Effectiveness of Preventive Therapy for Persons Exposed at Home to Drug-Resistant Tuberculosis,Karachi, Pakistan

In Karachi, Pakistan, a South Asian megacity with a high prevalence of tuberculosis (TB) and low HIV prevalence, we assessed the effectiveness of fluoroquinolone-based preventive therapy for drug-resistant (DR) TB exposure. During February 2016–March 2017, high-risk household contacts of DR TB patients began a 6-month course of preventive therapy with a fluoroquinolone-based, 2-drug regimen. We assessed effectiveness in this cohort by comparing the rate and risk for TB disease over 2 years to the rates and risks reported in the literature. Of 172 participants, TB occurred in 2 persons over 336 person-years of observation. TB disease incidence rate observed in the cohort was 6.0/1,000 person-years. The incidence rate ratio ranged from 0.29 (95% CI 0.04–1.3) to 0.50 (95% CI 0.06–2.8), with a pooled estimate of 0.35 (95% CI 0.14–0.87). Overall, fluoroquinolone-based preventive therapy for DR TB exposure reduced risk for TB disease by 65%.     

A novel assay for lysosomal pepstatin-insensitive proteinase and its application for the diagnosis of late-infantile neuronal ceroid lipofuscinosis

A highly sensitive assay for mammalian lysosomal pepstatin-insensitive proteinase (LPIP) is described using a synthetic peptide substrate coupled to aminotrifluoromethyl coumarin (AFC). LPIP is an endocarboxyl proteinase which has specific sequence requirements of Phe-Phe around the carboxyl terminal. This HPLC based assay can detect patients suffering from late-infantile neuronal ceroid lipofuscinosis (LINCL) and also heterozygote carriers in cultured lymphoid cells and skin fibroblasts. None of the patients analyzed had detectable enzyme activity confirming the defective gene product, while carriers had about 50% activity when compared with the normal controls. Neurological controls comprised of patients with other neurodegenerative disorders have LPIP activities similar to normal controls. LPIP activity is also detectable in amniocytes and chorionic villi. Thus the assay reported can also be used for prenatal diagnosis of LINCL.     

First-Principles Computational Study of the Modification Mechanism of Graphene/Graphene Oxide on Hydroxyapatite

Due to its unique crystal structure and nano-properties, hydroxyapatite (HA) has become an important inorganic material with broad development prospects in electrical materials, for fire resistance and insulation, and in bone repair. However, its application is limited to some extent because of its low strength, brittleness and other shortcomings. Graphene (G) and its derivative graphene oxide (GO) are well known for their excellent mechanical properties, and are widely used to modify HA by domestic and foreign scholars, who expect to achieve better reinforcement and toughening effects. However, the enhancement mechanism has not been made clear. Accordingly, in this study, G and GO were selected to modify HA using the first-principles calculation method to explore the theory of interfacial bonding of composites and explain the microscopic mechanism of interfacial bonding. First-principles calculation is a powerful tool used to solve experimental and theoretical problems and predict the structure and properties of new materials with precise control at the atomic level. Therefore, the bonding behaviors of hydroxyapatite (100), (110) and (111) crystal planes with G or GO were comprehensively and systematically studied using first-principles calculation; this included analyses of the density of states and differential charge density, and calculations of interfacial adhesion work and elastic moduli. Compared to HA (100) and (111) crystal planes, HA (110) had the best bonding performance with G and with GO, as revealed by the calculation results. The composite material systems of HA (110)/G and HA (110)/GO had the smallest density of states at the Fermi level, the largest charge transfers of Ca atoms, the largest interfacial adhesion work and the most outstanding elastic moduli. These results provide a theoretical basis for the modification of HA to a certain extent, and are beneficial to the expansion of the scope of its application.     

