Pityriasiform drug eruption associated with venetoclax for acute myeloid leukaemia.

Venetoclax is a targeted antileukaemic therapy that has emerged as the primary treatment of acute myeloid leukaemia in patients of advanced age or who would otherwise be ineligible for standard chemotherapy. Despite the documented evidence of cutaneous side effects of venetoclax, few reports have clarified presenting cutaneous features beyond the descriptors 'rash' and 'pruritus'. In this report, we describe the development of a pityriasiform drug eruption following venetoclax-based induction therapy for acute myeloid leukaemia. This study provides further evidence to characterise the range of cutaneous adverse events that are associated with venetoclax-based therapy. Further studies are needed to elucidate the epidemiology and pathophysiology of venetoclax-induced cutaneous toxicities.

Impact of dental state and surgical factors on postoperative neck infection in oral cancer patients.

Postoperative neck infection (PONI) is a known complication of neck dissection. In this study we explored the impact of dental status on the development of PONI, using orthopantomograms to assess edentulism, periodontal health, and caries status. Retrospective analysis was performed for all new oral cancer patients who had neck dissection between January 2008 and January 2020 in a tertiary head and neck centre. PONI risk factors assessed included patient characteristics, dental status, tumour, and surgical factors. Development of PONI was the primary outcome. Edentulous patients had lower risk of PONI (OR 0.06, p = 0.026) compared to those with 21 or more teeth. Periodontitis and dental caries were not statistically significant. Current smokers (OR 2.09, p = 0.044) and free flap reconstruction (OR 5.41, p < 0.001) were also significant predictors for development of PONI. This study highlights the presence of teeth as a potential source of infection post neck dissection and that orthopantomogram assessment may be inadequate to identify at risk patients. Future studies are required on direct clinical assessment of dentition to evaluate the impact of dental optimisation in prevention of PONI.

Cataloging formal medical student surgical funding opportunities: A retrospective characterization.

Representation of female surgical residents has slowly increased, but underrepresented in medicine (URiM) representation remains disappointingly low. National residency matching reports suggest that meaningful research experience improves surgical residency match success - therefore, formal funding opportunities and early mentorship for URiM medical students. In this study, we catalog medical student (MS) funding opportunities (funding type, eligibility by year, mission, compensation, length of commitment, number of awardees, and dollar investment amount per student) from 7 surgical departments (general surgery, thoracic surgery, vascular surgery, plastic surgery, otorhinolaryngology, orthopedic surgery, neurosurgery) within 196 US medical schools and 20 professional surgical educational organizations through manually searching web pages. We recorded 146 surgical funding opportunities from medical school surgical departments and 16 surgical funding opportunities from professional organizations. Overall, we find that medical institutions' surgical departments and professional surgical educational organizations may not be effectively utilizing recruitment strategies in MS funding opportunities.

Bisphosphonate conjugation enhances the bone-specificity of NELL-1-based systemic therapy for spaceflight-induced bone loss in mice.

Microgravity-induced bone loss results in a 1% bone mineral density loss monthly and can be a mission critical factor in long-duration spaceflight. Biomolecular therapies with dual osteogenic and anti-resorptive functions are promising for treating extreme osteoporosis. We previously confirmed that NELL-like molecule-1 (NELL-1) is crucial for bone density maintenance. We further PEGylated NELL-1 (NELL-polyethylene glycol, or NELL-PEG) to increase systemic delivery half-life from 5.5 to 15.5 h. In this study, we used a bio-inert bisphosphonate (BP) moiety to chemically engineer NELL-PEG into BP-NELL-PEG and specifically target bone tissues. We found conjugation with BP improved hydroxyapatite (HA) binding and protein stability of NELL-PEG while preserving NELL-1's osteogenicity in vitro. Furthermore, BP-NELL-PEG showed superior in vivo bone specificity without observable pathology in liver, spleen, lungs, brain, heart, muscles, or ovaries of mice. Finally, we tested BP-NELL-PEG through spaceflight exposure onboard the International Space Station (ISS) at maximal animal capacity (n = 40) in a long-term (9 week) osteoporosis therapeutic study and found that BP-NELL-PEG significantly increased bone formation in flight and ground control mice without obvious adverse health effects. Our results highlight BP-NELL-PEG as a promising therapeutic to mitigate extreme bone loss from long-duration microgravity exposure and musculoskeletal degeneration on Earth, especially when resistance training is not possible due to incapacity (e.g., bone fracture, stroke).

Prediction nomogram development and validation for postoperative radiotherapy in the management of oral squamous cell carcinoma.

BACKGROUND: Predictive nomograms are useful tools to guide clinicians in estimating disease course. Oral squamous cell carcinoma (OSCC) patients would benefit from an interactive prediction calculator that defines their levels of survival-risk specific to their tumors to guide the use of postoperative radiotherapy (PORT). METHODS: Patients with OSCC surgically treated with curative intent at four Head and Neck Cancer Centres were recruited retrospectively for development and validation of nomograms. Predictor variables include PORT, age, T and N classification, surgical margins, perineural invasion, and lymphovascular invasion. Outcomes were disease-free, disease-specific, and overall survivals over 5 years. RESULTS: 1296 patients with OSCC were in training cohort for nomogram analysis. Algorithms were developed to show relative benefit of PORT in survivals for higher-risk patients. External validation on 1212 patients found the nomogram to be robust with favorable discrimination and calibration. CONCLUSION: The proposed calculator can assist clinicians and patients in the decision-making process for PORT.

