Theoretical prediction of broadband ambient light optogenetic vision restoration with ChRmine and its mutants.

Vision restoration is one of the most promising applications of optogenetics. However, it is limited due to the poor-sensitivity, slow-kinetics and narrow band absorption spectra of opsins. Here, a detailed theoretical study of retinal ganglion neurons (RGNs) expressed with ChRmine, ReaChR, CoChR, CatCh and their mutants, with near monochromatic LEDs, and broadband sunlight, halogen lamp, RGB LED light, and pure white light sources has been presented. All the opsins exhibit improved light sensitivity and larger photocurrent on illuminating with broadband light sources compared to narrow band LEDs. ChRmine allows firing at ambient sunlight (1.5 nW/mm2) and pure white light (1.2 nW/mm2), which is lowest among the opsins considered. The broadband activation spectrum of ChRmine and its mutants is also useful to restore color sensitivity. Although ChRmine exhibits slower turn-off kinetics with broadband light, high-fidelity spikes can be evoked upto 50 Hz. This limit extends upto 80 Hz with the improved hsChRmine mutant although it requires double the irradiance compared to ChRmine. The present study shows that ChRmine and its mutants allow activation of RGNs with ambient light which is useful for goggle-free white light optogenetic retinal prostheses with improved quality of restored vision.

Minimally invasive endoscopic management of tubercular tenosynovitis of the anterior tibial tendon.

The incidence of tubercular tenosynovitis around the foot and ankle is rare even in endemic areas. We present an unusual case involving the isolated tubercular tenosynovitis of the Anterior Tibial tendon, which was successfully managed through a combination of medical treatment and endoscopic intervention. Our patient, a 30-year-old female, sought medical attention due to a gradually worsening painful swelling localized to the anterior aspect of her left ankle. Diagnostic imaging, specifically Magnetic Resonance Imaging (MRI), revealed alterations in signal intensity within the Anterior Tibial tendon. Importantly, the infection had not spread to involve the ankle joint. We performed both diagnostic and therapeutic tenosynovectomy endoscopically and subsequently sent the tissue for histopathological examination. The histopathological findings revealed the presence of histiocytic granulomas containing Langhans' giant cells, which strongly suggested a tuberculosis infection. Consequently, we initiated anti-tubercular chemotherapy as the treatment approach. Our patient exhibited a positive response to the treatment, and after one year, she experienced complete resolution of the disease. This case underscores the importance of maintaining a high level of clinical suspicion for tuberculosis, especially in endemic areas, when encountering unusual presentations. Level of evidence: V.

Optogenetically mediated large volume suppression and synchronized excitation of human ventricular cardiomyocytes.

A major challenge in cardiac optogenetics is to have minimally invasive large volume excitation and suppression for effective cardioversion and treatment of tachycardia. It is important to study the effect of light attenuation on the electrical activity of cells in in vivo cardiac optogenetic experiments. In this computational study, we present a detailed analysis of the effect of light attenuation in different channelrhodopsins (ChRs)-expressing human ventricular cardiomyocytes. The study shows that sustained illumination from the myocardium surface used for suppression, simultaneously results in spurious excitation in deeper tissue regions. Tissue depths of suppressed and excited regions have been determined for different opsin expression levels. It is shown that increasing the expression level by 5-fold enhances the depth of suppressed tissue from 2.24 to 3.73 mm with ChR2(H134R) (ChR2 with a single point mutation at position H134), 3.78 to 5.12 mm with GtACR1 (anion-conducting ChR from cryptophyte algae Guillardia theta) and 6.63 to 9.31 mm with ChRmine (a marine opsin gene from Tiarina fusus). Light attenuation also results in desynchrony in action potentials in different tissue regions under pulsed illumination. It is further shown that gradient-opsin expression not only enables suppression up to the same level of tissue depth but also enables synchronized excitation under pulsed illumination. The study is important for the effective treatment of tachycardia and cardiac pacing and for extending the scale of cardiac optogenetics.

AZD1222-induced nasal antibody responses are shaped by prior SARS-CoV-2 infection and correlate with virologic outcomes in breakthrough infection.

