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X-linked lymphoproliferative disease is a rare inherited immune disorder, caused by mutations or deletions in the SH2D1A gene that encodes an intracellular adapter protein SAP (Slam-associated protein). SAP is essential for mediating several key immune processes and the immune system - T cells in particular - are dysregulated in its absence. Patients present with a spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinemia, lymphoma and autoimmunity. Treatment options are limited, and patients rarely survive to adulthood without an allogeneic haematopoietic stem cell transplant (HSCT). However, this procedure can have poor outcomes in the mismatched donor setting or in the presence of active HLH, leaving an unmet clinical need. Autologous haematopoeitic stem cell or T cell therapy may offer alternative treatment options, removing the need to find a suitable donor for HSCT and any risk of alloreactivity. SAP has a tightly controlled expression profile that a conventional lentiviral gene delivery platform may not be able to fully replicate. A gene editing approach could preserve more of the endogenous regulatory elements that govern SAP expression, potentially providing a more optimum therapy. Here, we assessed the ability of TALEN, CRISPR-Cas9 and CRISPR-Cas12a nucleases to drive targeted insertion of SAP cDNA at the first exon of the SH2D1A locus using an adeno-associated virus serotype 6 (AAV6)-based vector containing the donor template. All nuclease platforms were capable of high efficiency gene editing, which was optimised using a serum-free AAV6 transduction protocol. We show that T cells from XLP patients corrected by gene editing tools have restored physiological levels of SAP gene expression and restore SAP-dependent immune functions, indicating a new therapeutic opportunity for XLP patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Houghton, Panchal, Haas, Chmielewski, Hildenbeutel, Whittaker, Mussolino, Cathomen, Thrasher and Booth.)

Purpose: This study compared opioid prescription patterns among oral and maxillofacial surgeons (OMSs) treating Medicare beneficiaries in urban and rural settings, in an effort to identify avenues to further promote responsible opioid prescribing in a patient demographic vulnerable to opioid diversion., Materials and Methods: This study used Medicare Provider Utilization and Payment Data from 2014 to 2018, focusing on providers labeled as an OMS. Rural-urban commuting area codes were used to categorize each OMS as urban or rural. The demographic variables included total number of OMSs, provider gender, beneficiaries per provider, beneficiaries' age, and beneficiary hierarchal condition category (proxy for clinical complexity). The outcome variables included opioid prescribing rate, opioid claims per provider, opioid claims per beneficiary, and number of days' supply of opioids per claim. Descriptive statistics, χ 2 tests, 2-tailed t tests, and Wilcoxon rank-sum tests were used as appropriate., Results: Across all years, the data consisted of mostly urban and male OMSs. The mean number of Medicare beneficiaries prescribed opioids per OMS varied widely, and the mean age of beneficiaries was 70.4 ± 4.4 and 69.9 ± 4.1 years for urban and rural OMSs, respectively. Mean opioid claims per provider were higher among rural OMSs, with large standard deviations among both rural and urban OMSs. However, there were no significant differences in the opioid prescribing rate or in the mean opioid claims per beneficiary in all 5 years included in the study. There were also no clinically significant differences between urban and rural OMSs in the number of days' supply per claim (between 3 and 4 days in all periods). However, in each year, there was a significantly higher proportion of urban OMSs who prescribed more than 7 days' supply per claim., Conclusions: Opioid prescription practices were generally similar between rural and urban OMSs treating Medicare beneficiaries. The small subset of longer-term opioid prescribers, which were more prevalent in urban areas, warrants further investigation., (Copyright © 2021 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background & Objectives: Globally, several countries consider HIV self-test as an important element in the toolbox to end AIDS by 2030. Against this background, the present investigation was conducted to pilot test the performance of an indigenous HIV oral self-test (HIVOST) and explore its acceptability. The overall purpose was to examine if this kit could serve as a promising tool and merit future larger clinical evaluation., Methods: A concurrent mixed-method investigation was undertaken during March-October 2019. One hundred and thirty two consecutive HIV/sexually transmitted diseases/tuberculosis clinic attendees were invited for participation; of whom, 100 were enrolled, and among them, 40 provided consent for qualitative in-depth interviews. The HIVOST kit assessed for its performance served as the 'index test', which worked on the principle of lateral flow chromatography. The results of the HIVOST were interpreted independently by the study physicians and participants at 20 min. HIVOST kit performance was assessed against the HIV confirmatory blood test result based on the national algorithm (3 rapid test or 1 ELISA and 2 rapid test) serving as the 'reference'. Sensitivity, specificity, positive predictive value, negative predictive value and inter-rater agreement were estimated. The voices and concerns of the study participants were coded followed by identification of qualitative themes and ideas., Results: The sensitivity and specificity of the index test at the end of 20 min as interpreted by the participants were 83.3 per cent [95% confidence interval (CI): 69.8 to 92.5] and 98 per cent (95% CI: 89.4 to 99.5), respectively. Study physicians and participants independently interpreted HIVOST results with substantial inter-rater agreement (kappa value 0.88; 95% CI: 0.78-0.97). All HIVOST test strips were valid. Majority of the participants preferred saliva over blood for HIV self-test. 'Comfort', 'confidentiality' and 'convenience' were the perceived advantages of HIVOST. Some of the participants wished the package inserts contained 'how-to-do instructions in local languages', 'expiry date (if any)' and 'contact helpline number'. A few of them highlighted the need for a confirmatory HIV result following oral self-test. Concerns of the participants revolved around potential self-harm following HIVOST-positive result and safe disposal of kits., Interpretation & Conclusions: Two major highlights of the present investigation are (i) high level of concordance in HIVOST results interpreted by participants and physicians, and (ii) encouraging level of acceptance of HIVOST. These findings and encouraging HIVOST performance statistics lend support towards large-scale clinical evaluation of this index test.

