trend=0.002). When we excluded daily drinkers from the analysis, all risk estimates remained essentially the same and statistically significant. CONCLUSION: Our findings strongly implicate tobacco smoke as a causal factor of HCC development.

Aloe vera and its two bioactive constituents in alleviation of diabetes -proteomic & mechanistic insights.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe barbadensis Miller, commonly known as Aloe vera has been used since time immemorial for treatment of various diseases such as cancer, inflammatory disorders, diabetes, wound healing etc. AIM: Diabetes mellitus is a complex disorder and understanding the molecular mechanisms involved is a key to identify different markers for early diagnosis of the disease. The proteomic approach offers a plethora of opportunities to identify markers and targets involved in pathogenesis of diabetes. The present study was undertaken to understand the mechanism of action of Aloe vera and its two constituents (Carbohydrates and Polypeptides) in the alleviation of diabetes in streptozotocin-induced diabetic rats through a proteomics approach. METHODS: Different groups of rats were fed with Aloe vera extract, carbohydrate fraction and peptide/polypeptide fraction for three weeks. The diabetic rats fed with Aloe vera and its two fractions restored the glucose and insulin levels to normal. The plasma of the rats was depleted with IgG and albumin and proteomic analysis was carried out. Apolipoproteins (dyslipidemia), complement factors (inflammatory pathways), zonulin (intestinal permeability), anti-oxidant related proteins were selected in this study as these are involved in the progression of diabetes. RESULTS: It was observed that Aloe vera extract is involved in the alleviation of diabetes through these pathways while the carbohydrate fraction alleviates diabetes through an anti-oxidant mechanism and glucose uptake while the polypeptide fraction alleviates diabetes through the restoration of intestinal permeability by reduced zonulin levels. CONCLUSION: The constituents of Aloe vera works different pathways involved in diabetes and the synergistic effect of these constituents make Aloe vera extract a prospective candidate, which can alleviate diabetes through regulation of the pathways involved in the progression of diabetes.

Role of zonulin and GLP-1/DPP-IV in alleviation of diabetes mellitus by peptide/polypeptide fraction of Aloe vera in streptozotocin- induced diabetic wistar rats.

ETHNO-PHARMACOLOGICAL RELEVANCE: The genus Aloe has a long history of usage in medicine. Aloe barbadensis Miller, commonly known as Aloe vera, is said to possess anti-diabetic, anti-inflammatory, anti-cancer, anti-microbial, immunomodulation, wound healing properties. AIM OF THE STUDY: In diabetes mellitus, loss in intestinal permeability is observed with high levels of zonulin and low levels of glucagon-like peptide-1 (GLP-1) leading to hyperglycemia. The aim of the study was to understand the role of peptide/polypeptide fraction (PPF) of Aloe vera in the alleviation of diabetes through maintaining the intestinal permeability by regulating the zonulin and GLP-1 levels. MATERIALS AND METHODS: The PPF of Aloe vera was obtained through trichloroacetic acid precipitation. The anti-diabetic potential of the PPF was tested through DPP-IV inhibition, glucose diffusion assay, and by using Rin-m5F cells. The anti-diabetic potential of the PPF was tested at a dose of 0.450 mg/kg bw in vivo using streptozotocin-induced diabetic Wistar rats. The effect of PPF on fasting plasma glucose, insulin, glucagon, Zonulin, GLP-1, DPP-IV, levels were studied in diabetic rats. The histopathological studies of the pancreas, small intestine, and liver were carried out for organ-specific effects. RESULTS: PPF has the ability to reduce fasting plasma glucose levels with concomitant increase in insulin levels in streptozotocin-induced diabetic rats. It was also observed that increase in GLP-1 levels with a decrease in DPP-IV and zonulin levels thereby mitigating the loss of intestinal permeability. These findings correlate with the small intestine's histopathological observation where the excessive proliferation of epithelium in the small intestine of diabetic rats was reduced after PPF treatment. CONCLUSION: These results suggest that the PPF of Aloe vera alleviates diabetes through islet cell rejuvenation via GLP-1/DPP-IV pathway and thereby suggesting the usage of PPF as an alternate medicine for diabetes mellitus with the possibility to reduce the intestinal permeability and zonulin levels.

