SREBP signaling is essential for effective B cell responses.

Our previous study using systems vaccinology identified an association between the sterol regulatory binding protein (SREBP) pathway and humoral immune response to vaccination in humans. To investigate the role of SREBP signaling in modulating immune responses, we generated mice with B cell- or CD11c+ antigen-presenting cell (APC)-specific deletion of SCAP, an essential regulator of SREBP signaling. Ablation of SCAP in CD11c+ APCs had no effect on immune responses. In contrast, SREBP signaling in B cells was critical for antibody responses, as well as the generation of germinal centers,memory B cells and bone marrow plasma cells. SREBP signaling was required for metabolic reprogramming in activated B cells. Upon mitogen stimulation, SCAP-deficient B cells could not proliferate and had decreased lipid rafts. Deletion of SCAP in germinal center B cells using AID-Cre decreased lipid raft content and cell cycle progression. These studies provide mechanistic insights coupling sterol metabolism with the quality and longevity of humoral immunity.

Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine.

Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.

Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.

N6-Methyladenosine Modification Controls Circular RNA Immunity.

Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (m6A) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and m6A modification abrogates immune gene activation and adjuvant activity. m6A reader YTHDF2 sequesters m6A-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not m6A-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.

A TLR7-nanoparticle adjuvant promotes a broad immune response against heterologous strains of influenza and SARS-CoV-2.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

Functional near-infrared spectroscopy guided mapping of frontal cortex, a novel modality for assessing emergence delirium in children: A prospective observational study.

INTRODUCTION: Despite an 18%-30% prevalence, there is no consensus regarding pathogenesis of emergence delirium after anesthesia in children. Functional near-infrared spectroscopy (fNIRS) is an optical neuroimaging modality that relies on blood oxygen level-dependent response, translating to a mean increase in oxyhemoglobin and a decrease in deoxyhemoglobin. We aimed to correlate the emergence delirium in the postoperative period with the changes in the frontal cortex utilizing fNIRS reading primarily and also with blood glucose, serum electrolytes, and preoperative anxiety scores. METHODS: A total of 145 ASA I and II children aged 2-5 years, undergoing ocular examination under anesthesia, were recruited by recording the modified Yale Preoperative Anxiety Score after acquiring the Institute Ethics Committee approval and written informed parental consent. Induction and maintenance were done with O2, N2O, and Sevoflurane. The emergence delirium was assessed using the PAED score in the postoperative period. The frontal cortex fNIRS recordings were taken throughout anesthesia. RESULTS: A total of 59 children (40.7%) had emergence delirium. The ED+ group had a significant activation left superior frontal cortex (t = 2.26E+00; p = .02) and right middle frontal cortex (t = 2.27E+00; p = .02) during induction, significant depression in the left middle frontal (t = -2.22E+00; p = .02), left superior frontal and bilateral medial (t = -3.01E+00; p = .003), right superior frontal and bilateral medial (t = -2.44E+00; p = .015), bilateral medial and superior (t = -3.03E+00; p = .003), and right middle frontal cortex (t = -2.90E+00; p = .004) during the combined phase of maintenance, and significant activation in cortical activity in the left superior frontal cortex (t = 2.01E+00; p = .0047) during the emergence in comparison with the ED- group. CONCLUSION: There is significant difference in the change in oxyhemoglobin concentration during induction, maintenance, and emergence in specific frontal brain regions between children with and without emergence delirium.

Computational study on 2D three-phase lag bioheat model during cryosurgery using RBF meshfree method.

Biological tissue has a multidimensional and non-homogeneous inner structure by nature. The temperature distribution and freezing front locations in biological tissue are crucial to optimizing the damage to tissue during cryosurgery. There is a need for a good mathematical model and effective simulation techniques to predict the effectiveness of the therapy. The present study concerns the numerical study of phase change phenomena during cryosurgery using the three-phase lag (TPL) bioheat model in arbitrary soft tissue domains, i.e., circular (Γ1), ameba-like (Γ2), and multiconnected (Γ3). We employ the effective heat capacity formulation to solve the nonlinear governing equation. The Gaussian radial basis function and Crank-Nicolson finite difference approximation are applied for spatial and time derivatives, respectively. Using the present algorithm, we study the impact of phase lag (τv) due to thermal displacement involved in the TPL model on phase change interface position and thermal distribution in all three domains. The obtained results may be beneficial in the field of oncology.