The nasal mucosa is an important initial site of host defense against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, intramuscularly administered vaccines typically do not achieve high antibody titers in the nasal mucosa. We measure anti-SARS-CoV-2 spike immunoglobulin G (IgG) and IgA in nasal epithelial lining fluid (NELF) following intramuscular vaccination of 3,058 participants from the immunogenicity substudy of a phase 3, double-blind, placebo-controlled study of AZD1222 vaccination (ClinicalTrials.gov: NCT04516746). IgG is detected in NELF collected 14 days following the first AZD1222 vaccination. IgG levels increase with a second vaccination and exceed pre-existing levels in baseline-SARS-CoV-2-seropositive participants. Nasal IgG responses are durable and display strong correlations with serum IgG, suggesting serum-to-NELF transudation. AZD1222 induces short-lived increases to pre-existing nasal IgA levels in baseline-seropositive vaccinees. Vaccinees display a robust recall IgG response upon breakthrough infection, with overall magnitudes unaffected by time between vaccination and illness. Mucosal responses correlate with reduced viral loads and shorter durations of viral shedding in saliva.

Maskne: A side effect of wearing face mask and face mask-wearing attitudes and behavior during 1st, 2nd and 3rd waves of COVID-19 in rural population of Haryana.

Introduction: The term "maskne" originated during the SARS CoV-2 (COVID-19) pandemic; it is a variant of acne associated with continuous wearing of face mask. Maskne is mainly observational, and the most common cause of maskne is contact irritant dermatitis. Materials and methods: The average mask use percentage by OPD cases visiting the hospital for a month in each wave of the COVID -19, that is, in the month of June 2020 during the first wave, in the month of April 2021 during the second wave and in the month of December 2021 during the third wave was calculated. We also included 30 patients with a diagnosis of irritant contact dermatitis aka maskne and 30 patients with diagnosis of acne vulgaris, all >18 years of age from April 2020 to December 2021. Results: 66% of people wore masks coming to hospital in the month of June 2020 (first wave) which increased to 74% during the second wave in the month of April 2021 and during the third wave only 23% of people wore masks in the month of December 2021. Conclusion: Maskne and worsening of acne vulgaris can be due to wearing of dirty face masks for longer duration. Use of moisturizers and regular "mask breaks" are important aspects in management of maskne.

Multifocal Extramedullary Relapse With Neuroleukemiosis in a Case of Early T-Cell Precursor ALL: 18F-FDG PET/CT Findings.

ABSTRACT: Early T-cell precursor ALL (acute lymphoblastic leukemia) is a rare type of childhood and adult T-cell ALL. Disease recurrence is common within 2 years from the time of initial diagnosis. Outcomes of relapse have been characterized through risk stratification schemes, and one of the major determinants of overall survival is the overall tumor burden and sites of relapse. Although testicular recurrence is common; Peripheral nerve as a site of recurrence is relatively rare. We present a case of early T-cell ALL on maintenance therapy with multifocal relapse on FDG PET/CT in the cervical lymph nodes, the testis, and the left sciatic nerve. Bone marrow and flow cytometry confirmed the relapse.

Ultra-low power deep sustained optogenetic excitation of human ventricular cardiomyocytes with red-shifted opsins: a computational study.

The main challenge in cardiac optogenetics is to have low-power, high-fidelity deep excitation of cells with minimal invasiveness and heating. We present a detailed computational study of optogenetic excitation of human ventricular cardiomyocytes (HVCMs) with new ChRmine, bReaChES and CsChrimson red-shifted opsins to overcome the challenge. Action potentials (APs) in ChRmine-expressing HVCMs can be triggered at 6 µW mm-2 (10 ms pulse) and 0.7 µW mm-2 (100 ms pulse) at 585 nm, which is two orders of magnitude lower than ChR2(H134R). This enables safe sustained excitation of deeply situated cardiac cells with ChRmine (7.46 mm) and with bReaChES (6.21 mm) with the light source at the pericardium surface. Deeper excitation up to 10.2 mm can be achieved with ChRmine by illuminating at 650 nm. Photostimulation conditions for minimum charge transfer during APs have been determined, which is important for tissue health under sustained excitation. The AP duration for all the opsins is constant up to 100 ms pulse width but increases thereafter. Interestingly, the AP frequency increases with irradiance under continuous illumination, but APs are suppressed at higher irradiances. The optimal range of irradiance for each opsin to excite HVCMs has been determined. Under optimal photostimulation conditions, each opsin can precisely excite APs up to 2.5 Hz, while latency and power of light pulse for each AP in a sequence remain most stable and an order of magnitude lower, respectively, in ChRmine-expressing HVCMs. The study highlights the importance of ChRmine and bReaChES for resynchronization, termination of ventricular tachycardia and designing optogenetic cardiac pacemakers with enhanced battery life. KEY POINTS: This work is the formulation of accurate theoretical models of optogenetic control of human ventricular cardiomyocytes (HVCMs) expressed with newly discovered opsins (ChRmine, bReaChES and CsChrimson). Under continuous illumination, action potentials in each opsin-expressing HVCMs can only be evoked in a certain range of irradiances. Action potentials in ChRmine-expressing HVCMs can be triggered at ultra-low power (6 µW mm-2 at 10 ms pulse or 0.7 µW mm-2 at 100 ms pulse at 585 nm), which is two to three orders of magnitude lower than reported results. Ongoing action potentials in ChRmine-expressing HVCMs can be suppressed by continuous illumination of 585 nm light at 2 µW mm-2 . ChRmine enables sustained excitation due to its faster recovery from the desensitized state. Optogenetic excitation of deeply situated cardiac cells is possible up to ∼7.46 and 10.2 mm with ChRmine on illuminating the outer surface of pericardium at safe irradiance at 585 nm and 650 nm, respectively. The study opens up prospects for designing energy-efficient light-induced pacemakers, resynchronization and termination of ventricular tachycardia.

