Mechanopathology of biofilm-like Mycobacterium tuberculosis cords.

Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.

The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.

Polycystic Ovary Syndrome, Insulin Resistance, and Cardiovascular Disease.

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. It has been associated with metabolic, reproductive, and psychiatric disorders. Despite its association with insulin resistance (IR) and cardiovascular disease (CVD) risk factors, the association between PCOS and CVD outcomes has been conflicting. This review reports the updated evidence between PCOS, insulin resistance, and CVD events. RECENT FINDINGS: IR is highly prevalent occurring in 50 to 95% of general and obese PCOS women. The etiology of PCOS involves IR and hyperandrogenism, which lead to CVD risk factors, subclinical CVD, and CVD outcomes. Multiple studies including meta-analysis confirmed a strong association between PCOS and CVD events including ischemic heart disease, stroke, atrial fibrillation, and diabetes, particularly among premenopausal women, and these associations were mediated by metabolic abnormalities. PCOS is highly familial and has substantial CVD risk and transgenerational effects regardless of obesity. A personalized approach to the CVD risk assessment and management of symptom manifestations should be conducted according to its phenotypes. Lifestyle modifications and reduction in environmental stressors should be encouraged for CVD prevention among PCOS women.

Analytic Theory for the Dynamics of Wide Quantum Neural Networks.

Parametrized quantum circuits can be used as quantum neural networks and have the potential to outperform their classical counterparts when trained for addressing learning problems. To date, much of the results on their performance on practical problems are heuristic in nature. In particular, the convergence rate for the training of quantum neural networks is not fully understood. Here, we analyze the dynamics of gradient descent for the training error of a class of variational quantum machine learning models. We define wide quantum neural networks as parametrized quantum circuits in the limit of a large number of qubits and variational parameters. Then, we find a simple analytic formula that captures the average behavior of their loss function and discuss the consequences of our findings. For example, for random quantum circuits, we predict and characterize an exponential decay of the residual training error as a function of the parameters of the system. Finally, we validate our analytic results with numerical experiments.

Rapid endotheliitis and vascular damage characterize SARS-CoV-2 infection in a human lung-on-chip model.

Severe cases of SARS-CoV-2 infection are characterized by hypercoagulopathies and systemic endotheliitis of the lung microvasculature. The dynamics of vascular damage, and whether it is a direct consequence of endothelial infection or an indirect consequence of an immune cell-mediated cytokine storm remain unknown. Using a vascularized lung-on-chip model, we find that infection of alveolar epithelial cells leads to limited apical release of virions, consistent with reports of monoculture infection. However, viral RNA and proteins are rapidly detected in underlying endothelial cells, which are themselves refractory to apical infection in monocultures. Although endothelial infection is unproductive, it leads to the formation of cell clusters with low CD31 expression, a progressive loss of barrier integrity and a pro-coagulatory microenvironment. Viral RNA persists in individual cells generating an inflammatory response, which is transient in epithelial cells but persistent in endothelial cells and typified by IL-6 secretion even in the absence of immune cells. Inhibition of IL-6 signalling with tocilizumab reduces but does not prevent loss of barrier integrity. SARS-CoV-2-mediated endothelial cell damage thus occurs independently of cytokine storm.

Non-Invasive Treatment of Basal Cell Carcinoma: Photodynamic Therapy Following Curettage.

BACKGROUND: To investigate the effectiveness, safety, patient satisfaction, and cosmetic outcome of Methyl Aminolevulinate-Photodynamic Therapy (MAL-PDT) following curettage in order to make recommendations for its use in dermatology practices. METHODS: A retrospective chart review of patients who received MAL-PDT following curettage for the indication of basal cell carcinoma (BCC) between 2009 and 2016 at a single private clinic in Ontario, Canada. Two hundred and seventy-eight patients with 352 BCC lesions were included, consisting of 44.2% males (n=123) and 55.8% females (n=155) with a mean age of 57.24 years. The primary outcome measurement consisted of the cure rate. Secondary outcome measurements included side effects, patient satisfaction, and cosmetic outcome, as reported in the medical charts. RESULTS: The overall cure rate was 90.3% (n=318). After controlling for age, sex, and lesion type, nasal lesions were approximately 2.82 (95% CI: 1.24-6.40, P=0.01) times more likely to experience a recurrence. 18.3% of patients (n=51) reported side effects, the most common being burning (n=19). Of those who expressed satisfaction, 100% (n=25) reported being happy. Of lesions with cosmetic data, 90.3% displayed a good response (n=149). CONCLUSION: MAL-PDT following curettage is an effective and safe treatment option for BCC lesions with a good cosmetic outcome and suggested high patient satisfaction. J Drugs Dermatol. 2023;22(5): doi:10.36849/JDD.7133.