SARS-CoV-19-associated Rhino-orbital and cerebral mucormycosis: clinical and radiological presentations.

We describe presenting clinical and imaging manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated Rhino-oculo-cerebral mucormycosis (ROCM) in a hospital setting during the second wave of SARS-CoV-2 pandemic in India. Data on the presenting manifestations were collected from 1 March to 31 May 2021. Associations between clinical and imaging findings were explored, specifically: (1) the presence or absence of orbital pain and infiltration of a superior orbital fissure on imaging; (2) the presence of unilateral facial nerve palsy and pterygopalatine fossa infiltration and geniculate ganglion signal on contrast magnetic resonance imaging, and (3) vision loss and optic nerve findings on imaging. Orbital pain was reported by 6/36 subjects. A fixed, frozen eye with proptosis and congestion was documented in 26 (72%), complete vision loss in 23 (64%), and a unilateral lower motor neuron facial nerve palsy in 18 (50%). No association was found between the presence of orbital pain and superior orbital fissure infiltration on imaging. The ipsilateral geniculate ganglion was found to enhance more profoundly in 7/11 subjects with facial palsy and available magnetic resonance (MR) imaging, and the ipsilateral pterygopalatine fossa was found infiltrated in 14. Among 23 subjects with complete loss of vision, 9 (39%) demonstrated long-segment bright signal in the posterior optic nerve on diffusion MR images. We conclude that orbital pain might be absent in SARS-CoV-2-associated ROCM. Facial nerve palsy is more common than previously appreciated and ischemic lesions of the posterior portion of the optic nerve underlie complete vision loss.

Unique clinical and radiological manifestations identified in the outbreak of Rhino-oculo-cerebral mucormycosis (ROCM) during the second epidemic wave of coronavirus disease 2019 (COVID-19) infection included the common occurrence of facial paralysis, frequent absence of ocular pain, and long segments of optic nerve damage.

Assessment of psychological distress pattern & its correlates among people receiving COVID-19 vaccination during the COVID-19 pandemic: A cross-sectional study.

Background & objectives: There is a possibility that vaccinated people may experience lesser psychological distress due to the sense of safety felt by them against getting the COVID-19 infection as compared to those who are not vaccinated. However, there is a paucity of research examining the mental health status of this important sub-group of population. Thus, the present study was aimed to examine the pattern of psychological distress and its correlates among people receiving COVID-19 vaccine. Methods: This cross-sectional study assessed individuals receiving COVID-19 vaccine at a tertiary care hospital. Psychological distress and COVID-19-related anxiety were assessed using the Depression Anxiety Stress Scale (DASS-21) and the COVID-19 Anxiety Scale-7, respectively. Results: The study comprised 728 individuals with a mean age of 44.8 yr. Moderate levels of depression, anxiety and stress were reported by about 50, six and 15 per cent of the participants, respectively, as assessed on DASS-21. Generalized linear model and quantile regression analyses revealed COVID-19-related anxiety, and being a healthcare worker or front-line worker as significant correlates of psychological distress. Interpretation & conclusions: About half of the study participants receiving COVID-19 vaccine reported moderate to severe symptoms of depression. Strategies focusing on alleviation of COVID-19-related fear and anxiety might be effective in improving the symptoms of psychological distress.

Learning from telepsychiatry during COVID-19 pandemic in India: Boon for public mental health in low- & middle-income countries.

Novel coronavirus disease (COVID-19) pandemic has affected the mental well-being of the population and posed many challenges in availing mental healthcare. Telepsychiatry has been proven to be an effective route for the delivery of mental healthcare. We share our experience of using the telemedicine approach in providing mental health services at a tertiarycare hospital in India during the COVID-19 pandemic, following the break in routine outpatient services during the national lockdown. The telepsychiatry approach helped in ensuring the maintenance of mental healthcare. The utility of telepsychiatry as an option for such future situations and for its use in routine follow up care in indicated cases, have also been discussed.

