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Huntington's disease (HD) is a rare neurodegenerative disease caused due to aggregation of Huntingtin (HTT) protein. This study involves the cloning of 40 DnaJ chaperones from Drosophila, and overexpressing them in yeasts and fly models of HD. Accordingly, DnaJ chaperones were catalogued as enhancers or suppressors based on their growth phenotypes and aggregation properties. 2 of the chaperones that came up as targets were CG5001 and P58IPK. Protein aggregation and slow growth phenotype was rescued in yeasts, S2 cells, and Drosophila transgenic lines of HTT103Q with these overexpressed chaperones. Since DnaJ chaperones have protein sequence similarity across species, they can be used as possible tools to combat the effects of neurodegenerative diseases., (© 2024. The Author(s).)

Two-directional beam-tracking (2DBT) is a method for phase-contrast imaging and tomography that uses an intensity modulator to structure the X-ray beam into an array of independent circular beamlets that are resolved by a high-resolution detector. It features isotropic spatial resolution, provides two-dimensional phase sensitivity, and enables the three-dimensional reconstructions of the refractive index decrement, δ, and the attenuation coefficient, μ. In this work, the angular sensitivity and the spatial resolution of 2DBT images in a synchrotron-based implementation is reported. In its best configuration, angular sensitivities of ∼20 nrad and spatial resolution of at least 6.25 µm in phase-contrast images were obtained. Exemplar application to the three-dimensional imaging of soft tissue samples, including a mouse liver and a decellularized porcine dermis, is also demonstrated., (open access.)

Understanding the dynamic evolution of Salmonella is vital for effective bacterial infection management. This study explores the role of the flexible genome, organised in regions of genomic plasticity (RGP), in shaping the pathogenicity of Salmonella lineages. Through comprehensive genomic analysis of 12,244 Salmonella spp. genomes covering 2 species, 6 subspecies, and 46 serovars, we uncover distinct integration patterns of pathogenicity-related gene clusters into RGP, challenging traditional views of gene distribution. These RGP exhibit distinct preferences for specific genomic spots, and the presence or absence of such spots across Salmonella lineages profoundly shapes strain pathogenicity. RGP preferences are guided by conserved flanking genes surrounding integration spots, implicating their involvement in regulatory networks and functional synergies with integrated gene clusters. Additionally, we emphasise the multifaceted contributions of plasmids and prophages to the pathogenicity of diverse Salmonella lineages. Overall, this study provides a comprehensive blueprint of the pathogenicity potential of Salmonella. This unique insight identifies genomic spots in nonpathogenic lineages that hold the potential for harbouring pathogenicity genes, providing a foundation for predicting future adaptations and developing targeted strategies against emerging human pathogenic strains., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Krishnakant Kushwaha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mucoceles are the most common minor salivary gland disorder and represent the second most frequent benign soft tissue tumors of the oral cavity, following irritative fibroma. Various treatment modalities have been suggested for mucocele among which different types of lasers being the most recent and advanced. In the present case reports, diode laser was used for the excision of mucocele on the lower lip, and the advantages of it over the conventional scalpel method were minimal discomfort, bleeding, recurrence, and better compliance among patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Reactive astrogliosis is a common pathological hallmark of CNS injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These Srf GFAP-ER CKO astrocytes do not affect neuron survival, synapse numbers, synaptic plasticity or learning and memory. However, the brains of Srf CKO astrocytes abrogate nigral dopaminergic neuron death and reduce β-amyloid plaques in mouse models of Parkinson's and Alzheimer's disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases.Srf GFAP-ER CKO astrocytes abrogate nigral dopaminergic neuron death and reduce β-amyloid plaques in mouse models of Parkinson's and Alzheimer's disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases., Competing Interests: ST, MJ, SS, SD, VV, AN, DG, BJ, DN, JC, SM, NR No competing interests declared, (© 2024, Thumu et al.)

