Yoga Nidra for hypertension: A systematic review and meta-analysis.

BACKGROUND: Hypertension is a prevalent chronic condition that affects a substantial proportion of the world's population. Medications are commonly prescribed for hypertension management, but non-pharmacological interventions like yoga are gaining popularity. OBJECTIVE: The purpose of this systematic review and meta-analysis is to assess the efficacy of Yoga Nidra (YN) for the management of hypertension. METHODS: A systematic review and meta-analysis of clinical trials, i.e., non-randomized and randomized controlled trials (RCTs) was conducted to investigate the effects of YN on hypertension. PubMed, the Cochrane Library, SCOPUS, and EBSCO were searched for relevant studies published up to September 2022. The quality of the included studies was assessed using the Cochrane risk of bias tool. The primary outcome measure was the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) after YN intervention, analyzed as weighted mean difference (WMD), in comparison to control groups. The random-effects model was used for the meta-analysis. Risk of bias was assessed for RCTs and non-RCTs using Cochrane's RoB-2 and ROBINS-I tools, respectively. RESULTS: Five RCTs and three Non-RCTs involving a total of 482 participants (239 for YN vs 243 for controls) were included in this review. The meta-analysis indicated that YN significantly reduced SBP (WMD = 12.03 mm Hg, 95% CI [7.12, 16.93], Z = 4.80, p < 0.00001) and DBP (WMD = 6.32 mm Hg, 95% CI [3.53, 9.12], Z = 4.43, p < 0.00001) compared to control groups. The overall risk of bias for the three RCTs was high, whereas for the five non-RCTs, one had an overall moderate risk while the other four had an overall serious risk of bias. DISCUSSION: This systematic review and meta-analysis provides evidence supporting the efficacy of YN as a complementary therapy for hypertension management. YN is a safe, cost-effective, and easily accessible intervention that primarily relies on interoception and induces a deep relaxation response in practitioners, aiding them in coping with various components of high blood pressure, such as stress, vascular inflammation, peripheral vascular resistance, etc. Our understanding of the mechanisms of YN is constantly evolving, and there is a need for further research to fully explore and appreciate the significance of this ancient science and its potential efficacy on BP. Considering the results and the multifactorial role of YN, it can act as a safe and reliable adjuvant therapy to complement the pharmacological treatment of hypertension. However, further studies with larger sample sizes, longer follow-up periods, and homogenous populations are warranted. CONCLUSION: This meta-analysis suggests that YN is effective in reducing SBP and DBP, particularly in individuals with hypertension. The results highlight the potential of YN as a complementary therapy for hypertension management. Healthcare providers may consider recommending YN to patients with hypertension as an adjuvant therapy to medication. Further studies are required to identify standardized optimal forms and durations of YN best suited for hypertension management.

Submental Artery Island Flaps (SAIF) for Oral Cavity Cancer: Surgical Technique and Tertiary Care Experience.

In oral cancer surgeries, oncological outcomes take precious driverseat. But the copassengers like reconstruction, cosmesis, swallowing and speech outcomes deserve equivalent importance. Submental Artery Island Flaps (SAIF) provide an underutilized and extremely versatile option for reconstruction of defects following early stage oral cavity tumour resections. In this prospective observational analysis, we describe the technique, challenges and outcomes of SAIF at our tertiary care institute. Sixteen patients with Stage I and II oral cavity cancers were enrolled between June 2020 to May 2021. Verrucous carcinomas were five and well differentiated carcinomas were 11 patients. After tumour excision and neck dissections, defects were reconstructed with Pedicled submental flaps. Complications and functional outcomes were analyzed over two years. Nineteen percent were ladies and 81% were gentlemen. Median age was 52 years. Tongue tumours formed majority with 56% cases. Largest skin paddle taken was 36 cm2. Flap survival was 88%. There were variations in venous drainage of flaps which have been depicted in case figures. There was no report of orocutaneous fistula. Grade 3-4 speech satisfaction was achieved by 81.2% patients at 6 months. Swallowing was excellent, grade 4-5 for 100% of patients at 6 months. One patient had distant metastasis at 7 months and died. SRLR (Submental flap Recurrences) and trismus were zero percent at two years. The unexplored field of submental flaps can be used for oral cancer reconstructions in a versatile way. Donor site easy closures, no scars on face, early resumption of daily activities and short hospital stay makes it one of the ideal options in early stage oral cavity defects.