Objective: Proton pump inhibitors (PPIs) may be linked to implant failure by affecting bone metabolism and osseointegration. This study evaluated how PPIs influence long-term implant failure and peri-implantitis in PPI users and nonusers., Study Design: This was a retrospective cohort study of patients treated at the Philadelphia Veterans Affairs Medical Center between 2006 and 2013. The primary predictor variable was PPI use. Outcome variables were long-term implant failure and the presence of peri-implantitis. Data gathered included demographic characteristics, medical comorbidities, implant location, and dimensions. Multivariate regression models measured independent factor associations. The final study cohort contained 933 implants placed in 284 patients. A total of 323 (32.6%) implants were placed in patients with ongoing PPI use. PPI users were less likely to smoke (22.1% vs 31.9%; P < .01) and use illicit drugs (5.0% vs 9.7%; P = .01) and more likely to have undergone prior bone grafting (18.3% vs 12.9%; P = .03)., Results: PPI use lost significance after controlling for confounding factors and was not an independent predictor of implant failure (odds ratio [OR], 0.801; 95% confidence interval [CI], 0.56-1.15; P = .24) or peri-implantitis (OR, 0.801; 95% CI, 0.56-1.15; P = .24)., Conclusions: Our study found no independent associations between PPI use and implant failure or peri-implantitis. Contrary to published literature, PPIs may not influence implant health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The use of telemedicine has grown exponentially over the last decade, but its widespread adoption has been hindered, at least in part, by uncertainty over reimbursement rate for services. The aim of this study is to compare reimbursement rates of telemedicine and in-person visits in an academic oral and maxillofacial surgery practice., Methods: The investigators implemented a retrospective cohort study. The sample was composed of patients who were treated by the oral-maxillofacial surgery service at the University of Pennsylvania Health System from March 17, 2020 to February 27, 2021. The primary predictor variable was the type of patient visit, either telemedicine or in-person. Patient status, either established or new, was a covariate. The outcome variable was the mean reimbursement-to-charge (RC) ratio. Descriptive and bivariate statistics were computed, and the P value was set at .05., Results: This study included 6,082 submitted claims for 4,045 patients for in-person and telemedicine oral-maxillofacial surgery office visits. The mean reimbursement per insurance payor was $98.07 for a telemedicine visit (mean RC ratio = 0.48 with a standard deviation of ± 0.20) and $109.5 for an in-person visit (mean RC ratio = 0.50 with a standard deviation of ± 0.19). While there was a significant difference between the RC ratio for total telemedicine versus in-person visits (P = .001), the magnitude of the difference was only 2%. When stratifying the comparison by new (P = .73) and established patients (P = .20) for both telemedicine and in-person office visits, there was no significant difference in RC ratios., Conclusions: The results suggest that there are no major discrepancies in financial reimbursement rate between telemedicine and in-person office visits. Both methods of treatment may be financially effective for oral-maxillofacial surgery providers. Future studies can compare reimbursement rates among different insurance providers and among different institutions in the United States., (Copyright © 2021 The American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Amino acid restriction by inhibition of neutral amino acid transporter, B 0 AT1 (SLC6A19) activity has been recently shown to improve glyceamic control by upregulating glucagon like peptide (GLP1) and fibroblast growth factor (FGF21) in mice. Hence, pharmacological inhibition of B 0 AT1 is expected to treat type-2 diabetes and related disorder. In this study, rationally designed trifluoromethyl sulfonyl derivatives were identified as novel, potent and orally bioavailable B 0 AT1 inhibitors. Compound 39 was found to be nanomolar potent (IC 50 : 0.035 µM) B 0 AT1 inhibitor with excellent pharmacokinetic profile (%F: 66) in mice and efficacious in vivo in diet induced obese (DIO) mice model., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: To illuminate epidemiologic trends of maxillofacial trauma in an urban setting over an 11-year period., Materials and Methods: We performed an exhaustive database search at the University of Pennsylvania. The data were collected from 11 years of attending oral and maxillofacial surgery clinician and resident operating room logs and was conducted from 2011 to 2021. The procedures where then selected for those that represented maxillofacial trauma., Results: About 3,427 procedures met the inclusion and exclusion criteria to be considered a novel incidence of trauma. Dramatic differences in maxillofacial trauma exist between time of the year, patient age, and patient race. There is a correlation between summer time criminal activity and maxillofacial trauma. African-Americans ages 18 to 65 are the most affected patient demographic., Conclusions: With datasets of this size spanning over a decade, epidemiologic trends are able to be illuminated. There is a need for understanding the disparity between the demographics of the Philadelphia population and oral-maxillofacial (OM) trauma patients. A prospective extension of this study is to explore secondary, tertiary and quaternary ICD-10 codes to illuminate common injury patterns in OM trauma of varying patient populations., (Copyright © 2021 The American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Exercise may improve clinical and quality of life outcomes for men with prostate cancer. No randomized controlled trials (RCTs) have examined the feasibility, safety, and acceptability of remote exercise training in men with metastatic castrate-resistant prostate cancer (mCRPC)., Methods: We conducted a pilot RCT (1:1:1 aerobic or resistance exercise 3x/week or usual care) to determine the feasibility, safety, and acceptability of remotely monitored exercise over 12 weeks in 25 men with mCRPC. A prescribed exercise program was based on baseline testing including high- and moderate-intensity aerobic exercise or resistance exercise completed at a local exercise facility. Feasibility was based on attendance, adherence, and tolerance; safety on adverse events; and acceptability on participant interviews., Results: Between March 2016 and March 2020, 25 patients were randomized (8 aerobic, 7 resistance, and 10 control). Twenty-three men (82%) completed the 12-week study. Men who completed the remote intervention attempted 90% and 96% of prescribed aerobic and resistance training sessions, respectively, and 86% and 88% of attempted sessions were completed as or more than prescribed. We observed changes in performance tests that corresponded with the exercise prescription. No safety concerns were identified. Ninety percent of participants interviewed were satisfied with the program and would recommend it to others., Conclusions: Remotely monitored exercise training is feasible, safe, and acceptable in men with mCRPC; there was no difference in these outcomes by mode of exercise. Through this research, we provide direction and rationale for future studies of exercise and clinical outcomes in patients with metastatic prostate cancer., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To curb opioid overprescription and diversion, 49 states have implemented mandatory prescription drug monitoring programs (PDMPs). This study aims to examine the changes in analgesic prescription patterns associated with mandatory PDMP usage by oral and maxillofacial surgeons., Design: This retrospective observational cohort study analyzed analgesic prescriptions after third molar surgeries from the University of Pennsylvania from July 2016 to December 2019. Because Pennsylvania mandated PDMP usage on January 1, 2017, we analyzed prescriptions 6 months prior to and for each 6-month interval after implementation., Results: Prescriptions after 13,430 procedures on 6437 patients across 7 6-month periods were analyzed. Patients in all study periods had an average age of 40 years and there was a slight majority of females. After PDMP implementation, patients who received analgesics had an 80% lower odds of receiving an opioid option after adjusting for age, sex, and procedural severity. When an opioid was prescribed, the mean pills per script decreased from 20.18 to 10.96 1 year after PDMP implementation., Conclusions: Mandatory PDMP usage was associated with decreased odds of a patient receiving an opioid analgesic and with a decrease in mean opioid pills per script. PDMPs may be helpful in reducing opioid prescriptions by oral and maxillofacial surgeons after third molar surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Social factors have been implicated in the development of peri-implant pathologies, including implant failure. This study aims to investigate whether alcohol consumption affects late dental implant failures., Methods: A retrospective cohort study evaluated implants placed between 2006 and 2012 at the Philadelphia Veterans Affairs Medical Center. The primary predictor variable was alcohol consumption, measured as nonconsumption and mild, moderate, and heavy consumption. The primary outcome variable was late dental implant failure. Univariate, bivariate, and multivariate statistics were applied, with P < .05 used to define statistical significance., Results: Our cohort consisted of 103 patients and 295 implants with a 5-year minimum follow-up. Most patients were male (93%) with an average age of 60 at the time of implant placement. Late implant failure was associated with 30 implants. Compared to nonconsumption, mild consumption was associated with a 75% decrease in late implant failure (P = .0494), moderate consumption was associated with a 60% decrease (P = .3826), and heavy consumption was associated with a 200% increase (P < .1782). Compared to mild consumption, heavy consumption was associated with an 847% increase in late failure (P = .0135)., Conclusions: Results from this retrospective cohort analysis suggest that mild alcohol consumption is associated with a decrease in late dental implant failures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The coronavirus disease (COVID-19) pandemic has impacted the world in unprecedented ways. It is clear that this pandemic, unlike any public health challenge in recent memory, has the potential to fundamentally alter the delivery of many healthcare services, including dentistry. As evidence-based information on COVID-19 continues to emerge, this article serves as a means to disseminate current opinions, management strategies, and the impact of COVID-19 on dentistry.