Cardiopulmonary Outcomes in Covid-19 Patients Discharged From a Tertiary Care Center: A Prospective Study.

To determine the cardiopulmonary changes in the survivors of acute COVID-19 infection at 3-6 month and 6-12 month. We followed up 53 patients out of which 28 (52%) had mild COVID-19 and 25 (48%) had severe COVID-19. The first follow-up was between 3 month after diagnosis up to 6 month and second follow-up between 6 and 12 month from the date of diagnosis of acute COVID-19. They were monitored using vital parameters, pulmonary function tests, echocardiography and a chest computed tomography (CT) scan. We found improvement in diffusing capacity for carbon monoxide (DLCO) with a median of 52% of predicted and 80% of predicted at the first and second follow-up, respectively. There was improvement in the CTSS in severe group from 22 (18-24) to 12 (10-18; p-0.001). Multivariable logistic regression revealed increased odds of past severe disease with higher CTSS at follow-up (OR-1.7 [CI 1.14-2.77]; P = 0.01). Correlation was found between CTSS and DLCO at second follow-up (r2 = 0.36; p < 0.01). Most of patients recovered from COVID-19 but a subgroup of patients continued to have persistent radiological and pulmonary function abnormalities necessitating a structured follow-up.

Trainability of Dissipative Perceptron-Based Quantum Neural Networks.

Several architectures have been proposed for quantum neural networks (QNNs), with the goal of efficiently performing machine learning tasks on quantum data. Rigorous scaling results are urgently needed for specific QNN constructions to understand which, if any, will be trainable at a large scale. Here, we analyze the gradient scaling (and hence the trainability) for a recently proposed architecture that we call dissipative QNNs (DQNNs), where the input qubits of each layer are discarded at the layer's output. We find that DQNNs can exhibit barren plateaus, i.e., gradients that vanish exponentially in the number of qubits. Moreover, we provide quantitative bounds on the scaling of the gradient for DQNNs under different conditions, such as different cost functions and circuit depths, and show that trainability is not always guaranteed. Our work represents the first rigorous analysis of the scalability of a perceptron-based QNN.

Reformulation of the No-Free-Lunch Theorem for Entangled Datasets.

The no-free-lunch (NFL) theorem is a celebrated result in learning theory that limits one's ability to learn a function with a training dataset. With the recent rise of quantum machine learning, it is natural to ask whether there is a quantum analog of the NFL theorem, which would restrict a quantum computer's ability to learn a unitary process with quantum training data. However, in the quantum setting, the training data can possess entanglement, a strong correlation with no classical analog. In this Letter, we show that entangled datasets lead to an apparent violation of the (classical) NFL theorem. This motivates a reformulation that accounts for the degree of entanglement in the training set. As our main result, we prove a quantum NFL theorem whereby the fundamental limit on the learnability of a unitary is reduced by entanglement. We employ Rigetti's quantum computer to test both the classical and quantum NFL theorems. Our Letter establishes that entanglement is a commodity in quantum machine learning.

Therapeutic implications of cyclooxygenase (COX) inhibitors in ischemic injury.

INTRODUCTION: Ischemia-reperfusion injury (IRI) is the inexplicable aggravation of cellular dysfunction that results in blood flow restoration to previously ischemic tissues. COX mediates the oxidative conversion of AA to various prostaglandins and thromboxanes, which are involved in various physiological and pathological processes. In the pathophysiology of I/R injuries, COX has been found to play an important role. I/R injuries affect most vital organs and are characterized by inflammation, oxidative stress, cell death, and apoptosis, leading to morbidity and mortality. MATERIALS AND METHODS: A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the Cyclooxygenase modulations in ischemic injury. Here, we have discussed the COX Physiology and downstream signalling pathways modulated by COX, e.g., Camp Pathway, Peroxisome Proliferator-Activated Receptor Activity, NF-kB Signalling, PI3K/Akt Signalling in ischemic injury. CONCLUSION: This review will discuss the various COX types, specifically COX-1 and COX-2, which are involved in developing I/R injury in organs such as the brain, spinal cord, heart, kidney, liver, and intestine.

Gargle lavage & saliva: Feasible & cheaper alternatives to nasal & throat swabs for diagnosis of COVID-19.