A study to assess the relationship between vitamin D3 levels and the risk of acute exacerbation in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is one of the top three causes of mortality worldwide. Vitamin D deficiency in COPD has been associated with poor lung function and decreased muscle power, which further increases the risk of exacerbations. The role of vitamin D in preventing acute exacerbations of COPD has conflicting results in the literature. Hence, we planned this study to assess the relationship between vitamin D3 levels and the risk of acute exacerbations among COPD patients in a tertiary care center in north India. This was a prospective randomized control trial that was performed on 100 consecutive stable COPD patients attending the Department of Respiratory Medicine at Maharishi Markandeshwar Medical College and Hospital, Solan, India. The patients with subnormal vitamin D3 levels (i.e., less than 30 ng/mL) were divided into the intervention and control groups. Baseline demographic profiles, lung function, COPD assessment test (CAT) score, modified Medical Research Council grade and chest radiology were performed and repeated after 12 months in all these patients. All these parameters were recorded and compared with the baseline values obtained at the beginning of the study. Out of 100 subjects, 96 had vitamin D deficiency, of which 48 were assigned to the intervention group and 48 to the control group. Among the 100 subjects, 74 (74%) were males and 26 (26%) were females, with a mean age of 66.9±9.4 years. The mean vitamin D level was 14.71±6.69 in these 96 patients. The vitamin D level improved after 3 months of supplementation to the mean level of 45.56±16.18 in the intervention group. Vitamin D supplementation was positively correlated with a decrease in the rate of acute exacerbations in the intervention group in terms of reduction in mean CAT score (4.17 in intervention and 1.43 in non-interventional group, p<0.001), number of acute exacerbations (1.7 in intervention and -1.05 in non-interventional group, p<0.001), and number of emergency visits (p=0.0121) during the 9-month period after attainment of a normal vitamin D level. Vitamin D supplementation plays a key role in COPD patients with D3 hypovitaminosis in decreasing COPD acute exacerbations, improving the CAT score, and reducing the number of emergency visits.

The impact of radio-chemotherapy on tumour cells interaction with optimal control and sensitivity analysis.

Oncologists and applied mathematicians are interested in understanding the dynamics of cancer-immune interactions, mainly due to the unpredictable nature of tumour cell proliferation. In this regard, mathematical modelling offers a promising approach to comprehend this potentially harmful aspect of cancer biology. This paper presents a novel dynamical model that incorporates the interactions between tumour cells, healthy tissue cells, and immune-stimulated cells when subjected to simultaneous chemotherapy and radiotherapy for treatment. We analysed the equilibria and investigated their local stability behaviour. We also study transcritical, saddle-node, and Hopf bifurcations analytically and numerically. We derive the stability and direction conditions for periodic solutions. We identify conditions that lead to chaotic dynamics and rigorously demonstrate the existence of chaos. Furthermore, we formulated an optimal control problem that describes the dynamics of tumour-immune interactions, considering treatments such as radiotherapy and chemotherapy as control parameters. Our goal is to utilize optimal control theory to reduce the cost of radiotherapy and chemotherapy, minimize the harmful effects of medications on the body, and mitigate the burden of cancer cells by maintaining a sufficient population of healthy cells. Cost-effectiveness analysis is employed to identify the most economical strategy for reducing the disease burden. Additionally, we conduct a Latin hypercube sampling-based uncertainty analysis to observe the impact of parameter uncertainties on tumour growth, followed by a sensitivity analysis. Numerical simulations are presented to elucidate how dynamic behaviour of model is influenced by changes in system parameters. The numerical results validate the analytical findings and illustrate that a multi-therapeutic treatment plan can effectively reduce tumour burden within a given time frame of therapeutic intervention.