Purpose: Diabetes mellitus is associated with an increased risk of poor outcomes with dental implant placement. This study aims to identify if frequency of hygiene visits is a protective factor for the development of peri-implantitis in diabetic patients., Methods: A retrospective cohort design was conducted on patients presenting for dental implant placement at the Philadelphia Veterans Affairs (VA) Medical Center from 2006 to 2012. The primary predictor variable was hygiene frequency, recorded as either infrequent, annual (7-12 month recall), or biannual (≤6-month recall). The number of months between implant placement and the presence of peri-implantitis was the primary outcome (time-to-peri-implantitis) variable, which was assessed on a subject level and adjusted for clustered, correlated multiple implants on the same subject. Additional variables were greater than or equal to 60 years of age, male gender, smokers, short implant length, diabetes, uncontrolled diabetes, and removable prostheses. Descriptive, univariate, and Cox proportional hazards regression statistics were computed to measure associations with peri-implantitis with P ≤ .05 used to define statistical significance., Results: The study sample was composed of 286 patients. In total, 748 implants were placed. Subjects greater than or equal to 60 years of age were 2 times more likely to develop peri-implantitis (hazards ratio (HR) = 2.015, 95% Cl (0.985-4.119), P = .0549). Subjects receiving implant-supported removable prostheses were 2.3 times more likely to develop peri-implantitis (HR = 2.315, 95% CI (1.006-5.327), P = .0485). With each hygiene visit, patients' risk of developing peri-implantitis decreased 20% (HR = 0.805, 95% Cl (0.394-1.647), P = .5528). In addition, diabetic patients were 49% more likely to develop peri-implantitis (HR = 1.491, 95% CI (0.758-2.936), P = .2475) than nondiabetic patients., Conclusions: Diabetic patients may be at increased risk for the development of peri-implantitis and an increased frequency of hygiene visits may reduce peri-implant diseases., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has changed conventional patterns of medical practice across all health disciplines, including oral and maxillofacial surgery. The use of telemedicine has rapidly expanded to uphold safety strategies of physical distancing and disease transmission reduction while maintaining uninterrupted care of patients. To date, there are no specific guidelines to optimize telemedicine encounters in oral and maxillofacial surgery. The goal of this article is to provide best practices for both oral and maxillofacial surgeons and their patients to effectively use telemedicine for the duration of the COVID-19 pandemic and beyond., (Published by Elsevier Inc.)

