The First Differentiated TB Care Model From India: Delays and Predictors of Losses in the Care Cascade.

To reduce TB deaths in resource-limited settings, a differentiated care strategy can be used to triage patients with high risk of severe illness (i.e., those with very severe undernutrition, respiratory insufficiency, or inability to stand without support) at diagnosis and refer them for comprehensive assessment and inpatient care. Globally, there are few examples of implementing this type of strategy in routine program settings. Beginning in April 2022, the Indian state of Tamil Nadu implemented a differentiated care strategy called Tamil Nadu-Kasanoi Erappila Thittam (TN-KET) for all adults aged 15 years and older with drug-susceptible TB notified by public facilities. Before evaluating the impact on TB deaths, we sought to understand the retention and delays in the care cascade as well as predictors of losses. During April-June 2022, 14,961 TB patients were notified and 11,599 (78%) were triaged. Of those triaged, 1,509 (13%) were at high risk of severe illness; of these, 1,128 (75%) were comprehensively assessed at a nodal inpatient care facility. Of 993 confirmed as severely ill, 909 (92%) were admitted, with 8% unfavorable admission outcomes (4% deaths). Median admission duration was 4 days. From diagnosis, the median delay in triaging and admission of severely ill patients was 1 day each. Likelihood of triaging decreased for people with extrapulmonary TB, those diagnosed in high-notification districts or teaching hospitals, and those transferred out of district. Predictors of not being comprehensively assessed included: aged 25-34 years, able to stand without support, and diagnosis at a primary or secondary-level facility. Inability to stand without support was a predictor of unfavorable admission outcomes. To conclude, the first quarter of implementation suggests that TN-KET was feasible to implement but could be improved by addressing predictors of losses in the care cascade and increasing admission duration.

--Eleven tips for operational researchers working with health programmes: our experience based on implementing differentiated tuberculosis care in south India.

Due to the workload and lack of a critical mass of trained operational researchers within their ranks, health systems and programmes may not be able to dedicate sufficient time to conducting operational research (OR). Hence, they may need the technical support of operational researchers from research/academic organisations. Additionally, there is a knowledge gap regarding implementing differentiated tuberculosis (TB) care in programme settings. In this 'how we did it' paper, we share our experience of implementing a differentiated TB care model along with an inbuilt OR component in Tamil Nadu, a southern state in India. This was a health system initiative through a collaboration of the State TB cell with the Indian Council of Medical Research institutes and the World Health Organisation country office in India. The learnings are in the form of eleven tips: four broad principles (OR on priority areas and make it a health system initiative, implement simple and holistic ideas, embed OR within routine programme settings, aim for long-term engagement), four related to strategic planning (big team of investigators, joint leadership, decentralised decision-making, working in advance) and three about implementation planning (conducting pilots, smart use of e-tools and operational research publications at frequent intervals). These may act as a guide for other Indian states, high TB burden countries that want to implement differentiated care, and for operational researchers in providing technical assistance for strengthening implementation and conducting OR in health systems and programmes (TB or other health programmes). Following these tips may increase the chances of i) an enriching engagement, ii) policy/practice change, and iii) sustainable implementation.

A prospective study of anal symptoms and continence among obese patients before and after bariatric surgery.