Primary Hyperparathyroidism Masquerading as Acute Pancreatitis.

Acute pancreatitis as an initial manifestation of primary hyperparathyroidism (PHPT) is a rare occurrence and timely diagnosis of PHPT is crucial in preventing repeat attack of pancreatitis. The study aimed at evaluating the clinico-radiological profile of patients admitted with acute pancreatitis as the index presentation of PHPT and to determine the factors associated with development of severe pancreatitis. This series included retrospective analysis of medical records of 30 patients admitted with acute pancreatitis as initial manifestation of PHPT. Additionally, we analyzed the data of another 30 patients admitted with PHPT but without any evidence of pancreatitis, to serve as control group. The mean age of the subjects was 44.9±13.9 years with male to female ratio of 1.30. The mean serum calcium level was 12.24±2.79 mg/dl and five (16.6%) patients had normocalcemia at time of presentation. Presence of nephrolithiasis was significantly associated with severe pancreatitis. One patient had refractory hypercalcemia associated with renal failure and was successfully managed with denosumab. Patients with PHPT associated with acute pancreatitis had significantly higher calcium levels and lower frequency of skeletal involvement as compared to PHPT patients without pancreatitis. PHPT masquerading as acute pancreatitis is rare and high index of suspicion is required to diagnose this condition especially in the presence of normocalcemia at presentation. Patients with PHPT associated pancreatitis had male preponderance, higher calcium levels, and lower frequency of skeletal involvement as compared to PHPT patients without pancreatitis.

Concordance of recommendations across clinical practice guidelines for the management of hypertension in Southeast Asia with internationally reputable sources.

OBJECTIVES: This study aimed to assess the rate of concordance, and to investigate sources of non-concordance of recommendations in the management of hypertension across CPGs in Southeast Asia, with internationally reputable clinical practice guidelines (CPGs). METHODS: CPGs for the management of hypertension in Southeast Asia were retrieved from the websites of the Ministry of Health or cardiovascular specialty societies of the individual countries of Southeast Asia during November to December 2020. The recommendations for the management of hypertension specified in the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline and the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guideline were selected to be the reference standards; the recommendations concerning the management of hypertension in the included CPGs in Southeast Asia were assessed if they were concordant with the reference recommendations generated from both the 2017 ACC/AHA guideline and the 2018 ESC/ESH guideline, using the population (P)-intervention (I)-comparison (C) combinations approach. RESULTS: A total of 59 reference recommendations with unique and unambiguous P-I-C specifications was generated from the 2017 ACC/AHA guideline. In addition, a total of 51 reference recommendations with unique and unambiguous P-I-C specifications was generated from the 2018 ESC/ESH guideline. Considering the six included CPGs from Southeast Asia, concordance was observed for 30 reference recommendations (50.8%) out of 59 reference recommendations generated from the 2017 ACC/AHA guideline and for 31 reference recommendations (69.8%) out of 51 reference recommendations derived from the 2018 ESC/ESH guideline. CONCLUSIONS: Hypertension represents a significant issue that places health and economic strains in Southeast Asia and demands guideline-based care, yet CPGs in Southeast Asia have a high rate of non-concordance with internationally reputable CPGs. Concordant recommendations could perhaps be considered a standard of care for hypertension management in the Southeast Asia region.

Quality of clinical practice guidelines for the management of hypertension in six Southeast Asian countries.