The application of therapeutic T cells for a number of conditions has been developed over the past few decades with notable successes including donor lymphocyte infusions, virus-specific T cells and more recently CAR-T cell therapy. Primary immunodeficiencies are monogenetic disorders leading to abnormal development or function of the immune system. Haematopoietic stem cell transplantation and, in specific candidate diseases, haematopoietic stem cell gene therapy has been the only definitive treatment option so far. However, autologous gene-modified T cell therapy may offer a potential cure in conditions primarily affecting the lymphoid compartment. In this review we will highlight several T cell gene addition or gene-editing approaches in different target diseases with a focus on what we have learnt from clinical experience and promising preclinical studies in primary immunodeficiencies. Functional T cells are required not only for normal immune responses to infection (affected in CD40 ligand deficiency), but also for immune regulation [disrupted in IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-Linked) due to dysfunctional FOXP3 and CTLA4 deficiency] or cytotoxicity [defective in X-lymphoproliferative disease and familial haemophagocytic lymphohistiocytosis (HLH) syndromes]. In all these candidate diseases, restoration of T cell function by gene therapy could be of great value., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Diclofenac Sodium (DS) injection is widely used in the management of acute or chronic pain and inflammatory diseases. It incorporates 20% w/v Transcutol-P as a solubilizer to make the stable injectable formulation. However, the use of Transcutol-P in high concentration leads to adverse effects such as severe nephrotoxicity, etc. Some advancements have resulted in the formulation of an aqueous-based injectable but that too used benzyl alcohol which is reported to be toxic for human use., Objective: This study aimed to develop an injectable Self-Micro Emulsifying Drug Delivery System (SMEDDS) as a novel carrier of DS for prompt release with better safety and efficacy., Methods: A solubility study was performed with different surfactants and co-surfactants. The conventional stirring method was employed for the formulation of SMEDDS. Detailed in vitro characterization was done for different quality control parameters. In vivo studies were performed using Wistar rats for pharmacokinetic evaluation, toxicological analysis, and analgesic activity., Results: The optimized formulation exhibited good physical stability, ideal globule size (156±0.4 nm), quick release, better therapeutics, and safety, increase in LD50 (221.9 mg/kg) to that of the commercial counterpart (109.9 mg/kg). Furthermore, pre-treatment with optimized formulation reduced the carrageenan-induced rat paw oedema by 88±1.2% after 4 h, compared to 77±1.6% inhibition with commercial DS formulation. Moreover, optimized formulation significantly (p<0.05) inhibited the pain sensation in the acetic-acid induced writhing test in mice compared to its commercial equivalent with a better pharmacokinetic profile., Conclusion: The above findings confirmed that liquid SMEDDS can be a successful carrier for the safe and effective delivery of DS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The onset of coronavirus disease 19 (COVID-19) impacted all facets of global communities. As such, dental organizations must reconsider the traditional format of conferences in order to abide by public health guidelines. Such an adjustment is required in an effort to limit the footprint and ensure the safety of its participants. This article aims to provide guidance to reformat a traditional conference to a virtual platform. Recommendations are made pertaining to the structure of organizational committees, the intricacies of digital platforms, any associated costs, and adjustments to advertising and sponsorships. The authors also provide direction regarding changes in scheduling, and suggestions in order to replicate the social aspect of academic conferences. Careful consideration of the existing format can help design an efficient virtual platform that will continue to yield professional growth and drive the frontier of research in dentistry during this pandemic., (© 2020 American Dental Education Association.)

