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.

Increased Transferrin Sialylation Predicts Phenoconversion in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Sialic acid-protein interactions are involved in regulating central nervous system immunity; therefore, derangements in sialylation could be involved in neurodegeneration. OBJECTIVES: We evaluate the differences in serum transferrin sialylation in prodromal and early-stage Parkinson's disease (PD), its relation to substantia nigra degeneration, and the risk of phenoconversion to manifest disease. METHODS: Sixty treatment-naive PD patients; 72 polysomnography-confirmed isolated rapid eye movement sleep behavior disorder (iRBD) patients, that is, patients with prodromal synucleinopathy; and 46 healthy volunteers aged ≥45 years and drinking ≤60 standard drinks per month were included. The proportion of serum low-sialylated, carbohydrate-deficient transferrin (CDT) isoforms was assessed using high-performance liquid chromatography, and the values were adjusted for alcohol intake (CDTadj ). Dopamine transporter single-photon emission computed tomography (DaT-SPECT) imaging was performed. In iRBD, phenoconversion risk of DaT-SPECT and CDTadj was evaluated using Cox regression adjusted for age and sex. RESULTS: Median CDTadj was lower in PD (1.1 [interquartile range: 1.0-1.3]%) compared to controls (1.2 [1.1-1.6]%) (P = 0.001). In iRBD, median CDTadj was lower in subjects with abnormal (1.1 [0.9-1.3]%) than normal (1.3 [1.2-1.6]%) DaT-SPECT (P = 0.005). After a median 44-month follow-up, 20% of iRBD patients progressed to a manifest disease. Although iRBD converters and nonconverters did not significantly differ in CDTadj levels (P = 0.189), low CDTadj increased the risk of phenoconversion with hazard ratio 3.2 (P = 0.045) but did not refine the phenoconversion risk associated with abnormal DaT-SPECT yielding hazard ratio 15.8 (P < 0.001). CONCLUSIONS: Decreased serum CDTadj is associated with substantia nigra degeneration in synucleinopathies. iRBD patients with low CDTadj are more likely to phenoconvert to manifest disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

"Association of High Risk Factors and Hearing Impairment in Infants-A Hospital Based Study".

The aim of the study was to find the association of various risk factors with permanent hearing impairment in infants. A case-control study was designed on 420 infants with permanent hearing impairment and normal hearing. The case control ratio was 1:1. Alternate sampling method was used for selecting the control group. Review of medical records and parent interview was done to collect the information of risk factors. Family history(adj. OR 7.5; 95% CI 3, 14; P = 0.000), Consanguinity (adj. OR: 4; 95% CI 2,4; P = 0.000), intra uterine infection (adj. OR 18, 95% CI: 2.3-126.5, P = 0.000), post natal infection (adj. OR 3, 95% CI: 1.3-5, P = 0.004), low Apgar score (adj.OR: 4.6, 95% CI: 1.3-15), craniofacial anomaly (OR-4.6, 95% CI: 1.4-9.5, P = 0.005) and low birth weight (adj. OR: 2.3, 95% CI: 1.2-3.8) were significantly associated with hearing impairment. Among the risk factors, intra uterine infection was having highest significant association with permanent hearing impairment. This is followed by family history, low Apgar score, craniofacial anomaly, consanguinity, post natal infection and low birth weight.

Mortality Rate and Ten Years Survival of Elderly Patients Treated with Total Hip Arthroplasty for Femoral Neck Fractures.