Background: The endemic of hypertension along with high prevalence of uncontrolled hypertension in Southeast Asia indicates an important role for high-quality clinical practice guidelines (CPGs) to optimize the management of hypertension. However, there was no reported quality appraisal of the CPGs for the management of hypertension in Southeast Asia.Objective: This study aimed to evaluate methodological quality across the CPGs for the management of hypertension in Southeast Asia with a validated quality appraisal tool.Methods: The CPGs for the management of hypertension in Southeast Asia were retrieved from the websites of the Ministry of Health or cardiovascular specialty societies of the individual countries of Southeast Asia. Two reviewers with academic backgrounds independently appraised the methodological quality of all the included CPGs using the Appraisal of Guideline ResEarch and Evaluation (AGREE II) instrument.Results: Six CPGs were identified, each of them from Thailand, Malaysia, Indonesia, Brunei, Singapore, and Vietnam. The highest-scoring quality domain was 'clarity of presentation' (mean=78.7 ± 14.6%), whereas the lowest-scoring quality domains were 'applicability' and 'editorial independence' (mean=8.4 ± 6.0% and mean=8.3 ± 18.6%, respectively). Except for the CPG originated from Malaysia which was "recommended" for use in practice (standardized score for three domains was ≥50.0%), the remaining five CPGs were "weakly recommended" for use in practice (standardized score for one to two domains was ≥50%).Conclusion: More efforts are needed to improve the quality of the developed CPGs for the management of hypertension in Southeast Asia.

Auditory brainstem response testing using intranasal dexmedetomidine sedation in children: a pilot study.

OBJECTIVE: Auditory brainstem response (ABR) is used to determine hearing thresholds in children who cannot undergo behavioural testing. Children must remain still during testing, with general anaesthesia (GA) in theatre required for those who cannot. We developed a protocol whereby an ABR was undertaken in a ward environment using only intranasal dexmedetomidine for sedation. DESIGN: Prospective data were collected including the time of sedation onset, ABR duration and arrival to discharge time was recorded and feedback was requested using a questionnaire. STUDY SAMPLE: Twenty-nine consecutive patients routinely undergoing an ABR. RESULTS: From this pilot study, we demonstrated that intranasal dexmedetomidine could be used successfully to administer safe sedation to all twenty-nine children undergoing an ABR in a ward environment as opposed to theatre. CONCLUSIONS: This allowed for faster time to discharge compared to GA, produced what was felt to be a better quality ABR trace, better utilization of a theatre slot, negated the need for GA in a child and created a less stressful experience for both parent and child according to information from feedback questionnaires.

Effectiveness and Predictors of Response to 1-Hz Repetitive Transcranial Magnetic Stimulation in Patients With Obsessive-Compulsive Disorder.

OBJECTIVE: The present study aimed to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) treatment targeting either supplementary motor area (SMA) or orbitofrontal cortex (OFC) among patients with OCD in real-world clinical practice settings. Also, the present study explored for potential predictors of response to rTMS treatment. METHODS: Retrospective review and analysis of records of 79 patients with medication-refractory OCD, all of whom had received 20 sessions of 1-Hz rTMS as part of routine clinical care. Of 79 patients, 46 received rTMS over the bilateral SMA and 33 over the left OFC. A reduction of 25% and 35% in Yale-Brown Obsessive Compulsive Scale (YBOCS) scores was used to classify outcome as partial and complete response, respectively. Statistical analysis was done using SPSS version 23.0. RESULTS: There was a significant decrease in mean YBOCS score from baseline to end of treatment (7.68 ± 5.62; t = 12.14, P < 0.001). Forty-five patients (57%) met criteria for partial response, of which 32 patients (40.5%) showed complete response. There was no significant difference in outcomes between patients receiving rTMS over SMA or OFC. Binary logistic regression analysis revealed presence of comorbid depression and higher baseline YBOCS score to be associated with lesser likelihood of response to rTMS. CONCLUSIONS: This study provided evidence for overall effectiveness of adjunctive 1-Hz rTMS treatment over either SMA or OFC in patients with medication-refractory OCD, and reported comorbid depression and higher pretreatment YBOCS scores as potential predictors of poor response to rTMS.

Cutting Edge: ACVRL1 Signaling Augments CD8α+ Dendritic Cell Development.