Oral pigmented lesions have a wide range of clinical presentations, some of which correlate with cutaneous pigmented lesions. This article highlights these correlates and underscores important differences that can potentially have clinical impact. Moreover, given a nonspecific presentation of an oral pigmented lesion, the article provides a reference to aid clinicians with differential diagnoses based on clinical features. This article is an overview of pigmented lesions of the oral cavity, including localized reactive pigmented lesions, neoplastic pigmented lesions, and pigmented lesions as sequelae of a systemic disease., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diclofenac sodium is a potent NSAID, classified under BCS class II category having a poor aqueous solubility. Recently, its injectable formulation got banned and withdrawn from the market due to its severe nephrotoxicity caused by the use of synthetic surfactant, i.e. Transcutol-P as solubilizer. Therefore, the present study was aimed to prepare Transcutol-P free injectable using Vitamin E TPGS as a biosurfactant which is in list of inactive ingredients by US-FDA. Various cost effective aqueous injectable formulations were prepared by mixed solvency method that were characterized and optimized for different in vitro quality control parameters. Further, ex vivo hemolytic study showed the increased safety (23.4 ± 1.6%) of optimized formulation as compared with its commercial counterpart (100 ± 4.2%) at 75 mg/ml. Furthermore, in vivo acute and sub-acute toxicity study demonstrated an increase in LD 50 to 123.75 ± 6.2 mg/kg to that of a commercial counterpart (109.96 ± 5.5 mg/kg). In addition, optimized formulation demonstrated better mean residence time and area under curve when compared with commercial test group, respectively. Moreover, optimized formulation was also evaluated for its therapeutic efficacy. The results obtained from acetic acid-induced writhing test in albino mice showed 78 ± 2.1% protection from writhes after 120 min, whereas the commercial formulation had only 48.3 ± 1.9% protection. Additionally, carrageenan-induced rat paw edema model also confirmed the better anti-inflammatory activity of optimized aqueous injectable formulation than its commercial counterpart. Thus, the developed aqueous injectable formulation of diclofenac is free from toxic Transcutol-P with enhanced safety and therapeutic efficacy.

Several uncertainties exist regarding how we will conduct our clinical, didactic, business, and social activities as the coronavirus disease 2019 (COVID-19) global pandemic abates and social distancing guidelines are relaxed. We anticipate changes in how we interact with our patients and other providers, how patient workflow is designed, the methods used to conduct our teaching sessions, and how we perform procedures in different clinical settings. The objective of the present report is to review some of the changes to consider in the clinical and academic oral and maxillofacial surgery workflow and, allow for a smoother transition, with less risk to our patients and healthcare personnel. New infection control policies should be strictly enforced and monitored in all clinical and nonclinical settings, with an overall goal to decrease the risk of exposure and transmission. Screening for COVID-19 symptoms, testing when indicated, and establishing the epidemiologic linkage will be crucial to containing and preventing new COVID-19 cases until a vaccine or an alternate solution is available. Additionally, the shortage of essential supplies such as drugs and personal protective equipment, the design and ventilation of workspaces and waiting areas, the increase in overhead costs, and the possible absence of staff, if quarantine is necessary, must be considered. This shift in our workflow and patient care paths will likely continue in the short-term at least through 2021 or the next 12 to 24 months. Thus, we must prioritize surgery, balancing patient preferences and healthcare personnel risks. We have an opportunity now to make changes and embrace telemedicine and other collaborative virtual platforms for teaching and clinical care. It is crucial that we maintain COVID-19 awareness, proper surveillance in our microenvironments, good clinical judgment, and ethical values to continue to deliver high-quality, economical, and accessible patient care., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Pompe disease is a lysosomal storage disorder caused by malfunctions of the acid alpha-glucosidase (GAA) enzyme with a consequent toxic accumulation of glycogen in cells. Muscle wasting and hypertrophic cardiomyopathy are the most common clinical signs that can lead to cardiac and respiratory failure within the first year of age in the more severe infantile forms. Currently available treatments have significant limitations and are not curative, highlighting a need for the development of alternative therapies. In this study, we investigated the use of a clinically relevant lentiviral vector to deliver systemically GAA through genetic modification of hematopoietic stem and progenitor cells (HSPCs). The overexpression of GAA in human HSPCs did not exert any toxic effect on this cell population, which conserved its stem cell capacity in xenograft experiments. In a murine model of Pompe disease treated at young age, we observed phenotypic correction of heart and muscle function with a significant reduction of glycogen accumulation in tissues after 6 months of treatment. These findings suggest that lentiviral-mediated HSPC gene therapy can be a safe alternative therapy for Pompe disease., (© 2020 The Authors.)

Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Youth and adolescents are the priority population to target the interventions as risky behaviors persist and they contribute to almost half of the new Human immunodeficiency virus (HIV) infections. The youth in India have a unique and diverse need of sex health education. The present study was conducted with the objective to understand their sexual behavior and requirements of sexual health., Methods: Focus group discussions were conducted among 74 college students, separately for boys and girls. The participant students were from different streams of education. The domains of enquiry were related to the relationships, risk behaviors, sources of information and use of technology for sex health education. The qualitative data was analyzed based on the themes and subthemes derived from these discussions., Results: A majority of the youth favoured active involvement of parents, school teachers in sex health education. They suggested that better-informed parents lead to better-informed adolescents. Open discussion with experts was also desired by the students. The use of mobile/web based application for sex health education and awareness about HIV and sexually transmitted infections (STIs) was preferred, however, they suggested that based on personal requirements, individual need based counseling and guidance is important., Conclusions: Active parental involvement and open discussions on sexuality were the preferred options by the student to seek the knowledge and guidance. Innovative mobile application for sex health education will be useful for the young adults for information and communication. The study highlighted a need to develop a holistic approach to generate a culturally-sensitive sex health education and life skills model.

Purpose: Recent studies have pointed to the effects of social factors on the health of dental implants. We investigated whether varying levels of alcohol consumption will influence the health of dental implants and associated peri-implant inflammation., Patients and Methods: A retrospective cohort study was performed to evaluate implants placed from 2006 to 2012 at the Philadelphia Veteran's Affairs Medical Center. Alcohol consumption was gathered from the health maintenance records within 3 months of implant placement and served as the predictor variable. Analysis was performed at follow-up visits for the presence of the outcome variable, peri-implantitis, which was assessed at an implant level. A multivariable generalized estimating equation logistic regression model was constructed, and a Wald test was used to analyze the statistical significance of each parameter. The results were interpreted as an odds ratio estimate, including the 95% confidence interval. Descriptive statistics were used to compute and analyze the data, with P < .05 used to define statistical significance., Results: Demographically, our cohort consisted mainly of male patients (92%), with an average age of 60 years at implant placement. The mean interval to peri-implantitis was 30 ± 25 months. Peri-implantitis occurred most frequently within 2 years of implant placement. The incidence of peri-implantitis was greatest among heavy alcohol consumers (42%) and lowest among mild and moderate consumers (12 and 6%, respectively). Compared with no consumption, mild alcohol consumption was associated with a 47% decrease in peri-implantitis (P < .0223) and moderate consumption was associated with a 75% decrease (P < .0250). Heavy consumption was associated with a nearly threefold increase in peri-implantitis (P < .0001)., Conclusions: The results from our retrospective cohort analysis revealed that mild to moderate alcohol consumption is associated with a lower rate of peri-implantitis. However, heavy consumption was associated with an increase in the incidence of peri-implantitis among patients with dental implants., (Copyright © 2019 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Dynamic navigation (DN) has been used by many fields previously and recently applied to dental implant surgery. DN allows the implant surgeon to evaluate a patient, scan the patient, plan the implant position, and perform the implant surgery in the same day without the delay or cost of fabrication of a static surgical guide stent. The current DN workflow requires (1) cone-beam computed tomography with fiducials, (2) virtual implant planning, (3) calibration, and (4) implant placement in accordance to the 3-D image on the navigation screen. This technology allows for improved precision and accuracy in the placement of dental implants., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study aimed to develop microsponges based topical gel formulation of 5-Fluorouracil (5-FU) for the treatment of skin cancer with enhanced skin deposition and reduced skin irritation potential. Microsponges were prepared by Quasi-emulsion solvent diffusion method using ethyl cellulose and Eudragit RL 30 D; and was optimised through detailed in vitro characterisation. Brunauer-Emmett-Teller (BET) analysis demonstrated higher surface area (2.4393 m 2 /g) and pore volume of developed microsponges formulation. Optimised formulation showed better thixotropic and texture properties compared to commercial cream formulation, used as control for comparison purpose. Further, the optimised formulation demonstrated 5.5-fold increase in skin deposition documented via in-vivo local bioavailability study, with significant reduction in skin irritation compared to the commercial formulation. Hence, the developed microsponges based formulation seems to be a viable alternative with enhanced topical delivery of 5-FU as compared to the commercial formulation.