Lack of protective immunity against reinfection with hepatitis C virus.

Some individuals infected with hepatitis C virus (HCV) experience multiple episodes of acute hepatitis. It is unclear whether these episodes are due to reinfection with HCV or to reactivation of the original virus infection. Markers of viral replication and host immunity were studied in five chimpanzees sequentially inoculated over a period of 3 years with different HCV strains of proven infectivity. Each rechallenge of a convalescent chimpanzee with the same or a different HCV strain resulted in the reappearance of viremia, which was due to infection with the subsequent challenge virus. The evidence indicates that HCV infection does not elicit protective immunity against reinfection with homologous or heterologous strains, which raises concerns for the development of effective vaccines against HCV.

Amino-guanidinium hydrogen succinate.

The title compound, CH(7)N(4) (+)·C(4)H(5)O(4) (-), is a molecular salt containing discrete amino-guanidinium and succinate ions. The amino-guanidinium cation is nearly planar, with a maximum deviation of 0.035 (1) Å. The dihedral angle between the amino-guanidinium cation and the succinate anion is 3.35 (6)°. The crystal packing exhibits inter-molecular N-H⋯O and O-H⋯·O hydrogen bonds.

Piperazinediium dioxamate.

The title compound, C(4)H(12)N(2) (2+)·2C(2)H(2)NO(3) (-), contains a network of doubly protanated piperazinium cations (lying about centres of inversion) and dioxamate anions. The piperazinium dication adopts a typical chair conformation. The crystal structure is stabilized by cation-to-anion N-H⋯O and anion-to-anion N-H⋯O hydrogen bonds.

Water-soluble Cobalt(II) & Cobalt(III) complexes supported by new triazine Schiff base ligands: Synthesis, structure and biological evaluation.

A new class of triazine ligands (E)-2-(2-(6-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)hydrazono)propanoic acid hydrate (HL1.H2O) and (Z)-2-(((E)-4-amino-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3(2H)ylidene)hydrazono)propanoic acid (H2L2) has been synthesized by the condensation reaction of pyruvic acid with diaminoguanidine and triaminoguanidine respectively. The corresponding Schiff base cobalt complexes [Co(L1)2].2H2O (1) and [Co(HL2)(L2)].H2O (2) have also been synthesized and characterized by analytical, thermal, spectroscopic and diffraction studies. Strong field ligand results low spin Co(III) centre in 2, which was evidenced by the shorter bond length of Co(III) complex. In H2L2 there is a choice of coordination modes based on distinct sets of donor atoms, both of which are seen in complex 2, involving either an -NH2 group on position 4 of the triazine ring, or via a ring nitrogen of the triazine itself. The deprotonation of one version of L2 allows the formation of the ligand field stabilized low spin Co(III) in 2. In complex 1, each ligand binds to the metal via pyruvate oxygen, azomethine nitrogen and triazine nitrogen forming two five-membered stable chelate rings. In complex 2, the coordination sphere assembled by two types of coordinating atoms from the same ligand with different conformation. Their binding ability and mode of binding with CT-DNA and BSA was studied by UV- absorption, fluorescence and CD spectroscopy. Density Functional Theory (DFT) studies provide further insights into the mode of binding, structure and mechanism. The HOMO and LUMO energy gap values indicate that both the complexes are prone to interact with CT-DNA and BSA. We have also performed molecular docking calculations to understand the mode of binding and the corresponding results confirm our experimental findings.

Intrahepatic lymphocyte phenotypes in hepatitis C virus infection: a comparison between cirrhotic and non-cirrhotic livers.