INTRODUCTION: Mortality following traumatic femoral neck fractures in the elderly (age >60 years) is influenced by many factors. Addressing some of them may reduce the mortality rate thus improving patient survival and quality of life. MATERIALS AND METHODS: This study was a retrospective research using data collected from Hospital Sultanah Bahiyah, Kedah between the years 2008-2018. We measured outcomes such as age, gender, hospital stay, default rate, ambulation post-surgery, American Society of Anaesthesiologists score (ASA) and surgical timing in correlation with mortality rate and 10-year survival of elderly patients treated with Total Hip Arthroplasty for femoral neck fractures in this centre. RESULTS: A total of 291 traumatic femoral neck fractures aged above 60 years post total hip arthroplasty performed were included. There was higher number of female (n =233) compared to male (n=53) Estimated 10 years survival from Kaplan Meier was 42.88% (95% CI: 33.15, 52.54). One year mortality rate in our study was found to be 18.9%. The average time to event was 7.1 years (95% CI:33.15, 52.24) with a mean age group of 75. DISCUSSION: Total hip arthroplasty patients not ambulating after surgery had a 4.2 times higher hazard ratio compared to ambulators. Those with pre-existing systemic disease (ASA III and IV) were found to have the highest hazard ratio, almost five times that of healthy patients, after adjusting for confounding factors. Delay of more than seven days to surgery was found to be a significant factor in 10-year survival with a hazard ratio of 3.8, compared to surgery performed earlier. CONCLUSION: Delay of more than 7 days to surgery in 10 years survival was significant with high hazard ratio. It is a predictor factor for survival in 10 years. A larger sample size with a prospective design is required to confirm our findings regarding "unacceptable surgical timing" for femoral neck fractures in patients above 60 years of age.

Chest radiographs in Coronavirus Disease 2019 (COVID-19).

OBJECTIVES: To recognize the radiographic patterns of coronavirus disease 2019 (COVID-19) in Malaysia. MATERIALS AND METHODS: Chest radiographs of patients confirmed with COVID-19 in Hospital Tawau, Sabah, Malaysia were retrospectively analyzed by two radiologists. The radiographic pattern, distribution among subgroups and evolution of the disease over time were determined. RESULTS: Among the 82 patients studied, 65 (79.3%) were males. Mean age of our cohorts was 37 ± 15 years. Baseline chest radiographs were abnormal in 37 patients (45.1%). Over half (52.9%) of the symptomatic patients had abnormal baseline radiograph. Among the children, patients with comorbidities, and patients 60 years of age and above, the abnormal radiographs were 14.3%, 71.4% and 69.3% respectively. Ground glass opacities were the commonest abnormal radiographic feature (35.4%), were peripherally located (35.4%) with predilection for the lower zones (29.3%). Most radiographic abnormalities were multifocal (20.7%) and frequently located in the left lung (19.5%). Radiographic recovery was observed in 15 of 18 patients (83%). Computed tomography (CT) scan demonstrated greater extent of the disease than observed in radiographs of the same patient. CONCLUSIONS: COVID-19 pneumonia presented with a specific radiographic pattern in our cohort of patients, comprising of ground glass opacities in peripheral and basilar distribution, affecting a single lung field and was observed in both symptomatic and asymptomatic patients. Chest radiograph is a useful adjunct screening tool, and in combination with clinical and epidemiological assessment may facilitate in early diagnosis of COVID-19 pneumonia.

Highly reactive crystalline-phase-embedded strontium-bioactive nanorods for multimodal bioactive applications.

In the present work, a crystallization-induced strontium-bioactive material, with a composition similar to Bioglass 45S5 system, was obtained using a sol-gel-assisted microwave method with nanorod morphologies of 30-80 nm in size. The effect of crystallization induced in the glass network, and its influence on the bioactivity and mechanical properties of bone and dentin regeneration, were the main novel findings of this work. Rietveld analysis of X-ray diffraction spectra showed the best fit with sodium (combeite, Na2Ca2Si3O9) and calcium (clinophosinaite, Ca2Na6O14P2Si2; calcium strontium silicate, Ca1.5O4SiSr0.5; and calcium carbonate, CaCO3) enriched crystal systems. Multinuclear solid-state NMR studies provided detailed atomistic insight into the presence of crystalline mineral phases in the bioactive material. The dentin matrix and antibacterial studies showed good results for 5% strontium-substituted calcium compared with basic 45S5 composition due to its smaller particle size (30 nm), which suggested applications to dentin regeneration. Simulation studies have been demonstrated with clinophosinaite crystal data from the XRD spectra, with the glycoprotein salivary metabolites also showing that 5% strontium-substituted calcium has a higher binding affinity for the salivary compound, which is suitable for dentin regeneration applications. In vitro apatite formation studies showed that this material is suitable for bone regeneration applications.

A Relook of Cefuroxime in Community Infections: An Option Still Beneficial.

