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Sustainability in livestock production system is largely affected by climate change. An imbalance between metabolic heat production inside the animal body and its dissipation to the surroundings results to heat stress (HS) under high air temperature and humid climates. The foremost reaction of animals under thermal weather is increases in respiration rate, rectal temperature and heart rate. It directly affect feed intake thereby, reduces growth rate, milk yield, reproductive performance, and even death in extreme cases. Dairy breeds are typically more sensitive to HS than meat breeds, and higher producing animals are, furthermore, susceptible since they generates more metabolic heat. HS suppresses the immune and endocrine system thereby enhances susceptibility of an animal to various diseases. Hence, sustainable dairy farming remains a vast challenge in these changing climatic conditions globally.

Polyarteritis nodosa (PAN) is a rare necrotising vasculitis affecting small to medium-sized arteries, characterised by diverse clinical manifestations. This report describes two paediatric cases of PAN with unique presentations, diagnostic challenges and therapeutic responses. The first case involved recurrent lower motor neuron facial palsy, which is a rare manifestation of PAN (only a very few reported cases of isolated cranial nerve involvement), severe hypertension and cardiac involvement, while the second case presented with recurrent systemic inflammation, digital gangrene followed by autoamputation and peripheral vascular involvement. The diagnostic approach, including digital subtraction angiography and histopathology, along with tailored immunosuppressive management, is discussed. These cases highlight the importance of clinical suspicion, multisystemic involvement and early intervention in PAN.

Background B-cell acute lymphoblastic leukemia (B-ALL) is characterized by the malignant burgeoning of abnormal B-cell lymphoblasts. In recent years, the use of chimeric antigen receptor T-cell (CAR-T) therapy which targets CD19 antigen present on the surface of B-cells, has gained significant attention as a treatment option against aggressive and refractory forms of B-ALL. However, the loss of CD19 antigen on B-cell surface due to aberrant splicing under therapy pressure has been suggested as one of the main factors for the emerging CAR-T therapy resistance. The primary aim of this study was to elucidate the presence and characteristics of aberrant CD19 splicing patterns in pediatric B-ALL patients at the time of initial diagnosis stage. Methodology Herein, using RT-PCR based splice assays we have examined CD19 splicing patterns in 43 primary pediatric B-ALL patient samples spread across various subtypes, and investigated underlying mechanisms harboring aberrant splicing. Results We observe that CD19 isoform lacking exon 5-6 is present in ~ 55% of pediatric patients at the initial diagnosis stage itself. Our in-silico analysis identified splicing regulator MBNL1 as a potential modulator of CD19 exon 5-6 splicing. Subsequent qRT-PCR analysis in patient samples revealed that MBNL1 is overexpressed in patient samples exhibiting exon 5-6 skipping. Furthermore, our functional studies demonstrate that loss of MBNL1 in B-ALL cell line induces exon 5-6 skipping, thereby confirming its mechanistic role in CD19 splicing regulation. Conclusions Taken together, we for the first time report the existence of aberrantly spliced CD19 isoform lacking exon 5-6 in primary pediatric patients at the diagnosis stage. Our results suggest that this MBNL1 dysregulation contributes to this splicing event, potentially predisposing patients to resistance against CD19-directed immunotherapies.

Background: The auricular branch of the vagus nerve runs superficially, which makes it a favorable target for non-invasive stimulation techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. These trials often report conflicting results for the same indication. Methods: Using the Cochrane Risk of Bias tool we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) to identify the factors that led to these conflicting results. The majority of aVNS studies were assessed as having “some” or “high” risk of bias, which makes it difficult to interpret their results in a broader context. Results: There is evidence of a modest decrease in heart rate during higher stimulation dosages, sometimes at above the level of sensory discomfort. Findings on heart rate variability conflict between studies and are hindered by trial design, including inappropriate washout periods, and multiple methods used to quantify heart rate variability. There is early-stage evidence to suggest aVNS may reduce circulating levels and endotoxin-induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ameliorated pathological pain but not evoked pain. Discussion: Based on results of the Cochrane analysis we list common improvements for the reporting of results, which can be implemented immediately to improve the quality of evidence. In the long term, existing data from aVNS studies and salient lessons from drug development highlight the need for direct measures of local neural target engagement. Direct measures of neural activity around the electrode will provide data for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target activation. Furthermore, direct measures of target engagement, along with consistent evaluation of blinding success, must be used to improve the design of controls—a major source of concern identified in the Cochrane analysis. The need for direct measures of neural target engagement and consistent evaluation of blinding success is applicable to the development of other paresthesia-inducing neuromodulation therapies and their control designs.