BACKGROUND: The effects of bariatric surgery on anal continence are not known. Data about proctologic lesions are very rare and do not include clinical data. The aim of this prospective study was to evaluate anal continence and anal lesions before and after sleeve gastrectomy (SG). METHODS: We prospectively included all patients presenting for bariatric surgery consultation at Bichat-Claude Bernard University Hospital, Paris, France, between 20 April 2015 and 16 December 2017. The patients were evaluated with questionnaires, anorectal manometry and clinical examination before SG (at enrollment) and between 12 and 24 months after (SG). Anal incontinence was defined as a Vaizey score above 4. RESULTS: Of 118 enrolled patients, 98 had SG. The patients were mostly women (n = 99, 84.6%). Median patient age was 45 years (IQR 34-54 years). The median follow-up period after surgery among the 86 patients who completed follow-up was 15 months (IQR 12.5-17.3 months). There was no significant change in the prevalence of anal incontinence after SG (12.8% preoperatively vs 24.4% postoperatively, p = 0.06). The median Vaizey score was 4 (IQR 4-4) both before and after SG (p = 0.1). No patient had de novo anal incontinence but worsening of anal incontinence was noted in 10 patients. Manometry revealed significantly lower median resting pressure (29 mmHg [IQR 22-68 mmHg] vs 22 mmHg [IQR 15-30 mmHg], p = 0.0015) and maximal squeeze pressure (IQR 29-74 mmHg vs IQR 30-60 mmHg, p = 0.0008) after SG. Anismus was more frequent after SG and was associated with constipation and Bristol type 1-2 stool consistency. Quality of life was unchanged. Proctologic lesions were rare and were present in 11 patients (12%) at enrollment and in 2 (2.4%) at follow-up. CONCLUSIONS: SG affected clinical anal continence but not significantly, and manometric measurements for anal pressures were lower postoperatively. Proctologic lesions were rare in this study population.

Gaussian mixture model based clustering of Manual muscle testing grades using surface Electromyogram signals.

Muscle strength testing has long been an important assessment procedure in rehabilitation setups, though the subjectivity and standardization of this procedure has been widely debated. To address this issue, this study involves the use of Electromyogram (EMG) features that are intuitively related to muscle strength to classify Manual muscle testing (MMT) grades of '4 -', '4', '4 + ' and '5' of the Medical Research Council scale. MMT was performed on Tibialis anterior muscle of 50 healthy participants whose MMT grades and EMG were simultaneously acquired. Chi square goodness of fit and Spectrum Decomposition of Graph Laplacian (SPEC) feature selection algorithms are used in selecting five features, namely Integrated EMG, Root Mean Square EMG, Waveform Length, Wilsons' amplitude and Energy. Gaussian Mixture Model (GMM) approach is used for unsupervised clustering into one of the grades. Internal cluster evaluation resulted in Silhouette score of 0.76 and Davies Bouldin Index of 0.42 indicating good cluster separability. Agreement between the machine-based grade and manual grade has been quantified using Cohens' Kappa coefficient. A value of '0.44' has revealed a moderate agreement, with greater differences reported in grading '4' and '4 + ' strength levels. The comparative advantage of EMG based grading over the manual method has been proved. The suggested method can be extended for muscle strength testing of all muscles across different age groups to assist physicians in evaluating patient strength and plan appropriate strength conditioning exercises as a part of rehabilitative assessment.

Switching "on" and "off" the adhesion in stimuli-responsive elastomers.

The present work aims at the preparation of dry adhesives with switchable bonding properties by using the reversible nature of the [4πs+4πs] cycloaddition of anthracenes. Photo-responsive hydrogenated carboxylated nitrile butadiene rubber with photo-responsive pendant anthracene groups is prepared by one-pot synthesis. The formation of 3D networks relies on the photodimerization of the anthracene moieties upon UV exposure (λ > 300 nm). Controlled cleavage of the crosslink sites is achieved by either deep UV exposure (λ = 254 nm) or thermal dissociation at 70 °C. The kinetics of the optical and thermal cleavage routes are compared in thin films using UV-vis spectroscopy and their influence on the reversibility of the network is detailed. Going from thin films to free standing samples the modulation of the network structure and thermo-mechanical properties over repeated crosslinking and cleavage cycles are characterized by low-field NMR spectroscopy and dynamic mechanical analysis. The applicability of the stimuli-responsive networks as adhesives with reversible bonding properties is demonstrated. The results evidence that the reversibility of the crosslinking reaction enables a controlled switching "on" and "off" of adhesion properties. The recovery of the adhesion force amounts to 75 and 80% for photo- and thermal dissociation, respectively. Spatial control of adhesion properties is evidenced by adhesion force mapping experiments of photo-patterned films.