AIM: The pathogenesis of viral hepatitis involves the activation of cellular immunity, including intrahepatic lymphocytes (IHL). Lym-phocyte phenotypes play a fundamental role in the pathogenesis of chronic hepatitis C virus (HCV) infection, the progression of liver fibrosis and subsequent hepatocellular carcinoma. The aim of this study was to evaluate the frequency of intrahepatic mononuclear cell phenotypes in patients with chronic HCV. Another aim was to assess the relationship of nonparenchymal cells with liver fibrosis. METHODS: Liver fibrosis was evaluated with the Histologic Activity Index. Fourteen liver biopsies showed mild fibrosis (group 1), and 11 bridging fibrosis (group 2). Fourteen samples were explants from HCV patients who underwent liver transplantation (group 3). CD4 and CD8 T-lymphocytes, CD20 (B lymphocytes), CD16 (macrophage), and CD57 (NK) cells were detected using monoclonal antibodies on paraffin-embedded tissue. RESULTS: A minority of lobular cells stained for T- or B-lymphocytes. Most lobular cells stained with macrophage antibodies, and were more common in bridging fibrosis, compared to mild fibrosis. The percentages of lobular CD4 and CD8 cells were significantly lower in regenerative nodules of cirrhotic livers. There was a strong negative correlation between lobular CD8 and fibrosis score (R= -0.65), and a strong positive correlation between CD16-stained mononuclear cells (macrophages) and fibrosis score (R=0.66). In portal and periportal areas, CD4 but not CD8 lymphocytes decreased in parallel with fibrosis. B-lymphocytes were more commonly found in the portal areas than in the lobule. CD57-positive cells were rare in both lobule and portal areas, and their frequency was not different in the three groups studied. CONCLUSIONS: In hepatitis C, lobular mononuclear cells are mostly macrophages and appear associated with bridging fibrosis. Cirrhotic livers display significantly lower numbers of lobular CD4 and CD8 lymphocytes. This finding could help explain a decrease in immune surveillance and the promotion of neoplastic growth in HCV-associated cirrhosis.

Prevalence of rifampicin-resistant Mycobacterium tuberculosis among human-immunodeficiency-virus-seropositive patients and their treatment outcomes.

Multidrug resistant (MDR) and extensively drug resistant tuberculosis (TB) are a threat to the TB control programs in developing countries, and the situation is worsened by the human immunodeficiency virus (HIV) pandemic. This study was performed to correlate treatment outcome with the resistance patterns in HIV-seropositive patients coinfected with pulmonary TB. Sputum specimens were collected from 1643 HIV-seropositive patients and subjected to microscopy and liquid culture for TB. The smear- and culture-positive Mycobacterium tuberculosis isolates were subjected to Genotype MTBDRplus assay version 2.0. The M. tuberculosis culture-positivity rate was 39.44% (648/1643) among the 1643 HIV-seropositive patients and the overall MDR-TB rate was 5.6% (36/648). There were 421 newly diagnosed and 227 previously treated patients, among whom, MDR-TB was associated with 2.9% and 10.57% cases, respectively. The rate of rifampicin monoresistant TB among the cases of MDR-TB was 2.31% (15/648) and the rate of combined rifampicin and isoniazid resistance was 3.24% (21/648). The cure and death rates among the 20 registered cases were 30% (6/20) and 35% (7/20), respectively. Five cases were on treatment and two cases were defaulters among the 20 registered cases. High death rate (13, 36.1%, 95% confidence interval 20.8-53.8) was observed in this study among the patients who had mutations at the 530-533 codons. The present study emphasized the prerequisite to monitor the trend of drug-resistant TB in various mutant populations in order to timely implement appropriate interventions to curb the threat of MDR-TB.

A comparison of 7-day versus 10-day course of low-dose dexamethasone for chronically ventilated preterm infants.