Background & objectives: In the present scenario, the most common sample for diagnosis of COVID-19 by reverse transcription polymerase chain reaction (RT-PCR) is nasal and throat swab (NTS). Other sampling options such as gargle lavage have found limited application in clinical use mostly because of unavailability of an appropriate gargling liquid. This study was conducted to assess the stability of SARS-CoV-2 RNA in normal saline at 4°C that can serve as a gargling liquid as well as a transport medium. The study also looked at the agreement between NTS and gargle lavage/saliva for the detection of SARS-CoV-2. Methods: In 29 consecutive real-time RT-PCR (rRT-PCR) positive COVID-19 patients, paired NTS, gargle and saliva samples were taken. Samples were processed by rRT-PCR for the detection of SARS-CoV-2 RNA. To assess the SARS-CoV-2 RNA stability in normal saline, gargle lavage specimens were divided into two aliquots; one subset of the specimen was run within 4-6 h along with the routine samples (NTS and saliva) and the other subset was stored at 4°C and processed after 24-30 h. Agreement between cycle threshold (Ct) values from both the runs was compared using Bland-Altman (BA) analysis. Results: The positivity rates of rRT-PCR in NTS, saliva and gargle lavage samples were 82.7 (24/29), 79.3 (23/29) and 86.2 per cent (25/29), respectively. BA plot showed a good agreement between the Ct values of fresh and stored gargle samples, stipulating that there were no significant differences in the approximate viral load levels between the fresh and stored gargle lavage samples (bias: E gene -0.64, N gene -0.51, ORF gene -0.19). Interpretation & conclusions: Our study results show stability of SARS-CoV-2 RNA in the gargle samples collected using normal saline up to 24-30 h. Gargle lavage and saliva specimen collection are cost-effective and acceptable methods of sampling for the detection of SARS-CoV-2 RNA by rRT-PCR. These simplified, inexpensive and acceptable methods of specimen collection would reduce the cost and workload on healthcare workers for sample collection.

Conditional Quantum One-Time Pad.

Suppose that Alice and Bob are located in distant laboratories, which are connected by an ideal quantum channel. Suppose further that they share many copies of a quantum state ρ_{ABE}, such that Alice possesses the A systems and Bob the BE systems. In our model, there is an identifiable part of Bob's laboratory that is insecure: a third party named Eve has infiltrated Bob's laboratory and gained control of the E systems. Alice, knowing this, would like use their shared state and the ideal quantum channel to communicate a message in such a way that Bob, who has access to the whole of his laboratory (BE systems), can decode it, while Eve, who has access only to a sector of Bob's laboratory (E systems) and the ideal quantum channel connecting Alice to Bob, cannot learn anything about Alice's transmitted message. We call this task the conditional one-time pad, and in this Letter, we prove that the optimal rate of secret communication for this task is equal to the conditional quantum mutual information I(A;B|E) of their shared state. We thus give the conditional quantum mutual information an operational meaning that is different from those given in prior works, via state redistribution, conditional erasure, or state deconstruction. We also generalize the model and method in several ways, one of which is a secret-sharing task, i.e., the case in which Alice's message should be secure from someone possessing only the AB or AE systems, but should be decodable by someone possessing all systems A, B, and E.

Daylight-Mediated Photodynamic Therapy With Methyl Aminolevulinate in Actinic Keratosis Treatment.

BACKGROUND: Research has shown daylight-mediated photodynamic therapy (PDT) for the treatment of actinic keratosis (AK) to be effective, tolerable, and convenient, with excellent patient satisfaction and cosmesis. Although success has been demonstrated in areas with similar latitudes to Switzerland and Scandinavia, this treatment has not been studied in a Canadian population. OBJECTIVES: The purpose of this study is to investigate the effectiveness, safety, and patient satisfaction of daylight-mediated methyl 5-aminolevulinate (MAL)-PDT to make recommendations for its use in Canadian practice. METHODS: A retrospective chart review of patients who received treatment of daylight-mediated MAL-PDT for the indication of AK at the Institute of Cosmetic and Laser Surgery in Oakville, Ontario, between 2009 and 2016. RESULTS: A total of 112 patients were included, consisting of 94 males and 18 females with a mean age of 63.79 years. A total of 177 sites were treated among all patients, mostly consisting of the face (n = 92) and scalp (n = 55). A total of 13.4% of patients experienced side effects, the most common being redness (n = 4) and scabbing (n = 4). Of the 42 patients who expressed their level of satisfaction, 83.3% reported being happy with the treatment, χ2(1) = 18.67, P ≤ .05; 6.3% of patients were noted to be completely clear, 86.6% had a good response, 0.9% had a mild response, and 0% had no response, χ2(1) = 101.04, P ≤ .05. CONCLUSIONS: Daylight-mediated MAL-PDT is a suitable treatment option for AK lesions in a Canadian population due to the demonstrated efficacy, patient satisfaction, tolerability, and convenience.