Factors influencing the attainment of major motor milestones in CDKL5 deficiency disorder

This study investigated the influence of factors at birth and in infancy on the likelihood of achieving major motor milestones in CDKL5 Deficiency Disorder (CDD). Data on 350 individuals with a pathogenic CDKL5 variant was sourced from the International CDKL5 Disorder Database. A first model included factors available at birth (e.g., sex, variant group and mosaicism) and the second additionally included factors available during infancy (e.g., age at seizure onset, number of anti-seizure medications used, experience of a honeymoon period and formal therapy). Cox regression was used to model the time to achieve the milestones. The probability of attaining the outcomes at specific ages was estimated by evaluating the time-to-event function at specific covariate values. Independent sitting and walking were achieved by 177/350 and 57/325 children respectively. By seven years of age, 67.1% of females but only 37.3% of males could sit independently. About a quarter each of females and males achieved independent walking by eight and six years, respectively. When observed from birth, female gender, a late truncating variant and mosaicism impacted most positively on the likelihood of independent sitting. When observed from one year, later seizure onset and experiencing a honeymoon period also improved the likelihood of independent sitting. Factors that favoured sitting (except gender) also improved walking. Having a truncating variant between aa178 and aa781 reduced the likelihood of achieving independent sitting and walking. It is possible to utilise factors occurring early in life to inform the likelihood of future motor development in CDD.Subject terms: Genetics research, Paediatrics     

Aggregation induced emission based fluorenes as dual-channel fluorescent probes for rapid detection of cyanide: applications of smartphones and logic gates

Rational modification of molecular structure by incorporating electron donating groups can play a potential role for designing aggregation induced emission (AIE) active fluorescent probes. Based on this principle, fluorescent probes (1a–c) were synthesized, and they displayed excellent aggregation induced emission (AIE) behavior in a H₂O/DMF (4 : 1, v/v) mixture due to restrictions in intramolecular charge transfer (ICT). As a comparison, probe 1d was synthesized by installing an electron withdrawing (–NO₂) group that surprisingly quenched the aggregation behaviour. Additionally, AIE active probes 1a–c displayed a highly sensitive dual channel (fluorometric and colorimetric) response towards rapid detection of CN⁻, which is an active toxic material. Probes 1a–c showed selectively enhanced fluorescence emission behavior towards CN⁻ with detection limits of 1.34 ppb, 1.38 ppb, and 1.54 ppb, respectively. The sensing mechanism involves Michael type adduct formation due to the nucleophilic addition reaction of cyanide with probes and was confirmed through ¹H NMR titration experiments. In contrast, probe 1d containing an electron withdrawing moiety showed insensitivity towards CN⁻. Therefore, this study provides the efficient strategy to induce AIE character in fluorescent probes and expands the mechanistic approach toward the sensing of toxic CN⁻.

Rational modification of molecular structure by incorporating electron donating groups can play a potential role for designing aggregation induced emission (AIE) active fluorescent probes.     

Morbidity compression or expansion? A temporal analysis of the age at onset of non-communicable diseases in India

While there is evidence of morbidity compression in many countries, temporal patterns of non-communicable diseases (NCDs) in developing countries, such as India, are less clear. Age at onset of disease offers insights to understanding epidemiologic trends and is a key input for public health programs. Changes in age at onset and duration of major NCDs were estimated for 2004 (n = 38,044) and 2018 (n = 43,239) using health surveys from the India National Sample Survey (NSS). Survival regression models were used to compare trends by sociodemographic characteristics. Comparing 2004 to 2018, there were reductions in age at onset and increases in duration for overall and cause-specific NCDs. Median age at onset decreased for NCDs overall (57 to 53 years) and for diabetes, hypertension, heart disease, asthma, mental diseases, eye disease, and bone disease in the range of 2–7 years and increased for cancer, neurological disorders, some genitourinary disorders, and injuries/accidents in the range of 2–14 years. Hazards of NCDs were higher among females for cancers (HR 1.51, 95% CI 1.19–1.90) and neurological disorders (HR 1.18, 95% CI 1.06–1.32) but lower for heart diseases (HR 0.88, 95% CI 0.79–0.97) and injuries/accidents (HR 0.87, 95% CI 0.77–0.99). Hazards were greater among those with lower educational attainment at younger ages and higher educational attainment later in life. Unlike many countries, chronic disease morbidity may be expanding in India for many chronic diseases, indicating excess strain on the health system. Public health programs should focus on early diagnosis and prevention of NCDs.