Noninvasive electronic bone growth stimulators (EBGSs) have been in clinical use for decades. However, systematic reviews show inconsistent and limited clinical efficacy. Further, noninvasive EBGS studies in small animals, where the stimulation electrode is closer to the fracture site, have shown promising efficacy, which has not translated to large animals or humans. We propose that this is due to the weaker electric fields reaching the fracture site when scaling from small animals to large animals and humans. To address this gap, we measured the electric field strength reaching the bone during noninvasive EBGS therapy in human and sheep cadaver legs and in finite element method (FEM) models of human and sheep legs. During application of 1100 V/m with an external EBGS, only 21 V/m reached the fracture site in humans. Substantially weaker electric fields reached the fracture site during the later stages of healing and at increased bone depths. To augment the electric field strength reaching the fracture site during noninvasive EBGS therapy, we introduced the Injectrode, an injectable electrode that spans the distance between the bone and subcutaneous tissue. Our study lays the groundwork to improve the efficacy of noninvasive EBGSs by increasing the electric field strength reaching the fracture site.

Typhoid fever, measles, and rubella continue to contribute significantly to childhood morbidity and mortality in India. In line with WHO recommendations for co-administration of Typhoid Conjugate Vaccine (TCV) and measles–rubella (MR) vaccine at 9 months of age, this phase IV, randomized, open-label, multicenter clinical trial was conducted to assess their immunological compatibility and safety when administered concomitantly. A total of 900 healthy Indian infants aged 9–10 months were randomized into three groups: Group A received TCV and MR vaccine concomitantly; Group B received MR on Day 0 and TCV on Day 28; Group C received TCV on Day 0 and MR on Day 28. Subjects were followed for 6 months after concomitant/last vaccination. Seroconversion rates (SC) in Groups A/B/C at Day 28 were 90.2%/75.3%/89.5% for anti-Vi; 80.4%/75.2%/77.7% for anti-measles, and 87.7%/84.0%/85.2% for anti-rubella antibodies. By study end, SC for anti-Vi was 87.1%/71.6%/83.0%, while SC for anti-measles and anti-rubella reached ~90% and ≥98%, respectively, across all groups. Geometric mean titers increased significantly for all antigens, with no evidence of immunological interference. Safety assessments showed adverse events in 23.9%/32.0%/32.7% participants in Group A/B/C. Most adverse events were mild, and only one serious adverse event was reported. These findings support the co-administration of TCV and MR vaccine as a safe and effective strategy.

Many forms of chronic pain remain refractory to existing pharmacotherapies and electrical neuromodulation. We have recently reported the clinical efficacy of a novel form of analgesic electrical neuromodulation that uses ultra low frequency (ULF ) biphasic current and studied its effects on sensory nerve fibers. Here, we show that in anesthetized rats, epidural ULF current reversibly inhibits activation of neurons in the thalamus receiving sensory spinothalamic input. In naïve, neuropathic and sham-operated rats, recordings of ongoing and evoked activity were made from thalamic neurons, targeting the ventral posterolateral (VPL) nucleus. Responses to electrical stimulation of hind limb receptive fields were reduced in 25 of 32 (78%) neurons tested with lumbar epidural ULF neuromodulation. Cells preferentially responsive to low intensity stimulation were more likely to be found than cells responding to a range of stimulus intensities, or high intensity only; and low threshold responses were more likely to be inhibited by ULF than high threshold responses. On-going activity unrelated to hindlimb stimulation, observed in 17 of 39 neurons in naïve animals (44%), was reduced by lumbar epidural ULF current in only 3 of 14 (21%) neurons tested with ULF. By contrast, in rats with a well-characterized neuropathic injury, spinal nerve ligation (SNL), we found a much higher incidence of on-going activity in thalamic neurons: 53 of 55 neurons (96%) displayed firing unrelated to hindlimb stimulation. In this group, ULF current reduced thalamic neurone discharge rate in 19 of 29 (66%) neurons tested. In sham-operated animals, the incidence of such activity in thalamic neurons and the effect of ULF current were not significantly different from the naïve group. We conclude firstly that ULF current can acutely and reversibly interrupt signaling between sensory afferent fibers and relay neurons of the thalamus. Second, ongoing activity of thalamic neurons increases dramatically in the early stages following neuropathic injury. Third, this novel form of neuromodulation preferentially attenuates pathological thalamic activity in this neuropathic model compared to normal activity in naïve and sham-operated animals. This study, therefore, demonstrates that epidural ULF current can reduce nerve injury-related abnormal activity reaching the brain. These findings help advance understanding of possible mechanisms for the analgesic effects of ULF neuromodulation.