OBJECTIVE: The objective of the study was to compare the effect of two different dexamethasone regimens on respiratory outcomes of ventilator-dependent preterm infants. STUDY DESIGN: Retrospective study of ventilated preterm infants <29 weeks gestational age treated with either 7-day or 10-day dexamethasone course. Primary outcome was days to successful extubation. Other outcomes included rate of successful extubation and need for repeat steroid therapy. RESULTS: Fifty-nine infants were identified; 32 (54%) received 7 days of dexamethasone and 27 (46%) received 10 days of dexamethasone. Both groups had comparable baseline demographics and clinical characteristics. Mean time to successful extubation was similar between the two groups (5.1±2.7 days in 7-day group and 6.0±3.7 days in 10-day group, P=0.42). Successful extubation by end of treatment (56% versus 67%, P=0.44) and need for repeat steroid therapy (47% versus 33%, P=0.43) were also similar. CONCLUSION: 7-day and 10-day course of dexamethasone have comparable efficacy in facilitating extubation of ventilator-dependent preterm infants.

Comorbidities in pulmonary tuberculosis cases in Puducherry and Tamil Nadu, India: Opportunities for intervention.

BACKGROUND: We aimed to define characteristics of TB patients in Puducherry and two districts of Tamil Nadu, India and calculate the population attributable fractions (PAF) of TB from malnutrition and alcohol. METHODS: New smear-positive TB cases were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT India) cohort. Census and National Family Health Survey data were used for comparisons. RESULTS: Data were analyzed for 409 participants enrolled between May 2014-June 2016; 307 (75.1%) were male, 60.2% were malnourished (body mass index [BMI] <18.5 kg/m2), and 29.1% severely malnourished (BMI <16). "Hazardous" alcohol use (based on AUDIT-C score) was reported by 155/305 (50.8%) of males. Tuberculosis cases were more likely than the Puducherry population to be malnourished (62.6% v 10.2% males and 71.7% v 11.3% of females; both p<0.001), and male cases were more likely to use alcohol than male non-cases (84.4% v 41%; p < .001). The PAF of malnutrition was 57.4% in males and 61.5% in females; the PAF for alcohol use was 73.8% in males and 1.7% in females. CONCLUSIONS: Alcohol use in men and malnutrition are helping drive the TB epidemic in Southern India. Reducing the TB burden in this population will require efforts to mitigate these risk factors.

Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma.

A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.

Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California.

We conducted interviews on 74 patients with histologically confirmed hepatocellular carcinoma. These patients, aged 18-74 years, were black or white residents of Los Angeles County. We also interviewed 162 population control subjects who were comparable to the case patients by age, sex, and race. Cigarette smoking was a significant risk factor for hepatocellular carcinoma [relative risk (RR) = 2.1; 95% confidence limits (CL) = 1.1, 4.0]; the effects were similar in men and in women. Heavy alcohol consumption was another risk factor for hepatocellular carcinoma in men; men who consumed 80 g or more of ethanol per day had an RR of 4.7 (95% CL = 1.4, 15.4) relative to those who had never drunk alcohol on a weekly basis. The level of alcohol intake was relatively low in women, and no significant effect on risk of hepatocellular carcinoma was observed. Use of oral contraceptives was significantly related to risk of hepatocellular carcinoma in women (RR = 3.0; 95% CL = 1.0, 8.8); those who were exposed for more than 5 years exhibited a 5.5-fold increased risk (95% CL = 1.2, 24.8). The effects of these three risk factors on hepatocellular carcinoma development were independent of each other and independent of serologically determined viral hepatitis. Our data suggest that cigarette smoking, alcohol consumption, and use of oral contraceptives are major risk factors for hepatocellular carcinoma among non-Asian residents of Los Angeles County. We also observed a significant association between a history of diabetes and hepatocellular carcinoma (RR = 3.3; 95% CL = 1.5, 7.2), especially among those who had received insulin treatment (RR = 18.5; 95% CL = 2.2, 156.0). This association may have etiological significance.