High-resolution spatial and temporal analysis and 3D visualization of time-dependent processes, such as human dental enamel acid demineralization, often present a challenging task. Overcoming this challenge often requires the development of special methods. Dental caries remains one of the most important oral diseases that involves the demineralization of hard dental tissues as a consequence of acid production by oral bacteria. Enamel has a hierarchically organized architecture that extends down to the nanostructural level and requires high resolution to study its evolution in detail. Enamel demineralization is a dynamic process that is best investigated with the help of in situ experiments. In previous studies, synchrotron tomography was applied to study the 3D enamel structure at certain time points (time-lapse tomography). Here, another distinct approach to time-evolving tomography studies is presented, whereby the sample image is reconstructed as it undergoes continuous rotation over a virtually unlimited angular range. The resulting (single) data set contains the data for multiple (potentially overlapping) intermediate tomograms that can be extracted and analyzed as desired using time-stepping selection of data subsets from the continuous fly-scan recording. One of the advantages of this approach is that it reduces the amount of time required to collect an equivalent number of single tomograms. Another advantage is that the nominal time step between successive reconstructions can be significantly reduced. We applied this approach to the study of acidic enamel demineralization and observed the progression of demineralization over time steps significantly smaller than the total acquisition time of a single tomogram, with a voxel size smaller than 0.5 μm. It is expected that the approach presented in this paper can be useful for high-resolution studies of other dynamic processes and for assessing small structural modifications in evolving hierarchical materials., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Co-published by Nanjing University and American Chemical Society.)

Introduction: Root canal success requires working length (WL) optimization. The current study examined how different apex locators on vital and non-vital teeth responded to instrument size., Materials and Methods: Three hundred patients (180 men and 120 women) receiving root canal therapy at the department of Conservative Dentistry and Endodontics were evaluated. Therefore, we determined that 200 of the patients' teeth (100 vital and 100 non-vital teeth from the upper and lower jaws' first molars) qualified for inclusion in our study. The pulp chamber was accessed using a sterile round bur. The coronal region of the root canal was preflared with successive Gates Glidden drills (Mani Inc. Japan) and irrigated with any one of the solutions 3% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX), or 17% ethylenediaminetetraacetic acid (EDTA) solution after checking canal patency with a size #10 K file, where (#-number). Later, the working length was established using Ingle's technique and a radiovisiograph (RVG) 0.5 mm short of the radiographic apex. Two endodontists approved this RVG., Results: Overall, the #15 K file and apex locators did not differ from Ingle's method. While the #8 K file differs significantly from all apex locators, the #10 K file showed a significant difference with all apex locators except Root ZX with 2% CHX ( P = 0.06). Irrigation didn't influence apex locators' accuracy., Conclusion: Even in the presence of irrigating solutions, electronic apex locator (EAL) can be utilized to calculate the working length with accuracy. The apex locators #15 k files, #10 k files, and #8 k files showed the most promising results., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Journal of Pharmacy and Bioallied Sciences.)

Caries is a chronic disease that causes the alteration of the structure of dental tissues by acid dissolution (in enamel, dentine and cementum) and proteolytic degradation (dentine and cementum) and generates an important cost of care. There is a need to visualise and characterise the acid dissolution process on enamel due to its hierarchical structure leading to complex structural modifications. The process starts at the enamel surface and progresses into depth, which necessitates the study of the internal enamel structure. Artificial demineralisation is usually employed to simulate the process experimentally. In the present study, the demineralisation of human enamel was studied using surface analysis carried out with atomic force microscopy as well as 3D internal analysis using synchrotron X-ray tomography during acid exposure with repeated scans to generate a time-lapse visualisation sequence. Two-dimensional analysis from projections and virtual slices and 3D analysis of the enamel mass provided details of tissue changes at the level of the rods and inter-rod substance. In addition to the visualisation of structural modifications, the rate of dissolution was determined, which demonstrated the feasibility and usefulness of these techniques. The temporal analysis of enamel demineralisation is not limited to dissolution and can be applied to other experimental conditions for the analysis of treated enamel or remineralisation.

In this work, the application of a time resolved multi-contrast beam tracking technique to the investigation of the melting and solidification process in metals is presented. The use of such a technique allows retrieval of three contrast channels, transmission, refraction and dark-field, with millisecond time resolution. We investigated different melting conditions to characterize, at a proof-of-concept level, the features visible in each of the contrast channels. We found that the phase contrast channel provides a superior visibility of the density variations, allowing the liquid metal pool to be clearly distinguished. Refraction and dark-field were found to highlight surface roughness formed during solidification. This work demonstrates that the availability of the additional contrast channels provided by multi-contrast X-ray imaging delivers additional information, also when imaging high atomic number specimens with a significant absorption., (© 2022. The Author(s).)