Dermatomyositis Masquerading As Generalized Body Swelling: A Case Report.

Dermatomyositis (DM) is a systemic autoimmune disease that primarily affects the skin and muscles. The hallmark skin manifestation is a violaceous rash on the face, neck, shoulders, upper chest, and extensor surfaces of the arms and legs, which is often accompanied by edema and can be exacerbated by exposure to sunlight. Generalized limb edema and dysphagia are rare presentations of dermatomyositis. Here we present a case of a 69-year-old woman presenting with generalized limb swelling, periorbital swelling, and dysphagia which was diagnosed as dermatomyositis based on a combination of clinical, laboratory, and imaging findings. The patient had an absence of complaints of limb weakness and a predominance of complaints of edema and dysphagia which posed a diagnostic challenge. The patient was treated with high-dose steroids and immunosuppressive therapy, leading to a significant improvement in her symptoms. Edematous dermatomyositis has been associated with underlying malignancy in 25% of the cases and this warrants close follow-up and malignancy screening for such patients. In some cases, subcutaneous edema might be the only manifestation of the disease. This case underscores the importance of recognizing DM as a potential differential diagnosis in patients presenting with generalized edema and dysphagia, particularly in the initial absence of classic skin findings. This rare presentation of dermatomyositis may be a hallmark of a severe form of the disease and requires prompt recognition and aggressive treatment.

Association of Vitamin D Status With Metabolic Syndrome and Its Individual Risk Factors: A Cross-Sectional Study.

Background Vitamin D deficiency has been associated with metabolic syndrome and its related outcomes, including type 2 diabetes mellitus, cardiovascular disease, myocardial infarction, and stroke. However, studies in Indian populations have provided conflicting results. Methods This single-center cross-sectional study was conducted in a tertiary care hospital in north India to determine the prevalence of vitamin D deficiency in patients with metabolic syndrome and to study the correlations of individual components of metabolic syndrome with 25 hydroxy vitamin D levels. The study included 235 patients aged between 30 to 70 years who met the criteria for metabolic syndrome. Patients with diabetes, hypothyroidism, Cushing's, and other disorders affecting vitamin D status, on supplements of vitamin D or anti-dyslipidaemic drugs were excluded. Information regarding socio-demographic characteristics, medical history, and anthropometric measurements were collected. Blood samples were collected to assess vitamin D levels. Results The prevalence of vitamin D deficiency (<20 ng/ml) was 76% among the study population. There was a significant negative correlation between vitamin D levels and diastolic blood pressure (Spearman's rho: -0.134, 95% CI: -0.82,-0.260, p=0.040), fasting blood glucose (Spearman's rho: -0.142, 95% CI: -0.101,-0.269, p=0.029), A weak correlation was also found between vitamin D3 levels and total cholesterol (Spearman's rho: -0.246, 95% CI: -0.119,-0.367, p<0.001), triglyceride levels (Spearman's rho: -0.246, 95% CI: -0.118,-0.370, p<0.001) and low-density lipoprotein (LDL) levels (Spearman's rho: -0.229, 95% CI: -0.102,-0.351, p<0.001). Conclusion The study findings suggest that vitamin D deficiency is prevalent among patients with metabolic syndrome in north India. There is a significant negative correlation between vitamin D levels and some components of metabolic syndrome. This highlights the need for further research to understand the underlying mechanisms and potential benefits of vitamin D supplementation in this population. Identification of high-risk individuals for hypovitaminosis D can aid in streamlining treatment guidelines and preventing unnecessary prescription of investigations in developing countries.