In community and family practice, infections are a common OPD presentation. In the management of common bacterial infections seen in community especially RTI, UTI, SSTI; cefuroxime a second generation cephalosporin with a broad spectrum of activity can be used for empirical treatment. To know current place of cefuroxime in the management of infections, physicians, surgeons, microbiologist, chest physician, gynecologist and pediatrician came together to discuss and debate their experience with cefuroxime and its place in today's world. Cefuroxime is a drug which balances efficacy with safety. Several international bodies and guidelines including the US FDA and The British Thoracic Society, the World Society of Emergency Surgery (WSES) have recommended cefuroxime for the management of community acquired pneumonia and skin and soft tissue infection respectively. Cefuroxime has been recommended in the 2015 list of the US FDA list of drugs which can be used safely during pregnancy. Cefuroxime can become a useful empiric choice antibiotic for the Indian physicians treating urinary tract infections, respiratory tract infections and skin and soft tissue infections in their outpatient departments.

A randomised comparison between ultrasound and nerve stimulation for infraclavicular catheter placement.

We conducted this study to determine if placement of infraclavicular catheters guided by ultrasound is quicker than placement guided by nerve stimulation. Infraclavicular brachial plexus catheters were inserted in 210 randomly allocated patients who were scheduled for elective hand or elbow surgery. Needle and catheter placement was guided by ultrasound (n = 105) or by nerve stimulation (n = 105). The primary outcome was time to sensory block success. Success rate was similar between the two techniques (83.2% vs 81.4%, p = 0.738). However, placement of ultrasound-guided catheters took less time (7.2 [2.5] vs 9.6 [3.6] min, p < 0 .001). Pain and satisfaction scores, and incidence of nerve deficit, were also similar with both techniques.

Somatic human ZBTB7A zinc finger mutations promote cancer progression.

We recently reported that ZBTB7A is a bona fide transcription repressor of key glycolytic genes and its downregulation in human cancer contributes to tumor metabolism. As reduced expression of ZBTB7A is found only in a subset of human cancers, we explored alternative mechanisms of its inactivation by mining human cancer genome databases. We discovered recurrent somatic mutations of ZBTB7A in multiple types of human cancers with a marked enrichment of mutations within the zinc finger domain. Functional characterization of the mutants demonstrated that mutations within the zinc finger region of ZBTB7A invariably resulted in loss of function. As a consequence, the glycolytic genes were markedly upregulated in cancer cells harboring ZBTB7A zinc finger mutation, leading to increased glycolysis and proliferation. Our study uncovers the loss-of-function mutation in ZBTB7A as a novel mechanism causing elevated glycolysis in human cancer, which carries important therapeutic implication.

Comparative evaluation of the visibility and block characteristics of a stimulating needle and catheter vs an echogenic needle and catheter for sciatic nerve block with a low-frequency ultrasound probe.

BACKGROUND: Clear visibility of the needle and catheter tip is desirable to perform safe and successful ultrasound-guided peripheral nerve blocks. This can be challenging with deeper blocks in obese patients. This study compared the visibility of echogenic and non-echogenic block needles and catheters in proximal sciatic blocks when performed with a low-frequency curved probe. METHODS: Seventy-eight patients undergoing total knee joint arthroplasty were randomized to receive an ultrasound-guided continuous sciatic nerve block using either a non-echogenic needle and stimulating catheter or an echogenic needle and echogenic non-stimulating catheter. Block needles in both groups were placed using both neurostimulation and ultrasound guidance, after which the catheter was positioned using either neurostimulation alone (Stimulating group) or imaging alone (Echogenic group). Three anaesthetists blinded to group allocation graded video clips recorded during the blocks for nerve, needle and catheter visibility. Performance characteristics and block parameters were also compared. RESULTS: No significant differences between the two groups were observed with regard to needle or catheter visibility (P=0.516). The Stimulating group required more needle redirections (P=0.009), had a longer procedure time [Echogenic median 274 s vs Stimulating 344 s (P=0.016)], and resulted in greater patient discomfort (P=0.012). There were no significant differences between the two groups in terms of block onset or completion time. CONCLUSIONS: Use of echogenic needles and catheters reduced procedure time and patient discomfort compared with a stimulating catheter system. There were no differences in the visibility scores of the two systems. CLINICAL TRIAL REGISTRATION: CTR Protocol ID: R-11-495, Clinical Trials.Gov ID: NCT 01492660.