Prevalence of hepatitis B and C viral markers in black and white patients with hepatocellular carcinoma in the United States.

The recent cloning of the genome of a non-A, non-B hepatitis agent, designated the hepatitis C virus (HCV), has led to the development of an immunoassay for circulating HCV antibodies (anti-HCV). We used this immunoassay to investigate the possible association between HCV infection and hepatocellular carcinoma in black and white residents of Los Angeles County, California. Serum samples from 51 patients (12 black and 39 white) in Los Angeles County with hepatocellular carcinoma and 128 control subjects (1 black and 127 white) were tested for the presence of anti-HCV. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). Our results indicate that the presence of anti-HCV was a significant risk factor for hepatocellular carcinoma; the relative risk was 10.5 (95% confidence limits = 3.5, 31.3). Hepatocellular carcinoma risk was also significantly related to the presence of one or more of the hepatitis B virus (HBV) markers, primarily HBsAg and anti-HBc, and the relative risk was 7.0 (95% confidence limits = 3.1, 16.1). HCV and HBV independently contributed to hepatocellular carcinoma development. Significantly increased risk of hepatocellular carcinoma was demonstrated in individuals with HCV (relative risk = 4.8) or HBV (relative risk = 4.4) serologic markers alone. A synergistic effect on risk was observed when both hepatitis B and C viral markers were present in peripheral blood (10 cases vs. no controls). We estimate that approximately 47% of hepatocellular carcinoma occurring in black and white residents of Los Angeles County could be attributed to prior HCV and/or HBV infections: 9% were related to HCV alone, 20% to HBV alone, and 18% to occurrence of both HCV and HBV infections.

MDR-TB in Puducherry, India: reduction in attrition and turnaround time in the diagnosis and treatment pathway.

Setting: A mixed-methods operational research (OR) study was conducted to examine the diagnosis and treatment pathway of patients with presumptive multidrug-resistant tuberculosis (MDR-TB) during 2012-2013 under the national TB programme in Puducherry, India. High pre-diagnosis and pre-treatment attrition and the reasons for these were identified. The recommendations from this OR were implemented and we planned to assess systematically whether there were any improvements. Objectives: Among patients with presumptive MDR-TB (July-December 2014), 1) to determine pre-diagnosis and pre-treatment attrition, 2) to determine factors associated with pre-diagnosis attrition, 3) to determine the turnaround time (TAT) from eligibility to testing and from diagnosis to treatment initiation, and 4) to compare these findings with those of the previous study (2012-2013). Design: This was a retrospective cohort study based on record review. Results: Compared to the previous study, there was a decrease in pre-diagnosis attrition from 45% to 24% (P < 0.001), in pre-treatment attrition from 29% to 0% (P = 0.18), in the TAT from eligibility to testing from a median of 11 days to 10 days (P = 0.89) and in the TAT from diagnosis to treatment initiation from a median of 38 days to 19 days (P = 0.04). There is further scope for reducing pre-diagnosis attrition by addressing the high risk of patients with human immunodeficiency virus and TB co-infection or those with extra-pulmonary TB not undergoing drug susceptibility testing. Conclusion: The implementation of findings from OR resulted in improved programme outcomes.