Predictors of Poor Outcome in Patients with COVID-19 associated Respiratory Failure: A Retrospective Observational Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is majorly known to cause mild to moderate disease, but a small fraction of patients may develop respiratory failure due to diffuse lung injury, requiring management in the intensive care unit (ICU). This study attempts to identify factors that can predict unfavorable outcomes in moderate to severe COVID-19 patients. METHODS: Hospital records of 120 COVID-19 patients admitted to the ICU were retrospectively analyzed and data pertaining to demographic, clinical, and laboratory parameters were obtained. These data were then compared with outcome parameters like survival, duration of hospital stay, and various adverse events. RESULTS: Out of 120 patients, 70% were male, with a mean age of 54.44 years [standard deviation (SD) ± 14.24 years]. Presenting symptoms included breathlessness (100%), cough (94.17%), fever (82.5%), and sore throat (10.83%). Diabetes, hypertension, and chronic obstructive pulmonary disease (COPD) were the common comorbidities associated. Increased serum D-dimer, ferritin, interleukin-6 (IL-6) levels, and unvaccinated status were associated with higher mortality. Overall, 25.83% of patients survived, 24.41% of patients developed septic shock, and 10.6% of patients were discharged on oxygen. World Health Organization (WHO) clinical progression scale score ≥ 6 had 57 and 82% sensitivity and 83 and 77% specificity on days 7 and 14 after admission, respectively, for predicting mortality. A baseline National Early Warning Score 2 (NEWS 2) ≥ 9 had 48% sensitivity and 88% specificity for predicting mortality. CONCLUSION: Advanced age and associated comorbidities are linked to adverse outcomes in moderate to severe COVID-19. Persistently high D-dimer levels, despite standard treatment, may also contribute to increased mortality. WHO clinical progression scale and NEWS 2 have high specificity for predicting mortality.

Predictors of Mortality Among Post-COVID-19 Discharged Patients in Northern India: A Case-Control Study.

Introduction The post-discharge all-cause mortality of COVID-19 disease is known, but predictors for the same have not been studied as much. The objective of this study was to develop an understanding of predictors of mortality to guide in prioritizing patient care and preventive approaches. Methods This current research is a single-center unmatched case-control study conducted at a tertiary care center in northern India, between April and September 2022. The data were extracted retrospectively from the hospital's electronic medical records of patients with the assistance of trained physicians using a standardized data extraction sheet. Results A total of 184 patients were enrolled and were segregated into two groups, cases and control, with 92 in each. The mean age of patients was 49.3 ± 17.53 years. The mortality group had a higher mean age (53.24 ± 18.53 yrs) as compared to the control group (45.37 ± 15.58 yrs, p=0.002). Bivariate analysis revealed a significant difference in the two groups with respect to O2 saturation at the time of admission (case - 91.12 ± 12.49 %, control - 95.46 ± 5.01 %, p=0.003); maximum O2 flow rate (L/min) (case - 11.01 ± 22.2, control - 6.41 ± 13.31, p=0.04); ICU need (p=0.005), cancer (p=0.001), O2 requirement at discharge (p=0.001) and acute kidney injury (AKI; p=0.007). On multiple regression analysis, cancer (adjusted odds ratio (aOR) - 2.469; 95% CI 1.183-5.150, p=0.016), ICU admission (aOR - 2.446; 95% CI 1.212-4.938, p=0.013), oxygen at discharge (aOR - 2.340; 95% CI 0.971-5.640, p=0.0586) and AKI (aOR - 5.6; 95% CI 2.351- 13.370, p=0.00) only found to be significant. Conclusion Among the patients released from the hospital post-COVID-19 treatment, the following aspects oxygen requirement (2.3 times), malignancy (2.4 times), ICU admission (2.4 times), and AKI (5.6 times) are risk factors of mortality. The presence of these variables would warrant a close follow-up for these patients in order to decrease post-COVID mortality.

Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling.