Durability of protection and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine over 6 months.

BackgroundWe report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.MethodsAdults at increased risk of SARS-CoV-2 infection were randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCR-positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.FindingsData cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.ConclusionAZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registrationClinicalTrials.gov NCT04516746.FundingAstraZeneca; US government.

The impact of COVID-19 lockdown on mental health: A study from rural population of Haryana, India.

Introduction: COVID-19 (Coronavirus Disease 2019) is a disease caused by a virus named SARS-CoV-2 and was discovered in December 2019 in Wuhan, China, a global threat has largely affected the country's economic and social values. Moreover, the mitigation strategies being used to counterattack the pandemic attributes a lot of unrest and stress in the masses which has led to several mental health problems like anxiety, depression, sleep loss, post-traumatic stress disorder, etc. Objective: In this study, the impact of lockdown on mental health and its related disorders was observed. Method: A total of 367 patients from 69 villages of Narwana sub-division, Haryana, India was included in this study and their mental health status was assessed using Beck's Depression Inventory (BDI). Results: Out of the 367 mental health-related patients, half of them (~ 48%) showed the signs of depression ranging from mild to severe. Also, 40% of the patients showed signs and symptoms of anxiety, fear and stress and (~15%) showed signs of sleep loss. Women (~58%) were significantly found to be more prone to mental illness and psychiatric disorders than men (~42%). This study also reports the increase in domestic violence cases during the lockdown period. The study presents a clear understanding that although lockdown and social isolation helps in achieving the goal of reducing infections, a restricted access of social support systems leads to loneliness and various mental issues including anxiety and depression. Conclusion: We conclude that COVID-19 is a big threat to women safety and health especially in rural population and as the crisis evolves and continues, it is very essential to raise awareness and psychological counseling among the masses.

Serum levels of anti-PF4 IgG after AZD1222 (ChAdOx1 nCoV-19) vaccination.

Rare cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported after AZD1222. Anti-platelet factor-4 (PF4) antibodies were observed in patients following presentation of TTS, however it is unclear if AZD1222 was responsible for inducing production of anti-PF4. Paired samples (baseline and day-15) from a phase 3 trial of AZD1222 vs placebo were analyzed for anti-PF4 levels; 19/1727 (1.1%, AZD1222) vs 7/857 (0.8%, placebo) participants were anti-PF4-IgG-negative at baseline but had moderate Day-15 levels (P = 0.676) and 0/35 and 1/20 (5.0%) had moderate levels at baseline but high Day-15 levels. These data indicate that AZD1222 does not induce a clinically relevant general increase in anti-PF4 IgG.

Co-expressing fast channelrhodopsin with step-function opsin overcomes spike failure due to photocurrent desensitization in optogenetics: a theoretical study.