Cerebral venous sinus thrombophlebitis as a complication of acute otitis media.

BACKGROUND: While headache is a common emergency department chief complaint, cerebral venous sinus thrombosis (CVST) is an infrequently encountered cause of headache and is often not included in emergency physicians' differential diagnoses for headache. Our objective is to review the latest data on epidemiology, presenting symptoms, diagnosis, and treatment of CVST. CASE REPORT: A 27-year-old female presented to our emergency department with headache, blurred vision, and vomiting a day after being diagnosed with acute otitis media. Computed tomography scan of the brain without contrast in the emergency department was suggestive of CVST. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although a rare cause of headache, CVST should be considered for a subset of patients presenting to the emergency department with the common complaint of headache. CVST is diagnosed by magnetic resonance venogram or computed tomography venogram of the brain. Anticoagulation with close monitoring in consultation with appropriate experts is a safe first-line therapy for CVST, even in patients with hemorrhage on initial imaging.

Atypical Co-amplification with Co-localization of HER2 Gene in Breast Cancer: Combined IHC/FISH Approach as per ASCO/CAP 2018 Guidelines for Targeted Therapy Eligibility.

Breast cancer patients with HER2 gene amplification as assessed by FISH are eligible for HER2-targeted therapy. However, in a small subset of patients, unusual FISH pattern of co-localization and co-amplification can pose challenges in interpretation of the HER2 status and hence to assess the HER2 status accurately; our aim was to report their incidence and analyze them based on latest ASCO/CAP 2018 guidelines. We present seven cases with HER2/CEP17 co-amplification and co-localization from a total 4040 cases referred during the year 2017 to 2021 at Mumbai Reference Laboratory, SRL Diagnostics. Core needle biopsy/excision invasive breast carcinoma specimens from metastatic sites were tested for IHC for expressions of ER, PR, and HER2. The ones which came equivocal on HER2 IHC were then evaluated for HER2 amplification by FISH. Co-amplification and co-localization of HER2 and centromeric 17 was observed with a frequency of 0.1% that falls in the range of 0.5-0.1% as reported from other large-scale studies. Our study showed that implementation of a binary inhouse concurrent assessment with IHC as per the ASCO/CAP 2018 helps to reach the most definitive and accurate HER2 status. Our study is an attempt to report such challenging FISH patterns and their work-up for a better understanding on the interpretation. Cumulative data along with follow-up in these cases would bring an insight into exact therapeutic outcome.

PRESenting a Challenge: Posterior Reversible Encephalopathy Syndrome in Pediatric Patients With Guillain-Barré Syndrome: A Case Series and Review of Literature.

BACKGROUND: Guillain-Barré syndrome (GBS) is an autoimmune disorder characterized by demyelination of peripheral nerves. GBS-associated posterior reversible encephalopathy syndrome (PRES) is a rare and potentially life-threatening complication in the pediatric population. We aimed to report and analyze the clinical features, management, and outcomes of three cases of GBS-associated PRES in our setting in the light of the existing literature. METHODS: Medical records of 75 pediatric patients with GBS were reviewed for autonomic changes and GBS-associated PRES. Thirty-one developed dysautonomia while three were identified to have PRES. Clinical, radiological, laboratory, and treatment data were collected and analyzed. RESULTS: All three patients were male and presented with symptoms of acute flaccid paralysis and respiratory distress requiring mechanical ventilation. All three patients experienced various complications, including hypertension, seizures, and hyponatremia, and were subsequently diagnosed with PRES. Multimodal intensive care resulted in patient improvement and discharge in an ambulatory state after an average of 104 days of care. CONCLUSIONS: GBS-associated PRES is a rare and potentially life-threatening complication that can occur in pediatric patients with GBS. Our findings suggest that early recognition, prompt intervention, and multimodal intensive care can improve patient outcomes. Further studies are needed to determine optimal treatment strategies for GBS-associated PRES.

Mitochondrial toxicity induced by linezolid causing lactic acidosis.