Telehealth is a growing model of delivering health care. School-based health centers (SBHCs) provide access to health care for youth in schools and increasingly use telehealth in care delivery. This article examines the recent growth of telehealth use in SBHCs, and characteristics of SBHCs using telehealth, including provider types, operational characteristics, and schools and students served. The percentage of SBHCs using telehealth grew from 7% in 2007-2008 to 19% in 2016-2017. Over 1 million students in over 1800 public schools have access to an SBHC using telehealth, which represents 2% of students and nearly 2% of public schools in the United States. These SBHCs are primarily in rural communities and sponsored by hospitals. This growing model presents an opportunity to expand health care access to youth, particularly in underserved areas in the United States and globally. Further research is needed to fully describe how telehealth programs are implemented in school settings and their potential impacts., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Youth in underserved communities lack access to consistent sources of high-quality health care. School-based health centers (SBHCs) address this challenge through the provision of primary care, mental health care, and other health services in schools. This article describes the current status of SBHCs nationally, including changes over the past twenty years. Data were collected through the School-Based Health Alliance's National School-Based Health Care Census. The number of SBHCs doubled from 1,135 in 1998-99 to 2,584 in 2016-17. During this time they adapted to the changing health care landscape and community needs. Sponsorship shifted predominantly to federally qualified health centers, and SBHCs provided access to primary care and, often, to mental, oral, and other health services to 10,629 schools and over 6.3 million students. SBHCs have grown steadily since 1998, and recent expansion through federally qualified health centers and telehealth technology forecasts even greater growth, innovation, and access for underserved communities.

Background: Immunological non-responders (INR) represent a unique category of HIV-infected patients on antiretroviral therapy. These patients have suppressed viremia but a suboptimal increase in CD4 cell count, which might have opposing effects on functional immune reconstitution. Hence, the extent of immune reconstitution in INR patients was investigated in order to determine their susceptibility to opportunistic infections., Methods: Twenty-three INR patients (CD4 increase <50 cells/mm 3 , viral load <40 copies/ml), 40 age-, sex-, and baseline CD4 count-matched responders (CD4 increase >100 cells/mm 3 , viral load <40 copies/ml), and 18 treatment failures defined as per the national guidelines were enrolled at 1year of antiretroviral therapy. The following examinations were performed: haemogram, phenotypic characterization by flow cytometry, and assessment of functional immune status by ELISPOT and intracellular cytokine assays., Results: A higher percentage of INR patients had clinically symptomatic infections than the responders. CD8 + activation and innate immune parameters, including the absolute neutrophil count and natural killer (NK) cell frequency and functionality, were restored in the INR patients. They had significantly higher non-HIV antigen-specific T-cell responses and activated CD4 + cells, but significantly compromised T-cell functionality, as assessed after anti-CD3 stimulation, and lower CD31 + and CD62L + CD4 + cells., Conclusions: INR patients showed lower thymic output, incomplete functional T-cell reconstitution, higher responses to HIV co-pathogens, and higher symptomatic events, indicating the need for close monitoring and intervention strategies to overcome their continuing immunocompromised status., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Oral mucosa follows a distinctly different trajectory of wound healing than skin. Although there are contemporary guidelines regarding treatment of burns to the skin, there is no standard of care specific to intraoral burns. This narrative review proposes an evidence-based treatment algorithm for the management of intraoral burns. Data was collated through a comprehensive review of the literature and only included studies that have reported particular success with favorable short- and long-term prognoses. In order to critically appraise the strength of the treatment recommendations, the GRADE criteria was applied to each arm of the algorithm. The algorithm was initially subdivided into the four primary etiologies of intraoral burns - thermogenic, cryogenic, chemical, electrical. Our findings emphasize the importance of conservative modalities of intra-oral burn treatment., (Published by Elsevier Ltd.)

Background: X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match., Objectives: Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects., Methods: CD3 + lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3 + cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model., Results: In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model., Conclusions: These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1-6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1-6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1-6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors.

X-linked lymphoproliferative disease (XLP) was first described in the 1970s as a fatal lymphoproliferative syndrome associated with infection with Epstein-Barr virus (EBV). Features include hemophagocytic lymphohistiocytosis (HLH), lymphomas, and dysgammaglobulinemias. Molecular cloning of the causative gene, SH2D1A , has provided insight into the nature of disease, as well as helped characterize multiple features of normal immune cell function. Although XLP type 1 (XLP1) provides an example of a primary immunodeficiency in which patients have problems clearing primarily one infectious agent, it is clear that XLP1 is also a disease of severe immune dysregulation, even independent of EBV infection. Here, we describe clinical features of XLP1, how molecular and biological studies of the gene product, SAP, and the associated signaling lymphocyte activation molecule family receptors have provided insight into disease pathogenesis including specific immune cell defects, and current therapeutic approaches including the potential use of gene therapy. Together, these studies have helped change the outcome of this once almost uniformly fatal disease.