The management of retinoblastoma (RB) involves the use of invasive treatment regimens. Paclitaxel (PTX), an effective antineoplastic compound used in the treatment of a wide range of malignant tumors, poses treatment challenges due to systemic toxicity, rapid elimination, and development of resistance. The goal of this work was to develop PTX-loaded, α-tocopherol succinate (αTS)-based, nanostructured lipid carrier (NLCs; αTS-PTX-NLC) and PEGylated αTS-PTX-NLC (αTS-PTX-PEG-NLC) to improve ocular bioavailability. The hot homogenization method was used to prepare the NLCs, and repeated measures ANOVA analysis was used for formulation optimization. αTS-PTX-NLC and αTS-PTX-PEG-NLC had a mean particle size, polydispersity index and zeta potential of 186.2 ± 3.9 nm, 0.17 ± 0.03, −33.2 ± 1.3 mV and 96.2 ± 3.9 nm, 0.27 ± 0.03, −39.15 ± 3.2 mV, respectively. The assay and entrapment efficiency of both formulations was >95.0%. The NLC exhibited a spherical shape, as seen from TEM images. Sterilized (autoclaved) formulations were stable for up to 60 days (last time point checked) under refrigerated conditions. PTX-NLC formulations exhibited an initial burst release and 40% drug release, overall, in 48 h. The formulations exhibited desirable physicochemical properties and could lead to an effective therapeutic option in the management of RB.

Full-field transmission X-ray microscopy (TXM) is a very potent high-resolution X-ray imaging technique. However, it is challenging to achieve fast acquisitions because of the limited efficiency of the optics. Using a broader energy bandwidth, for example using a multilayer monochromator, directly increases the flux in the experiment. The advantage of more counts needs to be weighed against a deterioration in achievable resolution because focusing optics show chromatic aberrations. This study presents theoretical considerations of how much the resolution is affected by an increase in bandwidth as well as measurements at different energy bandwidths (ΔE/E = 0.013%, 0.27%, 0.63%) and the impact on achievable resolution. It is shown that using a multilayer monochromator instead of a classical silicon double-crystal monochromator can increase the flux by an order of magnitude with only a limited effect on the resolution., (open access.)

Forced swim test (FST) and tail suspension test (TST) are commonly used behavioral tests for screening antidepressant drugs with a high predictive validity. These tests have also proved useful to assess the non-motor symptoms in the animal models of movement disorders such as Parkinson's disease and Huntington's disease. Manual analysis of FST and TST is a time-consuming exercise and has large observer-to-observer variability. Automation of behavioral analysis alleviates these concerns, but there are no easy-to-use open-source tools for such analysis. Here, we describe the development of Depression Behavior Scorer (DBscorer), an open-source program installable on Windows, with an intuitive graphical user interface (GUI), that helps in accurate quantification of immobility behavior in FST and TST from video analysis. Several calibration options allow customization of various parameters to suit the experimental requirements. Apart from the readout of time spent immobile, DBscorer also provides additional data and graphics of immobility/mobility states across time revealing the evolution of behavioral despair over the duration of the test and allows the analysis of additional parameters. Such comprehensive analysis allows a more nuanced understanding of the expression of behavioral despair in FST and TST. We believe that DBscorer would make analysis of behavior in FST and TST unbiased, automated and rapid, and hence prove to be helpful to the wider neuroscience community., (Copyright © 2021 Nandi et al.)