Contexte : Une recherche opérationnelle basée sur un mélange de méthodes a été réalisée afin d'étudier le parcours de diagnostic et de traitement des patients atteints d'une tuberculose multirésistante (TB-MDR) présumée (2012­2013) dans le cadre du programme national TB, à Pondichéry, Inde. Nous avons identifié une attrition avant le diagnostic et avant le traitement, ainsi que les raisons de ce problème. Les recommandations de cette recherche opérationnelle ont été mises en œuvre et nous avons prévu d'évaluer systématiquement s'il y avait une amélioration.Objectifs : Parmi les patients présumés atteints de TB-MDR (juillet­décembre 2014), 1) déterminer l'attrition pré-diagnostic et pré-traitement ; 2) déterminer les facteurs associés à l'attrition pré diagnostic ; 3) déterminer le délai depuis l'éligibilité jusqu'au test et du diagnostic à la mise en route du traitement ; et 4) comparer ces résultats à l'étude précédente.Schéma : Etude de cohorte rétrospective impliquant une revue des dossiers.Résultats : Par comparaison aux études précédentes, il y a eu une réduction de l'attrition pré-diagnostique de 45% à 24% (P < 0,001), une attrition pré-traitement de 29% à 0% (P = 0,18), un délai entre l'éligibilité au test d'une médiane de 11 jours contre 10 jours (P = 0,89) et un délai entre le diagnostic et la mise en route du traitement d'une médiane de 38 jours contre 19 jours (P = 0,04). Il y a des perspectives supplémentaires de réduction de l'attrition avant le diagnostic en ciblant les patients à risque de ne pas être testés parmi ceux atteints de TB et le virus de l'immunodéficience humaine et de TB extra-pulmonaire.Conclusion : La mise en œuvre des résultats de la recherche opérationnelle a eu pour résultat une amélioration des résultats du programme.

Marco de referencia: Se llevó a cabo una intervención de investigación operativa con métodos mixtos, con el fin de estudiar la trayectoria del diagnóstico y el tratamiento de los pacientes con presunción clínica de tuberculosis multirresistente (TB-MDR) en el 2012 y 2013 en el contexto del Programa Nacional contra la Tuberculosis de Puducherry, en la India. Se detectaron altas proporciones de abandono antes del diagnóstico y antes de comenzar el tratamiento y se analizaron sus causas. Las recomendaciones de esta investigación operativa se pusieron en práctica y en el presente estudio se prevé una evaluación sistemática que permita valorar si se logró algún progreso.Objetivos: Analizar los siguientes resultados en los pacientes con presunción clínica de TB-MDR (de julio a diciembre del 2014): 1) si ocurrió abandono antes del diagnóstico o del tratamiento; 2) si existieron factores asociados con el abandono antes de definir el diagnóstico; 3) el lapso necesario entre el momento de la presunción clínica hasta la realización de las pruebas diagnósticas y desde la definición del diagnóstico hasta el comienzo del tratamiento; y 4) comparar estos resultados con los datos del estudio anterior.Método: Fue este un estudio retrospectivo de cohortes, con análisis de las historias clínicas.Resultados: En comparación con el estudio anterior, se observó una disminución del abandono antes del diagnóstico de 45% a 24% (P < 0,001) y antes del comienzo del tratamiento de 29% a 0% (P = 0,18); se redujo el lapso entre la presunción clínica y la práctica de las pruebas diagnósticas una mediana de 11 días a 10 días (P = 0,89) y también el lapso entre el diagnóstico y el inicio del tratamiento una mediana de 38 días a 19 días (P = 0,04). Existe aun margen para una mayor disminución de los abandonos anteriores al diagnóstico, si se aborda el alto riesgo de no practicar las pruebas diagnósticas a los pacientes coinfectados por el virus de la inmunodeficiencia humana y la TB y a los pacientes con TB extrapulmonar.Conclusion: La aplicación de los resultados de la investigación operativa tuvo como consecuencia un progreso en los resultados del programa.

Advances in directed protein evolution by recursive genetic recombination: applications to therapeutic proteins.

Recent developments in directed evolution technologies combined with innovations in robotics and screening methods have revolutionized protein engineering. These methods are being applied broadly to many fields of biotechnology, including chemical engineering, agriculture and human therapeutics. More specifically, DNA shuffling and other methods of genetic recombination and mutation have resulted in the improvement of proteins of therapeutic interest. Optimizing genetic diversity and fitness through iterative directed evolution will accelerate improvements in engineered protein therapeutics.