The proliferation of high resolution and affordable virtual reality (VR) headsets is quickly making room-scale VR experiences available in our homes. Most VR experiences strive to achieve complete immersion by creating a disconnect from the real world. However, due to the lack of a standardized notification management system and minimal context awareness in VR, an immersed user may face certain situations such as missing an important phone call (digital scenario), tripping over wandering pets (physical scenario), or losing track of time (temporal scenario). In this paper, we present the results of 1) a survey across 61 VR users to understand common interruptions and scenarios that would benefit from some form of notifications; 2) a design exercise with VR professionals to explore possible notification methods; and 3) an empirical study on the noticeability and perception of 5 different VR interruption scenarios across 6 modality combinations (e.g., audio, visual, haptic, audio + haptic, visual + haptic, and audio + visual) implemented in Unity and presented using the HTC Vive headset. Finally, we combine key learnings from each of these steps along with participant feedback to present a set of observations and recommendations for notification design in VR.

Treatment of head and neck cancer (HNC) is accompanied by a high rate of morbidity, and complications can have a lifelong, profound impact on both patients and caregivers. Radiation-related injury to the hard and soft tissue of the head and neck can significantly decrease patients' quality of life. The purpose of this study is to provide patent-specific guidelines for managing the oral health and related side effects of HNC patients treated with radiation therapy. Based on reviewed articles retrieved on the PubMed database, guidelines for management of the oral health of this patient population were organized into three separate categories: cancer, patient, and dentition. The location, type, and staging of the cancer, along with the radiation used to treat the cancer significantly impact dental treatment. Several unique patient characteristics such as motivation, presence of support system, socioeconomic status, nutrition, and race have all been found to affect outcomes. Dental disease and available supportive dental management was found to significantly impact treatment and quality of life in this patient population. By comprehensively assessing unique cancer, patient, and dental-related factors, this review provides individualized evidence-based guidelines on the proper management of this complex and vulnerable patient population., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Subcutaneous emphysema is a rare possible complication of dental procedures. The majority of the dental literature describes cases of localized areas of subcutaneous emphysema following various dental procedures, with a large number of these cases seen following intraoral surgical procedures. Classically, subcutaneous emphysema occurs within minutes to hours after conclusion of dental procedures and is commonly misdiagnosed as either an allergic reaction or acute post-operative swelling. This case report describes a four-year-old male who underwent dental rehabilitation for routine restorative dentistry without extractions under general anesthesia. He subsequently developed extensive subcutaneous emphysema involving the right periorbital region, cervicofacial spaces, and caudal extension to include the superior aspect of the mediastinum. The purpose of this report was to provide a brief review of the prior literature on the subject, report on the case, and review the management for patients with subcutaneous emphysema.

Introduction: Pierre Robin sequence (PRS) is a rare disorder classically observed as a triad of features including micrognathia, glossoptosis, and upper airway obstruction. It is associated with a syndrome in about 60% of cases. While odontogenic tumors are common findings in patients with familial adenomatous polyposis and nevoid basal cell carcinoma syndromes, PRS has not been found to be consistently associated with any tumors of the jaw., Case Report: The current report aims to describe a patient with PRS who presented with an extensive ameloblastic fibro-odontoma (AFO) of the maxilla., Conclusion: Continued observation for odontogenic tumors in PRS is necessary.

Background: Recent WHO guidelines identify virologic monitoring for diagnosing and confirming ART failure. In view of this, validation and scale up of point of care viral load technologies is essential in resource limited settings., Methods: A systematic validation of the GeneXpert® HIV-1 Quant assay (a point-of-care technology) in view of scaling up HIV-1 viral load in India to monitor the success of national ART programme was carried out. Two hundred nineteen plasma specimens falling in nine viral load ranges (<40 to >5 L copies/ml) were tested by the Abbott m2000rt Real Time and GeneXpert HIV-1 Quant assays. Additionally, 20 seronegative; 16 stored specimens and 10 spiked controls were also tested. Statistical analysis was done using Stata/IC and sensitivity, specificity, PPV, NPV and %misclassification rates were calculated as per DHSs/AISs, WHO, NACO cut-offs for virological failure., Results: The GeneXpert assay compared well with the Abbott assay with a higher sensitivity (97%), specificity (97-100%) and concordance (91.32%). The correlation between two assays (r = 0.886) was statistically significant (p < 0.01), the linear regression showed a moderate fit (R 2  = 0.784) and differences were within limits of agreement. Reproducibility showed an average variation of 4.15 and 3.52% while Lower limit of detection (LLD) and Upper limit of detection (ULD) were 42 and 1,740,000 copies/ml respectively. The misclassification rates for three viral load cut offs were not statistically different (p = 0.736). All seronegative samples were negative and viral loads of the stored samples showed a good fit (R 2  = 0.896 to 0.982)., Conclusion: The viral load results of GeneXpert HIV-1 Quant assay compared well with Abbott HIV-1 m2000 Real Time PCR; suggesting its use as a Point of care assay for viral load estimation in resource limited settings. Its ease of performance and rapidity will aid in timely diagnosis of ART failures, integrated HIV-TB management and will facilitate the UNAIDS 90-90-90 target.