Cellular senescence and the senescence-associated secretory phenotype (SASP) are implicated in aging and age-related disease, and SASP-related inflammation is thought to contribute to tissue dysfunction in aging and diseased animals. However, whether and how SASP factors influence the regenerative capacity of tissues remains unclear. Here, using intestinal organoids as a model of tissue regeneration, we show that SASP factors released by senescent fibroblasts deregulate stem cell activity and differentiation and ultimately impair crypt formation. We identify the secreted N-terminal domain of Ptk7 as a key component of the SASP that activates non-canonical Wnt / Ca2+ signaling through FZD7 in intestinal stem cells (ISCs). Changes in cytosolic [Ca2+] elicited by Ptk7 promote nuclear translocation of YAP and induce expression of YAP/TEAD target genes, impairing symmetry breaking and stem cell differentiation. Our study discovers secreted Ptk7 as a factor released by senescent cells and provides insight into the mechanism by which cellular senescence contributes to tissue dysfunction in aging and disease.

Tracheal bronchus: a rare cause of recurrent pneumonia in adults.

Tracheal bronchus, also known as bronchus suis, is a rare congenital anomaly of the airway where an accessory bronchus originates directly from the trachea. With an estimated incidence of 0.001%-2.0%, this condition is rarely reported in literature. It is usually discovered as an incidental finding in an otherwise asymptomatic individual. However, it can act as a focus of recurrent infection or present as persistent radiographic infiltrates. Multidetector CT imaging and bronchoscopy play a crucial role in the identification of this entity. We hereby report the case of a middle-aged man who presented with recurrent right upper lobe pneumonia, which was found to be due to an underlying tracheal bronchus.

Clinical Profile, Risk Factors, and Therapeutic Outcome of Cavitating Fungal Pneumonia Coinfection in COVID-19 Patients: A Retrospective Analysis.

BACKGROUND: An end to the novel coronavirus disease 2019 (COVID-19) pandemic appears to be a distant dream. To make matters worse, there has been an alarming upsurge in the incidence of cavitating invasive fungal pneumonia associated with COVID-19, reported from various parts of the world including India. Therefore, it remains important to identify the clinical profile, risk factors, and outcome of this group of patients. METHODS: Out of 50 moderate to severe COVID-19 inpatients with thoracic computed tomographic (CT) evidence of lung cavitation, we retrospectively collected demographic and clinical data of those diagnosed with fungal pneumonia for further investigation. We determined the association between risk factors related to 30-day and 60-day mortality. RESULTS: Of the 50 COVID-19 patients with cavitating lung lesions, 22 (44 %) were identified to have fungal pneumonia. Most of these patients (n = 16, 72.7 %) were male, with a median (range) age of 56 (38-64) years. On chest CT imaging, the most frequent findings were multiple cavities (n = 13, 59.1 %) and consolidation (n = 14, 63.6 %). Mucormycosis (n = 10, 45.5 %) followed by Aspergillus fumigatus (n = 9, 40.9 %) were the common fungi identified. 30-day and 60-day mortalities were seen in 12 (54.5 %) and 16 (72.7 %) patients, respectively. On subgroup analysis, high cumulative prednisolone dose was an independent risk factor associated with 30-day mortality (p = 0.024). CONCLUSION: High cumulative prednisolone dose, baseline neutropenia, hypoalbuminemia, multiple cavities on CT chest, leukopenia, lymphopenia and raised inflammatory markers were associated with poor prognosis in severe COVID-19 patients with cavitating fungal pneumonia.

Hydrocarbon pneumonitis with abscess formation following diesel siphoning.