Formation of supramolecular assemblies and liquid crystals by purine nucleobases and cyanuric acid in water: implications for the possible origins of RNA.

The free nucleobases and mononucleotides of RNA do not form Watson-Crick base pairs in water, a fact that presents several challenges for the prebiotic synthesis of RNA. 2,6-Diaminopurine and adenosine-5'-monophosphate (AMP) are shown to form supramolecular assemblies with cyanuric acid in water. These assemblies and their propensity to form liquid crystals suggest a possible means by which non-covalent structures might have originally selected the shape of the Watson-Crick base pairs.

Antidiabetic property of Symplocos cochinchinensis is mediated by inhibition of alpha glucosidase and enhanced insulin sensitivity.

The study is designed to find out the biochemical basis of antidiabetic property of Symplocos cochinchinensis (SC), the main ingredient of 'Nisakathakadi' an Ayurvedic decoction for diabetes. Since diabetes is a multifactorial disease, ethanolic extract of the bark (SCE) and its fractions (hexane, dichloromethane, ethyl acetate and 90% ethanol) were evaluated by in vitro methods against multiple targets relevant to diabetes such as the alpha glucosidase inhibition, glucose uptake, adipogenic potential, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B) and dipeptidyl peptidase-IV (DPP-IV). Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition (IC50 value-82.07 ± 2.10 µg/mL), insulin dependent glucose uptake (3 fold increase) in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F (3.5 fold increase) and reduced triglyceride accumulation (22% decrease) in 3T3L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells (59.57% decrease) with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence and quantity of bioactives (beta-sitosterol, phloretin 2'glucoside, oleanolic acid) in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. We conclude that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with moderate antiglycation and antioxidant activity.

Effect of insulin on excitatory synaptic transmission onto dopamine neurons of the ventral tegmental area in a mouse model of hyperinsulinemia.

Obesity has drastically increased over the last few decades. Obesity is associated with elevated insulin levels, which can gain access to the brain, including into dopamine neurons of the ventral tegmental area (VTA), a brain region critical for mediating reward-seeking behavior. Synaptic plasticity of VTA dopamine neurons is associated with altered motivation to obtain reinforcing substances such as food and drugs of abuse. Under physiological circumstances, insulin in the VTA can suppress excitatory synaptic transmission onto VTA dopamine neurons and reduce aspects of palatable feeding behavior. However, it is unknown how insulin modulates excitatory synaptic transmission in pathological circumstances such as hyperinsulinemia. Using patch-clamp electrophysiology, we demonstrate that, in a hyperinsulinemic mouse model, insulin has reduced capacity to cause a synaptic depression of VTA dopamine neurons, although both low-frequency stimulation-induced long-term depression and cannabinoid-induced depression were normal. These results suggest that insulin action in the VTA during pathological hyperinsulinemia is disrupted and may lead to increased feeding behavior.

Changes in network dynamics during status epilepticus.

Status epilepticus (SE) is an acute event, characterized by repeated or continuous seizures, which alters neuronal properties of the brain and can promote the epileptic disorder. Experimental observations indicate that SE becomes progressively less responsive to anti-epileptic drugs, suggesting changes in the underlying physiology. To assess the effect of SE on neuronal dynamics as it progresses, we measured changes in neuronal activity from CA3 hippocampus, ipsilateral and contralateral to a focal intrahippocampal injection of kainic acid during the full course of SE, 24 h post-SE, and one week post-SE. The progressively intensifying behavioral response during SE was accompanied by changes in intrinsic firing properties of single neurons, LFP oscillations and interaction between single neurons and the oscillations. These results show important changes in neuronal and network activity underlying the progression of SE.

Chain dynamics of a weakly adsorbing polymer in thin films.