Objective.A fundamental challenge in optogenetics is to elicit long-term high-fidelity neuronal spiking with negligible heating. Fast channelrhodopsins (ChRs) require higher irradiances and cause spike failure due to photocurrent desensitization under sustained illumination, whereas, more light-sensitive step-function opsins (SFOs) exhibit prolonged depolarization with insufficient photocurrent and fast response for high-fidelity spiking.Approach.We present a novel method to overcome this fundamental limitation by co-expressing fast ChRs with SFOs. A detailed theoretical analysis of ChETA co-expressed with different SFOs, namely ChR2(C128A), ChR2(C128S), stabilized step-function opsin (SSFO) and step-function opsin with ultra-high light sensitivity (SOUL), expressing hippocampal neurons has been carried out by formulating their accurate theoretical models.Main results.ChETA-SFO-expressing hippocampal neurons shows more stable photocurrent that overcomes spike failure. Spiking fidelity in these neurons can be sustained even at lower irradiances of subsequent pulses (77% of initial pulse intensity in ChETA-ChR2(C128A)-expressing neurons) or by using red-shifted light pulses at appropriate intervals. High-fidelity spiking upto 60 Hz can be evoked in ChETA-ChR2(C128S), ChETA-SSFO and ChETA-SOUL-expressing neurons, which cannot be attained with only SFOs.Significance.The present study provides important insights about photostimulation protocols for bi-stable switching of neurons. This new approach provides a means for sustained low-power, high-frequency and high-fidelity optogenetic switching of neurons, necessary to study various neural functions and neurodegenerative disorders, and enhance the utility of optogenetics for biomedical applications.

Orbital Plasmablastic Lymphoma: A Rare Variant of Diffuse Large B-Cell Lymphoma Staged and Followed Up by 18F-FDG PET/CT.

ABSTRACT: Plasmablastic lymphoma (PBL) is a rare and aggressive variant of diffuse large B-cell lymphoma which is associated with HIV infection. Recently, it has also been reported in immunocompetent and solid organ transplant patients. PBL commonly presents in extranodal regions such as oral cavity, digestive tract, and skin. Orbital involvement by PBL is extremely rare with only few reports in the literature. We present a case of PBL involving the bilateral orbits in an immunocompetent patient with 1-year follow-up on 18F-FDG PET/CT scan.

Primary Biliary Tuberculosis Masquerading Cholangiocarcinoma in 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

Hepatobiliary involvement is a less common manifestation of abdominal tuberculosis. We present the case of a 42-year-old female who presented with fever, abdominal pain, and jaundice of 2 months duration. 18F-fluorodeoxyglucose positron emission tomography/computed tomography done for disease evaluation suggested the likely possibility of cholangiocarcinoma but excision biopsy from periportal lymph node later confirmed a granulomatous etiology and she was successfully treated with antitubercular therapy.

Robust humoral and cellular recall responses to AZD1222 attenuate breakthrough SARS-CoV-2 infection compared to unvaccinated.

Background: Breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19) vaccinees typically produces milder disease than infection in unvaccinated individuals. Methods: To explore disease attenuation, we examined COVID-19 symptom burden and immuno-virologic responses to symptomatic SARS-CoV-2 infection in participants (AZD1222: n=177/17,617; placebo: n=203/8,528) from a 2:1 randomized, placebo-controlled, phase 3 study of two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccination (NCT04516746). Results: We observed that AZD1222 vaccinees had an overall lower incidence and shorter duration of COVID-19 symptoms compared with placebo recipients, as well as lower SARS-CoV-2 viral loads and a shorter median duration of viral shedding in saliva. Vaccinees demonstrated a robust antibody recall response versus placebo recipients with low-to-moderate inverse correlations with virologic endpoints. Vaccinees also demonstrated an enriched polyfunctional spike-specific Th-1-biased CD4+ and CD8+ T-cell response that was associated with strong inverse correlations with virologic endpoints. Conclusion: Robust immune responses following AZD1222 vaccination attenuate COVID-19 disease severity and restrict SARS-CoV-2 transmission potential by reducing viral loads and the duration of viral shedding in saliva. Collectively, these analyses underscore the essential role of vaccination in mitigating the COVID-19 pandemic.

Diagnostic comparison of biochemical profile in patients with Covid-19, dengue and Acute Febrile illness: Implications for patient management.