IL-9‒producing T cells are present in healthy skin as well as in the cutaneous lesions of inflammatory diseases and cancers. However, the roles of IL-9 in human skin during homeostasis and in the pathogenesis of inflammatory disorders remain obscure. In this study, we examined the roles of IL-9 in metabolic reprogramming of human primary keratinocytes (KCs). High-throughput quantitative proteomics revealed that IL-9 signaling in human primary KCs disrupts the electron transport chain by downregulating multiple electron transport chain proteins. Nuclear magnetic resonance-based metabolomics showed that IL-9 also reduced the production of tricarboxylic acid cycle intermediates in human primary KCs. An integration of multiomics data with systems-level analysis using the constraint-based MitoCore model predicted marked IL-9-dependent effects on central carbohydrate metabolism, particularly in relation to the glycolytic switch. Stable isotope metabolomics and biochemical assays confirmed increased glucose consumption and redirection of metabolic flux toward lactate by IL-9. Functionally, IL-9 inhibited ROS production by IFN-γ and promoted human primary KC survival by inhibiting apoptosis. In conclusion, our data reveal IL-9 as a master regulator of KC metabolic reprogramming and survival., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Justification: In India, till recently, breastfeeding women have been excluded from the coronavirus disease (COVID-19) vaccination program, rendering a significant population of the country, including frontline workers, ineligible to derive the benefits of the COVID-19 vaccine rollout., Objective: The objective of this recommendation is production of an evidence-based document to guide the pediatricians to give advice to breastfeeding mothers regarding the safety of COVID-19 vaccines in lactating women., Process: Formulation of key question was done under the chairmanship of president of the IAP. It was followed by review of literature regarding efficacy and safety of COVID-19 vaccines in breastfeeding women. The recommendations of other international and national professional bodies were also deliberated in detail. The available data was discussed in the ACVIP focused WhatsApp group. Opinion of all members was taken and the final document was prepared after achieving consensus., Recommendations: The IAP/ACVIP recommends the administration of COVID-19 vaccines to all breastfeeding women. The IAP/ACVIP endorses the recent recommendation of the Government of India, to consider all breastfeeding women as eligible for COVID-19 vaccination.

Nervous system development and plasticity involve changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyze the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by principal component analysis (PCA). SMorph was tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with the antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes in mice. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Pulmonary delivery is a promising alternative for the oral treatment of pulmonary aspergillosis. This study aimed to develop continuous and scalable itraconazole PEGylated nano-lipid carriers (ITZ-PEG-NLC) for inhalation delivery. The feasibility of preparing NLCs utilizing hot-melt extrusion (HME) coupled with probe sonication was investigated. The process parameters for HME and sonication were varied to optimize the formulation. ITZ-PEG-NLC (particle size, 101.20 ± 1.69 nm; polydispersity index, 0.26 ± 0.01) was successfully formulated. The drug entrapment efficiency of ITZ-PEG-NLC was 97.28 ± 0.50%. Transmission electron microscopy was used to characterize the shape of the particles. The developed formulations were evaluated for their aerodynamic properties for pulmonary delivery. The lung deposition of ITZ-PEG-NLC was determined using an Anderson Cascade Impactor and Philips Respironics Sami the Seal Nebulizer Compressor. In vitro cytotoxicity studies were performed using A549 cells. A burst-release pattern was observed in ITZ-PEG-NLC with a drug release of 41.74 ± 1.49% in 60 min. The in vitro aerosolization of the ITZ-PEG-NLC formulation showed a mass median aerodynamic diameter of 3.51 ± 0.28 μm and a geometric standard deviation of 2.44 ± 0.49. These findings indicate that HME technology could be used for the production of continuous scalable ITZ-PEG-NLC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Justification: In view of new developments in vaccinology and the availability of new vaccines, there is a need to revise/review the existing immunization recommendations., Process: Advisory Committee on Vaccines and Immunization Practices (ACVIP) of Indian Academy of Pediatrics (IAP) had a physical meeting in March, 2020 followed by online meetings (September-October, 2020), to discuss the updates and new recommendations. Opinion of each member was sought on the various recommendations and updates, following which an evidence-based consensus was reached., Objectives: To review and revise the IAP recommendations for 2020-21 and issue recommendations on existing and new vaccines., Recommendations: The major changes include recommendation of a booster dose of injectable polio vaccine (IPV) at 4-6 years for children who have received the initial IPV doses as per the ACVIP/IAP schedule, re-emphasis on the importance of IPV in the primary immunization schedule, preferred timing of second dose of varicella vaccine at 3-6 months after the first dose, and uniform dosing recommendation of 0.5 mL (15 µg HA) for inactivated influenza vaccines.