Thin films of weakly adsorbing poly(dimethyl siloxane) (PDMS) on porous alumina are examined with NMR fast field cycling (FFC) relaxometry and NMR transverse relaxometry. The longitudinal relaxation dispersion of polymer amounts corresponding to approximate monolayer coverage shows substantial deviation from the bulk and is characterized by a particularly weak temperature dependence. Thicker films, however, show relaxation behavior and temperature dependence more similar to the bulk polymer. Transverse relaxation times were found to cover a range of several orders of magnitudes for any sample investigated; their dependence on temperature is a function of the total amount of adsorbed polymer. While thick films see an overall increase of molecular mobility at higher temperatures, monolayer films are best characterized by the decreasing fraction of a short, i.e. relatively rigid, component. These effects are consistent with the concept of two regions, one in which chain dynamics deviate from bulk and another where chain dynamics are reduced but bulk-like, although chains inside each region may also experience motional heterogeneity.

Activation of p38 MAPK in the substantia nigra leads to nuclear translocation of NF-kappaB in MPTP-treated mice: implication in Parkinson's disease.

Activation and translocation of the transcription factor nuclear factor kappa B (NF-kappaB) from cytoplasm to the nucleus has been reported in models of Parkinson's disease (PD). Our focus was to discern the upstream events which ultimately lead to NF-kappaB nuclear translocation using animal model of PD. We demonstrate that p38 activation results in downstream phosphorylation of NF-kappaB and accumulation of p65 subunit of NF-kappaB selectively in ventral midbrain but not in striatum. Treatment with p38 inhibitor, SB239063, prevented downstream phosphorylation of IkappaB alpha and p65 translocation to the nucleus in the ventral midbrain. Phosphorylation of anti-apoptotic Bcl2, an NF-kappaB target gene by p38 to inactive pBcl2ser87 was also attenuated by SB239063. Increased staining of p65 in the nuclei of cells in the substantia nigra but not in the ventral tegmental area of MPTP-treated mice further suggests a role for NF-kappaB in PD. In agreement with the above, sustained caspase activation is seen in the ventral midbrain but not in striatum. We demonstrate the region specific p38-mediated activation of NF-kappaB following MPTP treatment demonstrating the role of p38/NF-kappaB signaling in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression.

NMR investigations of polymer dynamics in a partially filled porous matrix.

The interior surface of well-defined porous alumina membranes (Anopore) of 20 nm and 200 nm pore diameter, respectively, was coated with polymer layers generated from solution by the solvent evaporation method. Deposits of poly(dimethyl siloxane) (PDMS) with nominal thicknesses ranging from 0.15 to 4.5 nm --corresponding to submonolayer to multilayer films--were investigated, and were compared to poly(butadiene) (PB) as an example for non-wetting polymers. Molecular weights below and above the critical value were studied since the bulk dynamics of such polymers are known to be qualitatively different. First results of NMR relaxation dispersion experiments on these systems are presented, supplemented by transverse relaxation times and double-quantum measurements obtained from high-field NMR. A systematic decrease of relaxation times at low fields with decreasing polymer amount is found for PDMS, but molecules retain a high degree of mobility irrespective of molecular weight. The relaxation dispersion results are supported by T2 data and 1H residual dipolar coupling (RDC) constants, and are discussed in terms of molecular order and reorientational dynamics.

The effect of the menopause on prolactin levels in patients with hyperprolactinaemia.