     

Quantitative Ethnobotanical Approach to Analyze Local Importance of Tree Species in North Western Himalaya: A Case Study of Ponda Watershed,J&K

The present study has been carried out in the Ponda watershed of district Rajouri (J&K), northwestern Himalaya to analyze local importance of tree species by quantitative ethnobotanical approach and their status of availability in the study area. Data was analyzed using relative frequency of citation (RFC) and use value (UV) index along with Pearson and Spearman correlation coefficients. A total of 34 tree species were encountered represented by 31 genera and 22 families. All identified tree species were classified into 10 general use categories. As per indigenous use, 27 tree species are exploited for firewood followed by 15 for fodder, 12 each for fruits and making agriculture tools whereas very few tree species are being utilized by local people for various other uses. The UV and RFC of different tree species ranged from 0.02 to 0.12 and 0.04 to 0.80, respectively. The Pearson correlation coefficient was found to be higher (0.60) than the Spearman’s rank correlation (0.54), which reflects high linear relationship as compared to monotonic relationship between RFC and UV. The present study showed that Pinus roxburghii was an abundant species, whereas 3 tree species, i.e. Juglans regia, Ficus religiosa and Ulmus wallichiana were observed to be rare. However, according to the IUCN conservation status of the various trees observed in the study area, Juglans regia and Ulmus wallichiana are near threatened and vulnerable species, respectively, which are also exploited for their multiple uses by the locals.     

A one-pot synthesis of N2,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines and systematic evaluation of their ability to host ethanol in crystals

A convenient one-pot method for the preparation of N²,6-diaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines was developed using a three-component synthesis of 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-diamines followed by their Dimroth rearrangement to the desired products. The prepared compounds crystallized from ethanol as ethanol clathrates (1 : 1). X-ray crystallography on several products confirmed the adoption of 5,6-dihydro-tautomer. The thermal analysis and powder X-ray diffraction experiments on selected compounds suggested that thermal desolvation of crystals was irreversible.

One-pot synthesis and analysis of stable dihydrotriazine-EtOH clathrates.     

Angiotensin converting enzyme inhibitors effect on arterial stiffness and wave reflections: a meta-analysis and meta-regression of randomised controlled trials

ObjectiveSeveral studies have assessed the effect of angiotensin converting enzyme inhibitors (ACEIs) on arterial stiffness and wave reflections as measured by pulse wave velocity (PWV) and augmentation index (AIx), respectively. We conducted a meta-analysis to investigate this effect in comparison to placebo and to other antihypertensive agents. Additionally, we investigated this effect when ACEIs are combined with other antihypertensive agents and in comparison to a combination of antihypertensive agents.MethodsMEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to May 2011 on randomised controlled trials (RCTs) which assessed the effect of ACEIs on arterial stiffness vs. placebo or no treatment and ACEIs vs. angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), β-blockers and diuretics. RCTs which assessed the effect of ACEIs combined with other antihypertensives or compared ACEIs with a combination of antihypertensives were also sought. Data from included RCTs were pooled with use of fixed and random effects meta-analysis of the weighted mean change differences between the comparator groups. Heterogeneity across studies was assessed with the I² statistic.ResultsIn 5 trials including 469 patients, treatment with ACEIs (n = 227) vs. placebo (n = 216) significantly reduced PWV (pooled mean change difference ?1.69, 95% C.I. ?2.05, ?1.33, p < 0.00001 with insignificant heterogeneity). In 9 trials which included 378 patients, treatment with ACEIs (n = 178) insignificantly reduced PWV when compared with other antihypertensives (ARBs, CCBs, β-blockers, diuretics and a combination of ACEI and ARB) (n = 220) (pooled mean change difference ?0.19, 95% C.I. ?0.59, 0.21, p = 0.36, I² = 0%). ACEI effect on AIx in comparison to placebo was assessed in 7 trials. Treatment with ACEIs significantly reduced AIx (pooled mean change difference ?3.79, 95% C.I. ?5.96, ?1.63, p = 0.0006) with significant heterogeneity. In 7 trials, treatment with ACEIs significantly reduced AIx when compared with other antihypertensives (pooled mean change difference ?1.84, 95% C.I. ?3, ?0.68, p = 0.002, I² = 32%, p for heterogeneity = 0.11). However, this effect was only significant when compared with β-blockers (pooled mean change difference ?1.6, 95% C.I. ?2.84, ?0.36, p = 0.01). Mean BP differences between baseline and end of treatment did not predict the treatment (ACEI) induced changes in PWV.ConclusionsACEIs reduce PWV and AIx which are markers of arterial stiffness and wave reflections in patients with different pathological conditions. However, due to the lack of high quality and properly powered RCTs, it is not clear whether ACEIs are superior to other antihypertensive agents in their effect on arterial stiffness. The ability of ACEIs to reduce arterial stiffness (PWV) seems to be independent of its ability to reduce BP.