Dendritic cells (DCs) are a collection of different subtypes, each of which is characterized by specific surface markers, gene-expression patterns, and distinct functions. Members of the IFN regulatory factor family play critical roles in DC development and functions. Recently, Irf8 was shown to activate TGF-ß signaling, which led to exacerbated neuroinflammation in the experimental autoimmune encephalomyelitis mouse model. We analyzed the effect of Irf8 on TGF-ß/bone morphogenetic protein pathway-specific genes in DCs and identified Acvrl1, a type I TGF-ß superfamily receptor, as a gene strongly induced by Irf8 expression. Among various DC subtypes, Acvrl1 is differentially expressed in CD8α(+) DCs. ACVRL1 signaling augmented Irf8-directed classical CD8α(+) DC development. Irf8 expression is essential for plasmacytoid DC and CD8α(+) DC development, and this study demonstrates that ACVRL1 signaling plays a pivotal role whereby it suppresses plasmacytoid DC development while enhancing that of CD8α(+) DCs, thus contributing to DC diversity development.

The Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation at Orbitofrontal Cortex in the Treatment of Patients With Medication-Refractory Obsessive-Compulsive Disorder: A Retrospective Open Study.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic debilitating psychiatric disorder, with significant proportion of patients failing to respond with current first-line treatments. The present study assesses the safety and effectiveness of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over left-orbitofrontal cortex (Lt-OFC) as a potential augmentation strategy in treatment of patients with medication-refractory OCD in real-world clinical setting. The present report also aims to examine the factors affecting response to rTMS and the durability of effects produced by rTMS over 1 month of follow-up period. METHODS: Retrospective review and analysis of clinical case files of 25 patients with medication-refractory OCD, all of whom had received 20 sessions of LF-rTMS over Lt-OFC as part of routine clinical care. A reduction of 25% and 35% in Yale-Brown Obsessive Compulsive Scale scores was used to determine the proportion of partial and complete responders, respectively. RESULTS: There was a significant decrease in mean Yale-Brown Obsessive Compulsive Scale score at the end of 20 sessions of rTMS compared with baseline (7.04 ± 5.07; P < 0.001), with no further significant change during the subsequent 1-month follow-up period (0.20 ± 1.38; P = 0.47). Thirteen patients (52%) met criteria for partial response, of which 11 patients (44%) showed complete response. Furthermore, higher number of failed medication trials was found to be significantly associated with greater chances of nonresponse to rTMS treatment. CONCLUSIONS: There is a role of applying LF-rTMS over Lt-OFC as an augmentation strategy in ameliorating clinical symptoms among patients with medication-refractory OCD.

Cathodal neuromodulation of dominant temporoparietal cortex with transcranial direct current stimulation for tinnitus: A case series.

There is scant literature on the effectiveness of using transcranial direct current stimulation (tDCS) as an intervention modality for managing tinnitus. The current case series reflects the use of tDCS as an effective intervention for tinnitus while inhibiting the dominant temporoparietal cortex and simultaneous stimulating the non-dominant dorsolateral prefrontal cortex.

Effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) in patients with comorbid panic disorder and major depression.

OBJECTIVE: To explore the role of dorsolateral prefrontal cortex (DLPFC) stimulation in the treatment of panic disorder with comorbid depression. METHODS: The present study reports findings from retrospective analysis of 13 treatment-resistant patients diagnosed with comorbid panic disorder and depression, given 20 sessions of high-frequency transcranial magnetic stimulation (rTMS) over left-DLPFC over a period of 1 month. RESULTS: There was a significant reduction in both the panic and depressive symptom severity, assessed by applying Panic Disorder Severity Scale (PDSS) and Hamilton Depression Rating Scale (HDRS) at baseline and after 20 sessions of rTMS. There was a 38% and 40% reduction of PDSS and HDRS scores, respectively, in the sample. The changes in PDSS and HDRS scores were not significantly correlated (ρ = -0.103, p = 0.737). CONCLUSIONS: High-frequency rTMS delivered at left-DLPFC may have a potential role in treatment of comorbid panic disorder and depression. Future studies done on a larger sample in a controlled environment are required to establish its role.