A coronary artery crossing the right ventricular outflow tract is a subset of a larger pathomorphological cohort known as an anomalous coronary artery (ACA) in the tetralogy of Fallot (TOF). The best possible outcome in a patient with TOF and ACA is decided by judicious selection of optimum preoperative investigative information, the timing of surgery, astute assessment of preoperative surgical findings, and appropriate surgical technique from a wide array of choices. In most instances, the choice of surgical technique is determined by the size of the pulmonary annulus and the anatomical relation of ACA to the pulmonary annulus. In the present era, complete, accurate preoperative diagnosis and primary repair is a routine procedure with strategies to avoid a right ventricle-to-pulmonary artery conduit., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Annals of Pediatric Cardiology.)

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, immunization practices of all age groups, especially routine childhood vaccines, have been interrupted. Immunization is considered an essential health activity, which needs to be resumed as early as possible. This pandemic has created several unique issues related to routine immunization of individual children at clinics, which needs to be addressed. In this communication, the Advisory Committee on Vaccines and Immunization Practices (ACVIP) of Indian Academy of Pediatrics addresses the common questions and issues related to SARS-CoV-2 and routine immunization services. This also includes the recommendations for routine immunization of SARS-CoV-2 suspect and positive children, and for the logistics to be followed for immunization services.

Purpose: We report a rare case of unilateral progressive adult-onset myopia in a healthy 27 year old female patient., Observations: The patient presented to our clinic in 2014 with gradual decrease in vision in the right eye since one and a half years. Her uncorrected visual acuity (UCVA) in the right eye was 0.05, improving to 1.0 with -2.25 Diopter Sphere (DS). The left eye uncorrected visual acuity was 1.0 partial improving to 1.0 with -0.50 Diopter Cylinder (DC) at 10°. The myopia in her right eye continued to increase steadily until her last detailed ophthalmic examination in November 2018, at the age of 31 years, showed a refractive error of -6.75 Diopter Sphere with -0.5 Diopter Cylinder at 170°. Ocular biometry readings showed an axial length (AL) of 25.79mm in the right eye compared to 25.05mm in 2015. The ocular examination of both eyes including clinical examination of anterior and posterior segment, corneal topography, lens densitometry, ultrasound B scan all were within normal limits. Over the last two years she has gradually developed moderate constant esotropia in the right eye, currently +30 Prism Diopters. A short visit to the clinic in December 2019, showed a refraction of -6.75DS with -0.5DC at 170° in the right eye and -0.50DC at 10° in the left eye., Conclusions and Importance: The abrupt onset of myopia in one eye in a healthy individual in this case, the degree of myopia, the nature and rate of progression, absence of risk factors, and otherwise normal ocular examination except for progressive increase in axial length is unusual. Our case brings us to conjecture the role of powerful local factors in the intrinsic regulation of eyeball growth going askew. We believe more and more reporting of myopia cases deviating from natural history and their study might provide clues in a new direction about myopia pathogenesis and our understanding and tackling of one of the oldest eye disease with an ever increasing prevalence., Competing Interests: The following authors have no financial disclosures: Saleh Saif Al Messabi, Mohamed Dirani, Shobhana Mukhi-Marathe., (© 2020 Published by Elsevier Inc.)

The increasing prevalence of unethical practices such as unnecessary investigations, overcharging, and violation of patients' rights, especially in private hospitals, have drawn attention to the unregulated and overwhelmingly commercialised nature of the private healthcare sector in India.

Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL9-producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemotherapy and revealed distinct immune hallmarks of the disease. Importantly, there was a higher frequency of "skin homing" Th9 cells in CTCL patients with early (T1 and T2) and advanced-stage disease (T3 and T4). However, advanced-stage CTCL patients had severely impaired frequency of skin-homing Th1 and Th17 cells, indicating attenuated immunity. Treatment of CTCL patients with standard photo/chemotherapy decreased the skin-homing Th9 cells and increased the Th1 and Th17 cells. Interestingly, T cells of CTCL patients express IL9 receptor (IL9R), and there was negligible IL9R expression on T cells of healthy donors. Mechanistically, IL9/IL9R interaction on CD3 + T cells of CTCL patients and Jurkat cells reduced oxidative stress, lactic acidosis, and apoptosis and ultimately increased their survival. In conclusion, coexpression of IL9 and IL9R on T cells in CTCL patients indicates the autocrine-positive feedback loop of Th9 axis in promoting the survival of malignant T cells by reducing the oxidative stress. IMPLICATIONS: The critical role of Th9 axis in CTCL pathogenesis indicates that strategies targeting Th9 cells might harbor significant potential in developing robust CTCL therapy., (©2020 American Association for Cancer Research.)