A man in his early 40s presented with a 1-month history of fever after accidental diesel aspiration. He had received treatment with intravenous antibiotics, steroids and supportive care. Contrast-enhanced CT of the thorax revealed a right middle lobe lung abscess and bronchoscopy revealed hyperaemia around the middle lobe bronchus. The abscess was initially managed by drainage using a pigtail catheter and intravenous antibiotics. However, only partial drainage of the abscess was achieved and fever persisted. The cardiothoracic surgery team performed drainage of lung abscess through a right posterolateral thoracotomy. Postprocedure, the patient's symptoms improved and the patient was discharged in good health. This case demonstrates a rare complication of hydrocarbon aspiration pneumonitis and lung abscess. Post acute management of diesel aspiration, patients should be advised to return for medical assessment immediately, should symptoms like persistent fever and chest pain recur or persist as these symptoms may herald the development of post-hydrocarbon-aspiration lung abscess.

Disrupting autorepression circuitry generates "open-loop lethality" to yield escape-resistant antiviral agents.

Across biological scales, gene-regulatory networks employ autorepression (negative feedback) to maintain homeostasis and minimize failure from aberrant expression. Here, we present a proof of concept that disrupting transcriptional negative feedback dysregulates viral gene expression to therapeutically inhibit replication and confers a high evolutionary barrier to resistance. We find that nucleic-acid decoys mimicking cis-regulatory sites act as "feedback disruptors," break homeostasis, and increase viral transcription factors to cytotoxic levels (termed "open-loop lethality"). Feedback disruptors against herpesviruses reduced viral replication >2-logs without activating innate immunity, showed sub-nM IC50, synergized with standard-of-care antivirals, and inhibited virus replication in mice. In contrast to approved antivirals where resistance rapidly emerged, no feedback-disruptor escape mutants evolved in long-term cultures. For SARS-CoV-2, disruption of a putative feedback circuit also generated open-loop lethality, reducing viral titers by >1-log. These results demonstrate that generating open-loop lethality, via negative-feedback disruption, may yield a class of antimicrobials with a high genetic barrier to resistance.

The clinical course, biochemical markers, and clinical outcomes of COVID-19 positive patients from the third wave in Pakistan: A retrospective cohort study.

Background: Third wave of COVID-19 has affected several countries. Case fatality rates from first and second waves are expected to be surpassed by the current wave due to various variant transmissions. This study was aimed to compare and contrast the significant clinical markers between survivors and non-survivors during the third wave of COVID-19 to assess severity and prognosis. Methods: It includes all the patients who were diagnosed with COVID-19 polymerase chain reaction (PCR) during the third wave, and were monitored for their disease course and outcomes. A total of 209 patients were included in the analysis via non-probability consecutive sampling method. Results: The median age was higher in non-surviving patients (p = 0.010). Majority of deaths occurred in intensive care patients (p < 0.001) and those with diabetes (p = 0.032) and hypertension (p = 0.003). Fever was the most predominant symptom in all patients (78.9%), dyspnea was common among expired individuals (p = 0.043) while recovered patients were more likely to be asymptomatic (p = 0.044). Gastrointestinal symptoms were not found marked during this wave. Being on ventilator has higher mortality (p < 0.001). Predominant radiological findings were interstitial patches or infiltrate (43.7%). Multivariable analysis showed hypertension (p = 0.042), BiPAP/CPAP (p < 0.001), being on ventilator (p = 0.004), and ARDS (p < 0.001) was associated with poor survival while patchy interstitial infiltrates on X-ray had good survival probability (p = 0.032). On Kaplan-Meier survival analysis, hypertension (p = 0.003), BiPAP/CPAP (p = 0.008), ventilator (p = 0.025), ICU stay (p = 0.001), high-grade fever (p = 0.001), and ARDS (p < 0.001) had reduced cumulative survival. Conclusion: Certain biochemical markers were more predictive of disease severity in the third-wave than the preceding waves.

Identification of a therapeutic interfering particle-A single-dose SARS-CoV-2 antiviral intervention with a high barrier to resistance.