Initial efforts to artificially stimulate the heart were borne out of a necessity to prevent catastrophic bradycardic events. The initial pacemaker systems were large, bulky external devices. However, advancements in technology allowed for the development of internally powered, fully implantable devices. Further advancements resulted in more complex, programmable devices, but the overall systems have remained largely unchanged for more than 50 years. The most recent advancements in the field have represented fundamental paradigm shifts in both pacemaker design and the approach to cardiac pacing. These efforts have focused on reducing and eliminating hardware to reduce the risk of complications and to focus on improving cardiac efficiency to improve clinical outcomes. In this article, the authors explore these advances including leadless pacemaker systems, permanent His bundle pacing and advances in the field of cardiac resynchronisation therapy.

Relapse and default cases of pulmonary tuberculosis (PTB) present a significant challenge due to higher bacillary loads and the increased risk of developing multidrug-resistant tuberculosis (MDR-TB). Conventional diagnostic methods, such as smear microscopy, lack sensitivity and timeliness. This study evaluates the prognostic value of time to positivity (TTP) from liquid culture and cycle threshold (CT) values from GeneXpert /rifampicin (Cepheid, Sunnyvale, CA) in predicting treatment outcomes. This study aimed to assess the utility of baseline mycobacteria growth indicator tube (MGIT) TTP and GeneXpert CTvalues as early biomarkers for prognosis and the risk of MDR-TB development in smear-positive relapse and default PTB patients. This cross-sectional study with a prospective arm enrolled 72 adult PTB patients (relapse, default, or treatment failure). Sputum samples underwent smear microscopy, MGIT liquid culture, and GeneXpert testing. Baseline and three-month follow-up results were compared. TTP and CT values were correlated with microbiological outcomes. MGIT culture was positive in 52.8% (38/72) of patients (mean TTP: 26.5 days). In comparison, GeneXpert detected in 70.8% (51/72) (mean CT: 24.4). At follow-up, 7.8% (3/38) remained culture-positive (mean TTP: 29.7 days); one isolate was MDR. Patients with follow-up culture positivity had significantly lower baseline TTP (19.7 ± 3.4 vs. 25.8 ± 3.8 days). CT values trended lower among poor responders but did not reach statistical significance. Logistic regression suggested that a TTP threshold of ≤20.89 days might predict poor outcomes (model accuracy: 70%). Baseline MGIT TTP demonstrates significant prognostic potential in identifying patients with PTB at risk of treatment failure or MDR development. In contrast, GeneXpert CT values, while useful diagnostically, were less predictive of outcomes. Incorporating TTP into routine clinical practice could enable earlier intervention and improve TB control strategies in high-burden settings.

The metastatic gastric adenocarcinoma that diffusely invades the bone marrow frequently has a short clinical course and an unfavourable prognosis. This case study aimed to elucidate the clinicopathological characteristics and prognosis of gastric cancer patients with diffuse bone marrow metastases. The specific clinicopathologic features associated with diffuse bone metastasis from gastric cancer must be given special attention due to the poor prognosis of this condition. Regular follow-up and a bone marrow examination in high-risk patients can assist in identifying advanced disease early.