OBJECTIVE: Microprolactinomas have been reported to resolve spontaneously after pregnancy and there have been suggestions that oestrogen therapy increases the size of microprolactinomas. Little is known, however, about the effect of the menopause in patients previously known to be hyperprolactinaemic. The aim of this study was to find out if pregnancy or the menopause leads to an alteration in prolactin levels. DESIGN: We conducted a retrospective study of 148 case notes of patients with hyperprolactinaemia and microprolactinomas treated at the Radcliffe Infirmary during the period 1976-96. Sixty-nine female patients who had not had pituitary surgery as treatment for microprolactinoma were used as a control group. None of this group became pregnant or reached the menopause. They were compared with 25 female patients who became pregnant, 11 who became menopausal and 11 who were male. Subjects were excluded from the analysis if there were no follow-up data off dopamine agonist treatment or if they were surgically cured. Data were gathered on demographic parameters, treatment given, scan abnormalities, prolactin levels at diagnosis and last follow up, prolactin levels pre- and postpregnancy as well as pre- and postmenopause. The pregnancy, postmenopausal and male patient groups were compared with the control group and each other to see if they had a higher frequency of normalization of their prolactin levels during follow up. Various factors were examined as possible variables for the normalization of prolactin, including the detection of scan abnormalities at diagnosis, prolactin levels at diagnosis as well as treatment with dopamine agonists and duration of follow up. RESULTS: Forty-five percent of the menopausal group, 24% of the pregnancy group and 18% of the male group subsequently normalized their prolactin levels during the period of the study in comparison with 7% of the control group. The menopausal groups had a significantly higher chance of normalizing their prolactin compared to the control group (P < 0.005), whilst the pregnancy group showed a non-significant trend towards normalizing their prolactin (P = 0.06). The detection of scan abnormalities, treatment with dopamine agonist therapy and duration of follow up were not associated with normalization of prolactin levels. CONCLUSION: Female patients with hyperprolactinaemia who pass through the menopause have a significant chance of normalizing their prolactin levels. Females who pass through pregnancy may have a higher chance of normalizing their prolactin levels. The menopause is an indication for reassessment of the need to continue to treat hyperprolactinaemia and microprolactinoma.

Hidden cases of leprosy (in prison)

Leprosy survey conducted in eight prisons in seven districts of Bihar State revealed a prevalence of 13.3 per 1000 which was 12 times more than the recorded prevalence of leprosy in the State. Thus this finding supports the view that prisons could form a hyperendemic pocket for leprosy. Regular NLEP services need to be extended to the inmates of the prisons.

The Fasting Hyperglycaemia Study: III. Randomized controlled trial of sulfonylurea therapy in subjects with increased but not diabetic fasting plasma glucose.

Self-referred subjects (N = 227) thought to be at increased risk of developing diabetes who had fasting plasma glucose (FPG) values in the range of 5.5 to 7.7 mmol.L-1 on two consecutive occasions 2 weeks apart were randomized to sulfonylurea therapy (gliclazide, < or = 160 mg.d-1) or to a control group allocated either to double-blind placebo or to no tablets. Subjects were randomly allocated also to reinforced or basic healthy-living advice in a factorial design. A total of 201 subjects have been evaluated for 1 year in three English and two French hospital outpatient centers. Those allocated to sulfonylurea had a significant (P < .001) reduction in median FPG compared with the control group (6.0 mmol.L-1 to 5.6 mmol.L-1, P < .001, v 6.0 mmol.L-1 to 6.0 mmol.L-1, NS). Median hemoglobin A1c (HbA1c) also improved (P < .0002; 5.8% to 5.6%, P < .001, v 5.7% to 5.6%, NS), as did mean beta-cell function (62% to 70%, P < .01, v 62% to 61%, NS). Mean body weight was unchanged in subjects allocated to sulfonylurea (81.7 kg to 82.4 kg, NS), but decreased in the control group (81.6 kg to 80.4 kg, P < .01). More subjects in the sulfonylurea group versus the control group reported one or more minor symptoms of hypoglycemia over 1 year (50% v 24%, P < .0001). Only two subjects reported major hypoglycemic episodes requiring assistance, both of whom were taking sulfonylurea. Insulin sensitivity did not change between groups. Sulfonylurea therapy with gliclazide improved glycemic control and beta-cell function significantly in subjects with increased but not diabetic FPG levels. The study is being extended to determine whether sulfonylurea therapy prevents progression to non-insulin-dependent diabetes mellitus (NIDDM).