Viral-deletion mutants that conditionally replicate and inhibit the wild-type virus (i.e., defective interfering particles, DIPs) have long been proposed as single-administration interventions with high genetic barriers to resistance. However, theories predict that robust, therapeutic DIPs (i.e., therapeutic interfering particles, TIPs) must conditionally spread between cells with R0 >1. Here, we report engineering of TIPs that conditionally replicate with SARS-CoV-2, exhibit R0 >1, and inhibit viral replication 10- to 100-fold. Inhibition occurs via competition for viral replication machinery, and a single administration of TIP RNA inhibits SARS-CoV-2 sustainably in continuous cultures. Strikingly, TIPs maintain efficacy against neutralization-resistant variants (e.g., B.1.351). In hamsters, both prophylactic and therapeutic intranasal administration of lipid-nanoparticle TIPs durably suppressed SARS-CoV-2 by 100-fold in the lungs, reduced pro-inflammatory cytokine expression, and prevented severe pulmonary edema. These data provide proof of concept for a class of single-administration antivirals that may circumvent current requirements to continually update medical countermeasures against new variants.

Self-assembling Peptide Hydrogels Facilitate Vascularization in Two-Component Scaffolds.

One of the major constraints against using polymeric scaffolds as tissue-regenerative matrices is a lack of adequate implant vascularization. Self-assembling peptide hydrogels can sequester small molecules and biological macromolecules, and they can support infiltrating cells in vivo. Here we demonstrate the ability of self-assembling peptide hydrogels to facilitate angiogenic sprouting into polymeric scaffolds after subcutaneous implantation. We constructed two-component scaffolds that incorporated microporous polymeric scaffolds and viscoelastic nanoporous peptide hydrogels. Nanofibrous hydrogels modified the biocompatibility and vascular integration of polymeric scaffolds with microscopic pores (pore diameters: 100-250 µm). In spite of similar amphiphilic sequences, charges, secondary structures, and supramolecular nanostructures, two soft hydrogels studied herein had different abilities to aid implant vascularization, but had similar levels of cellular infiltration. The functional difference of the peptide hydrogels was predicted by the difference in the bioactive moieties inserted into the primary sequences of the peptide monomers. Our study highlights the utility of soft supramolecular hydrogels to facilitate host-implant integration and control implant vascularization in biodegradable polyester scaffolds in vivo. Our study provides useful tools in designing multi-component regenerative scaffolds that recapitulate vascularized architectures of native tissues.

Valproate usage in pregnancy: An audit from the Kerala Registry of Epilepsy and Pregnancy.

OBJECTIVE: This is an audit of the use of valproate (VPA) during pregnancy in women with epilepsy (WWE). METHODS: We identified all pregnancies exposed to VPA in the Kerala Registry of Epilepsy and Pregnancy between January 2010 and December 2019. Subjects' past usage of antiepileptic drugs (AEDs), seizure count before and during pregnancy, fetal outcome, and major congenital malformations (MCMs) were abstracted from the registry records. The presumed reason for usage of VPA was deducted from the clinical records. RESULTS: There were 221 pregnancies (17.75%) exposed to VPA (monotherapy, n = 149) during the audit period. The MCM rate for the completed pregnancies exposed to VPA was higher (n = 20, 10.36%) than that of VPA-unexposed pregnancies (n = 39, 4.96%). The relative risk for MCM with VPA exposure was 2.1 (95% confidence interval = 1.24-3.48, number needed to treat with VPA to result in MCM = 19). Reasons for using VPA during pregnancy (some women had more than one reason) were (1) VPA was the first AED prescribed and was effective (68, 29.06%), (2) other AEDs were ineffective (128, 54.70%), and (3) other AEDs were discontinued due to adverse effects (17, 7.28%). Other reasons (21, 8.97%) were (1) VPA was selected after the epilepsy classification was revised (3, 1.28%), (2) other AEDs were expensive (2, .85%), and (3) patient switched to VPA from other AEDs for unspecified reason (16, 6.83%). VPA was discontinued during pregnancy for 6 (2.71%) persons. Less than 10% of women were tried on lamotrigine or levetiracetam before switching to VPA. SIGNIFICANCE: Nine MCMs per thousand pregnancies can be avoided if VPA is not used in WWE. Safe and effective AEDs as alternatives to VPA are the need of the hour. Professional bodies and regulatory authorities need to implement updated guidelines on AED usage in girls and women.