A heterogeneous private sector dominates healthcare provision in many middle-income countries. In India, the contemporary period has seen this sector undergo corporatisation processes characterised by emergence of large private hospitals and the takeover of medium-sized and charitable hospitals by corporate entities. Little is known about the operations of these private providers and the effects on healthcare professions as employment shifts from practitioner-owned small and medium hospitals to larger corporate settings. This article uses data from a mixed-methods study in two large cities in Maharashtra, India, to consider the implications of these contemporary changes for the medical profession. Data were collected from semistructured interviews with 43 respondents who have detailed knowledge of healthcare in Maharashtra and from a witness seminar on the topic of transformation in Maharashtra's healthcare system. Transcripts from the interviews and witness seminar were analysed thematically through a combination of deductive and inductive approaches. Our findings point to a restructuring of medical practice in Maharashtra as training shifts towards private education and employment to those corporate hospitals. The latter is fuelled by substantial personal indebtedness, dwindling appeal of government employment, reduced opportunities to work in smaller private facilities and the perceived benefits of work in larger providers. We describe a 'reprofessionalisation' of medicine encompassing changes in employment relations, performance targets and constraints placed on professional autonomy within the private healthcare sector that is accompanied by trends in cost inflation, medical malpractice, and distrust in doctor-patient relationships. The accompanying 'restratification' within this part of the profession affords prestige and influence to 'star doctors' while eroding the status and opportunity for young and early career doctors. The research raises important questions about the role that government and medical professionals' bodies can, and should, play in contemporary transformation of private healthcare and the implications of these trends for health systems more broadly., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objectives: D-transposition of the great arteries and l-transposition of the great arteries with ventricular septal defect and left ventricular outflow tract obstruction are complex biventricular congenital heart diseases for which decision-making regarding surgical strategy remains challenging. We investigated the intermediate-term outcomes of Fontan versus biventricular procedures in these patients., Methods: We analyzed 129 patients with d-transposition of the great arteries/ventricular septal defect/left ventricular outflow tract obstruction (n = 85) or l-transposition of the great arteries/ventricular septal defect/left ventricular outflow tract obstruction (n = 44) and 2 functional ventricles from Australia who had primary surgical management (29 Fontan, 100 biventricular repair) undertaken between 1990 and 2015., Results: Median operative age of patients was 2.9 years (range, 0.2-26.8 years). During a median follow-up of 6.2 years (range, 2 days to 25.8 years), 9 patients died after biventricular repair (3 early and 6 late deaths). One patient received a transplant 1.2 years after Fontan completion. Overall transplant-free survivals at 1, 5, 10, and 15 years were 95%, 93%, 92%, and 90%, respectively. Overall reintervention-free survivals at 1, 5, 10, and 15 years were 79%, 64%, 45%, and 29% respectively. Biventricular repair tended to be associated with a higher rate of death, transplantation, or reintervention than the Fontan pathway (hazard ratio, 1.83; 95% confidence interval, 0.90-3.71; P = .10). Some 73% of transplant-free survivors had New York Heart Association class I. Functional status was similar between the Fontan and biventricular groups., Conclusions: Intermediate-term outcomes were comparable between patients with d-transposition of the great arteries/ventricular septal defect/left ventricular outflow tract obstruction and patients with l-transposition of the great arteries/ventricular septal defect/left ventricular outflow tract obstruction. Both Fontan and biventricular pathways are associated with excellent mortality and functional outcomes. Biventricular patients have a greater risk of reintervention. The Fontan procedure is a viable option when anatomic risk factors preclude biventricular repair., (Copyright © 2019 The American Association for Thoracic Surgery. All rights reserved.)

T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy., (© 2024. The Author(s).)

Competing Interests: None