Linezolid-induced lactic acidosis is a rare, but life-threatening complication of a commonly used drug. Patients present with persistent lactic acidosis, hypoglycaemia, high central venous oxygen saturation and shock. Linezolid causes mitochondrial toxicity due to impaired oxidative phosphorylation. This is evidenced by cytoplasmic vacuolations in the myeloid and erythroid precursors of bone marrow smear as illustrated in our case. Discontinuation of the drug, administration of thiamine and haemodialysis reduces lactic acid levels.

Multi-scale characterization of the spatio-temporal interplay between elemental composition, mineral deposition and remodelling in bone fracture healing.

Bone mineralization involves a complex orchestration of physico-chemical responses from the organism. Despite extensive studies, the detailed mechanisms of mineralization remain to be elucidated. This study aims to characterize bone mineralization using an in-vivo long bone fracture healing model in the rat. The spatio-temporal distribution of relevant elements was correlated to the deposition and maturation of hydroxyapatite and the presence of matrix remodeling compounds (MMP-13). Multi-scale measurements indicated that (i) zinc is required for both the initial mineral deposition and resorption processes during mature mineral remodeling; (ii) Zinc and MMP-13 show similar spatio-temporal trends during early mineralization; (iii) Iron acts locally and in coordination with zinc during mineralization, thus indicating novel evidence of the time-events and inter-play between the elements. These findings improve the understanding of bone mineralization by explaining the link between the different constituents of this process throughout the healing time. STATEMENT OF SIGNIFICANCE: Bone mineralization involves a complex orchestration of physico-chemical responses from the organism, the detailed mechanisms of which remain to be elucidated. This study presents a highly novel multi-scale multi-modal investigation of bone mineralization using bone fracture healing as a model system. We present original characterization of tissue mineralization, where we relate the spatio-temporal distribution of important trace elements to a key matrix remodeling compound (MMP-13), the initial deposition and maturation of hydroxyapatite and further remodeling processes. This is the first time that mineralization has been probed down to the nanometric level, and where key mineralization components have been investigated to achieve a comprehensive and mechanistic understanding of the underlying mineralization processes during bone healing.

Bone Mineral Density, Serum Calcium, and Vitamin D Levels in Adult Thalassemia Major Patients: Experience From a Single Center in Eastern India.

Background and objective Patients suffering from thalassemia major are at higher risk of osteoporosis. Due to their decreased life expectancy, the number of adult patients is low. However, their bone health is rarely checked in developing countries like India. There is no data available in the literature on the bone mineral density (BMD) of adult (aged ≥18 years) thalassemia major patients in eastern India. In this study, we aimed to measure the BMD and serum calcium and vitamin D levels in adult thalassemia major patients and to compare them with healthy controls. Materials and methods We conducted this cross-sectional observational study at a tertiary care hospital in eastern India. We recruited adult thalassemia major patients who were not on calcium or vitamin D supplements. Their BMD was measured by dual-energy X-ray absorptiometry (DXA) on the lumbar spine (L1-L4). Venous blood was tested for serum calcium and vitamin D levels. We compared the parameters between the cases and controls by using the Mann-Whitney U test. Results A total of 31 (male = 19, female = 12) patients with a median age of 28 years comprised the case group. Age- and sex-matched controls showed similar height but higher weight and BMI. The serum calcium level was similar (p = 0.43) in the case and control groups but T-score (p = 0.0003) and vitamin D levels (p: <0.0001) were significantly lower in thalassemia major patients. Conclusion Based on our findings, adult thalassemia major patients have lower BMD and vitamin D levels. Although the serum calcium may be normal in these patients, they should still be screened both for BMD and vitamin D for prompt and early detection of risks and complications so that a proper management strategy can be implemented.

Allosteric cooperation in ß-lactam binding to a non-classical transpeptidase.

L,D-transpeptidase function predominates in atypical 3 → 3 transpeptide networking of peptidoglycan (PG) layer in Mycobacterium tuberculosis. Prior studies of L,D-transpeptidases have identified only the catalytic site that binds to peptide moiety of the PG substrate or ß-lactam antibiotics. This insight was leveraged to develop mechanism of its activity and inhibition by ß-lactams. Here, we report identification of an allosteric site at a distance of 21 Å from the catalytic site that binds the sugar moiety of PG substrates (hereafter referred to as the S-pocket). This site also binds a second ß-lactam molecule and influences binding at the catalytic site. We provide evidence that two ß-lactam molecules bind co-operatively to this enzyme, one non-covalently at the S-pocket and one covalently at the catalytic site. This dual ß-lactam-binding phenomenon is previously unknown and is an observation that may offer novel approaches for the structure-based design of new drugs against M. tuberculosis.