Injectate spread following ultrasound-guided lateral to medial approach for dual transversus abdominis plane blocks.

BACKGROUND: Bilateral dual transversus abdominis plane (BD-TAP) injections were devised to cover the T7-8 and L1 dermatomes, which are usually spared with classical and mid-axillary TAP injections. The purpose of this study was to delineate the vertical and lateral extent of injectate spread following a lateral to medial approach for TAP injections in embalmed cadavers. METHODS: Ultrasound-guided subcostal and lateral TAP injections were performed on nine embalmed cadavers using 30 ml of 0.5% methylcellulose (20 ml for subcostal and 10 ml for lateral injections) with a 12-cm Tuohy needle in the first six cadavers (nine hemi-abdomens). Vertical extent and the medial to lateral extent of the dye spread were recorded after dissections of the abdominal wall. In a pilot of three cadavers not receiving TAP injections, anatomical impediments to proximal injectate spread were explored separately. RESULTS: The vertical spread of injectate was T7-L1 (n = 2/9), T8-L1 (n = 5/9) and T9-L1 (n = 2/9). None of the TAP injections extended beyond the mid-axillary line. No anatomical impediments for the flow of injectate to the T7 or T8 intercostal nerves were found at the level of the interdigitations of the transversus abdominis muscle and diaphragm. CONCLUSION: A lateral to medial approach for TAP injection resulted in spread of the injectate ranging from T7/8-L1 dermatomes in the majority of the hemi-abdomens. Subcostal and lateral TAP injections do not cover the lateral cutaneous branches of the segmental nerves.

Tumor macroenvironment and metabolism.

In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%-20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient's outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described.

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response.

Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1α, which is induced specifically by low-dose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to low-dose radiation has important implications in understanding and assessing the health risks of radiation exposure.

Elevated snoRNA biogenesis is essential in breast cancer.

Hyperactive ribosomal biogenesis is widely observed in cancer, which has been partly attributed to the increased rDNA transcription by Pol I in cancer. However, whether small nucleolar RNAs (snoRNAs), a class of non-coding RNAs crucial in ribosomal RNA (rRNA) maturation and functionality, are involved in cancer remains elusive. We report that snoRNAs and fibrillarin (FBL, an enzymatic small nucleolar ribonucleoprotein, snoRNP) are frequently overexpressed in both murine and human breast cancer as well as in prostate cancers, and significantly, that this overexpression is essential for tumorigenicity in vitro and in vivo. We demonstrate that when the elevated snoRNA pathway is suppressed, the tumor suppressor p53 can act as a sentinel of snoRNP perturbation, the activation of which mediates the growth inhibitory effect. On the other hand, high level of FBL interferes with the activation of p53 by stress. We further show that p53 activation by FBL knockdown is not only regulated by the ribosomal protein-MDM2-mediated protein stabilization pathway, but also by enhanced PTB-dependent, cap-independent translation. Together, our data uncover an essential role of deregulated snoRNA biogenesis in tumors and a new mechanism of nucleolar modulation of p53.

Low-dose arsenic induces chemotherapy protection via p53/NF-κB-mediated metabolic regulation.

Most chemotherapeutical drugs kill cancer cells chiefly by inducing DNA damage, which unfortunately also causes undesirable injuries to normal tissues, mainly due to p53 activation. We report a novel strategy of normal tissue protection that involves p53/NF-κB coordinated metabolic regulation. Pretreatment of untransformed cells with low doses of arsenic induced concerted p53 suppression and NF-κB activation, which elicited a marked induction of glycolysis. Significantly, this metabolic shift provided cells effective protection against cytotoxic chemotherapy, coupling the metabolic pathway to cellular resistance. Using both in vitro and in vivo models, we demonstrated an absolute requirement of functional p53 in arsenic-mediated protection. Consistently, a brief arsenic pretreatment selectively protected only normal tissues, but not tumors, from toxicity of chemotherapy. An indispensable role of glycolysis in protecting normal tissues was demonstrated by using an inhibitor of glycolysis, 2-deoxyglucose, which almost totally abolished low-dose arsenic-mediated protection. Together, our work demonstrates that low-dose arsenic renders normal cells and tissues resistant to chemotherapy-induced toxicity by inducting glycolysis.