PURPOSE: Although there are specific laboratory tests available for the diagnosis of Covid-19 and dengue, during the present pandemic era of prioritized focus on Covid-19 assessment, there are possibilities that persons with dengue may remain undiagnosed. The present study explores the role of biochemical markers in the differential diagnosis of Covid-19 and dengue. METHODS: A total of 212 participants with Acute Febrile Illness were tested for Covid-19 and dengue at the secondary care hospital, Civil Hospital Narwana, Haryana, India. The Covid-19 and dengue diagnosis were performed using standard tests followed by hematological profiling which included neutrophil lymphocyte ratio (NLR), platelet count, Vitamin D3 assessment, SGOT, SGPT, and SPO2 concentration levels. RESULTS: Out of 212 participants, 118 were diagnosed with Covid-19 positive only, 18 dengue positive only, 5 co-infected with Covid-19 and dengue, and 71 persons with Acute Febrile Illness (control group). ANOVA revealed that mean SPO2 was significantly lower in Covid-19 and dengue than control, while SGPT and SGOT levels of Covid-19 and dengue patients were significantly higher than the control group. The mean NLR was significantly higher in Covid-19 and dengue than control and Vitamin D3 levels were significantly reduced for Covid-19 patients. Besides, thrombocytopenia was observed only in dengue patients. CONCLUSION: The results advocate the potential use of combinations of these makers in differential diagnosis of these two fatal viral conditions and can help by enabling the adaptation of the therapeutic conduct to the needs of individual patients.

Theoretical analysis of optogenetic spiking with ChRmine, bReaChES and CsChrimson-expressing neurons for retinal prostheses.

Objective.Optogenetics has emerged as a promising technique for neural prosthetics, especially retinal prostheses, with unprecedented spatiotemporal resolution. Newly discovered opsins with high light sensitivity and fast temporal kinetics can provide sufficient temporal resolution at safe light powers and overcome the limitations of presently used opsins. It is also important to formulate accurate mathematical models for optogenetic retinal prostheses, which can facilitate optimization of photostimulation factors to improve the performance.Approach.A detailed theoretical analysis of optogenetic excitation of model retinal ganglion neurons (RGNs) and hippocampal neurons expressed with already tested opsins for retinal prostheses, namely, ChR2, ReaChR and ChrimsonR, and also with recently discovered potent opsins CsChrimson, bReaChES and ChRmine, was carried out.Main results.Under continuous illumination, ChRmine-expressing RGNs begin to respond at very low irradiances ∼10-4mW mm-2, and evoke firing upto ∼280 Hz, highest among other opsin-expressing RGNs, at 10-2mW mm-2. Under pulsed illumination at randomized photon fluxes, ChRmine-expressing RGNs respond to changes in pulse to pulse irradiances upto four logs, although very bright pulses >1014photons mm-2s-1block firing in these neurons. The minimum irradiance threshold for ChRmine-expressing RGNs is lower by two orders of magnitude, whereas, the first spike latency in ChRmine-expressing RGNs is shorter by an order of magnitude, alongwith stable latency of subsequest spikes compared to others. Further, a good set of photostimulation parameters were determined to achieve high-frequency control with single spike resolution at minimal power. Although ChrimsonR enables spiking upto 100 Hz in RGNs, it requires very high irradiances. ChRmine provides control at light powers that are two orders of magnitude smaller than that required with experimentally studied opsins, while maintaining single spike temporal resolution upto 40 Hz.Significance.The present study highlights the importance of ChRmine as a potential opsin for optogenetic retinal prostheses.

Diffuse White Adipose Tissue 18F-FDG Uptake-An Unusual Finding on 18F-FDG PET/CT.

ABSTRACT: Brown adipose tissue of cervical, supraclavicular, and paravertebral regions can show increased FDG uptake. But human white adipose tissue (WAT) shows negligible FDG uptake on 18F-FDG PET/CT scan. We present a case of carcinoma cervix treated with concurrent chemoradiation. 18F-FDG PET/CT shows altered biodistribution of FDG with intense FDG uptake throughout the WAT. Later on, patient confirmed taking herbal medication for herpes zoster infection, which could contain corticosteroids, resulting in enhanced WAT uptake of 18F-FDG.

Management of chronic quadriceps rupture with novel "chariot suture technique": A case report and review.

Quadriceps tendon is one of the important segment of knee extensor mechanism. Acute ruptures are more common than chronic ruptures and have better outcomes. Chronic ruptures are rare with lot of surgical challenges including tendon retraction, fibrosis, degenerative calcification. We present a rare case of a 48 year old male diabetic patient with history of fall eight months ago and chief complaint of inability to actively extend his left knee. Diagnosis was made clinically and was confirmed radiologically with MRI. Surgical management was done with the use of novel "Chariot Suture Technique". It involves use of three Krakow whipstitches with Ethibond No. 5 suture across the distal ruptured end of quadriceps tendon and their intraosseous passage through patella in longitudinal fashion followed by tying knot at the distal pole of patella. The formation of Chariot makes the construct stable. At one year follow up patient was actively able to extend the knee with good range of motion. The technique is relatively cost effective, has no donor site morbidity, easy to learn and practice.