Angiogenic hydrogels for dental pulp revascularization.

Angiogenesis is critical for tissue healing and regeneration. Promoting angiogenesis in materials implanted within dental pulp after pulpectomy is a major clinical challenge in endodontics. We demonstrate the ability of acellular self-assembling peptide hydrogels to create extracellular matrix mimetic architectures that guide in vivo development of neovasculature and tissue deposition. The hydrogels possess facile injectability, as well as sequence-level functionalizability. We explore the therapeutic utility of an angiogenic hydrogel to regenerate vascularized pulp-like soft tissue in a large animal (canine) orthotopic model. The regenerated soft tissue recapitulates key features of native pulp, such as blood vessels, neural filaments, and an odontoblast-like layer next to dentinal tubules. Our study establishes angiogenic peptide hydrogels as potent scaffolds for promoting soft tissue regeneration in vivo. STATEMENT OF SIGNIFICANCE: A major challenge to endodontic tissue engineering is the lack of in situ angiogenesis within intracanal implants, especially after complete removal of the dental pulp. The lack of a robust vasculature in implants limit integration of matrices with the host tissue and regeneration of soft tissue. We demonstrate the development of an acellular material that promotes tissue revascularization in vivo without added growth factors, in a preclinical canine model of pulp-like soft-tissue regeneration. Such acellular biomaterials would facilitate pulp revascularization approaches in large animal models, and translation into human clinical trials.

Gene Transfer in Adeno-Associated Virus Seropositive Rhesus Macaques Following Rapamycin Treatment and Subcutaneous Delivery of AAV6, but Not Retargeted AAV6 Vectors.

Adeno-associated virus (AAV) vectors such as AAV6, which shows tropism for primary human CD4+ T cells in vitro, are being explored for delivery of anti-HIV therapeutic modalities in vivo. However, pre-existing immunity and sequestration in nontarget organs can significantly hinder their performance. To overcome these challenges, we investigated whether immunosuppression would allow gene delivery by AAV6 or targeted AAV6 derivatives in seropositive rhesus macaques. Animals were immune suppressed with rapamycin before intravenous (IV) or subcutaneous (SC) delivery of AAV, and we monitored vector biodistribution, gene transfer, and safety. Macaques received phosphate-buffered saline, AAV6 alone, or an equal dose of AAV6 and an AAV6-55.2 vector retargeted to CD4 through a direct ankyrin repeat protein (DARPin). AAV6 and AAV6-55.2 vector genomes were found in peripheral blood mononuclear cells and most organs up to 28 days postadministration, with the highest levels seen in liver, spleen, lymph nodes (LNs), and muscle, suggesting that retargeting did not prevent vector sequestration. Despite vector genome detection, gene expression from AAV6-55.2 was not detected in any tissue. SC injection of AAV6 facilitated efficient gene expression in muscle adjacent to the injection site, plus low-level gene expression in spleen, LNs, and liver, whereas gene expression following IV injection of AAV6 was predominantly seen in the spleen. AAV vectors were well tolerated, although elevated liver enzymes were detected in three of four AAV-treated animals 14 days after rapamycin withdrawal. One SC-injected animal had muscle inflammation proximal to the injection site, plus detectable T cell responses against transgene and AAV6 capsid at study finish. Overall, our data suggest that rapamycin treatment may offer a possible strategy to express anti-HIV therapeutics such as broadly neutralizing antibodies from muscle. This study provides important safety and efficacy data that will aid study design for future anti-HIV gene therapies.