Novel Strategies for Orofacial Soft Tissue Regeneration.

Significance: Orofacial structures are indispensable for speech and eating, and impairment disrupts whole-body health through malnutrition and poor quality of life. However, due to the unique and highly specialized cell populations, tissue architecture, and healing microenvironments, regeneration in this region is challenging and inadequately addressed to date. Recent Advances: With increasing understanding of the nuanced physiology and cellular responses of orofacial soft tissue, novel scaffolds, seeded cells, and bioactive molecules were developed in the past 5 years to specifically target orofacial soft tissue regeneration, particularly for tissues primarily found within the orofacial region such as oral mucosa, taste buds, salivary glands, and masseter muscles. Critical Issues: Due to the tightly packed and complex anatomy, orofacial soft tissue injury commonly implicates multiple tissue types, and thus functional unit reconstruction in the orofacial region is more important than single tissue regeneration. Future Directions: This article reviews the up-to-date knowledge in this highly translational topic, which provides insights into novel biologically inspired and engineered strategies for regenerating orofacial component tissues and functional units.

Cytokine/Chemokine assessment as a complementary diagnostic tool for inflammatory skin diseases.

Inflammatory skin conditions are the 4th leading cause of non-fatal health burden in the general population worldwide. The diagnosis of skin lesions due to systemic drug reactions, viral or bacterial exanthems, or in patients with psoriasis, atopic dermatitis or contact dermatitis is often difficult and relies heavily upon conventional histopathologic examination. Conversely, it is widely accepted that the cutaneous profile of inflammatory markers, or 'inflammatory signature', is differentially expressed in various skin conditions. In this pilot study, we investigated the possibility of inflammatory skin disease diagnosis from an immunological perspective in small punch biopsies. We collected lesional and perilesional punch biopsies from 139 patients suffering from a variety of inflammatory skin conditions and attending the Dermatology Department at the Princess Alexandra Hospital in Brisbane, Australia. Using bead-based immunoassays we were able to measure 13 out of 17 inflammatory markers from a pre-selected multi-analyte panel and to detect significant differences between lesional and perilesional biopsies from each individual patient. Hierarchical and unbiased clustering methods based on inflammatory signatures grouped psoriasis and atopic dermatitis lesions into individual clusters in contrast to other skin conditions, highlighting the potential of inflammatory signatures to be used as diagnostic differentiators and to inform alternative targets in anti-inflammatory treatment strategies.

Virtual Reality-Augmented Physiotherapy for Chronic Pain in Youth: Protocol for a Randomized Controlled Trial Enhanced With a Single-Case Experimental Design.

BACKGROUND: Chronic musculoskeletal (MSK) pain is a prominent health concern, resulting in pain-related disability, loss of functioning, and high health care costs. Physiotherapy rehabilitation is a gold-standard treatment for improving functioning in youth with chronic MSK pain. However, increasing physical activity can feel unattainable for many adolescents because of pain-related fear and movement avoidance. Virtual reality (VR) offers an immersive experience that can interrupt the fear-avoidance cycle and improve engagement in physiotherapy. Despite promising initial findings, data are limited and often lack the rigor required to establish VR as an evidence-based treatment for MSK pain. OBJECTIVE: This trial evaluates physiorehabilitation with VR in adolescents with MSK pain. This protocol outlines the rationale, design, and implementation of a randomized controlled trial enhanced with a single-case experimental design. METHODS: This study is a 2-group randomized controlled trial assessing the use of physiorehabilitation with VR in adolescents with MSK pain. The authors will collaborate with physical therapists to integrate VR into their standard clinical care. For participants enrolled in standard physiotherapy, there will be no VR integrated into their physical therapy program. Primary outcomes include physical function and engagement in VR. Secondary outcomes include pain-related fear and treatment adherence. Moreover, we will obtain clinician perspectives regarding the feasibility of integrating the intervention into the flow of clinical practice. RESULTS: The pilot study implementing physiorehabilitation with VR demonstrated that high engagement and use of physiorehabilitation with VR were associated with improvements in pain, fear, avoidance, and function. Coupled with qualitative feedback from patients, families, and clinicians, the pilot study results provide support for this trial to evaluate physiorehabilitation with VR for youth with chronic MSK pain. Analysis of results from the main clinical trial will begin as recruitment progresses, and results are expected in early 2024. CONCLUSIONS: Significant breakthroughs for treating MSK pain require mechanistically informed innovative approaches. Physiorehabilitation with VR provides exposure to progressive challenges, real-time feedback, and reinforcement for movement and can include activities that are difficult to achieve in the real world. It has the added benefit of sustaining patient motivation and adherence while enabling clinicians to use objective benchmarks to influence progression. These findings will inform the decision of whether to proceed with a hybrid effectiveness-dissemination trial of physiorehabilitation with VR, serving as the basis for potential large-scale implementation of physiorehabilitation with VR. TRIAL REGISTRATION: ClinicalTrials.gov NCT04636177; https://clinicaltrials.gov/ct2/show/NCT04636177. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40705.

Updates on mesenchymal stem cell therapies for articular cartilage regeneration in large animal models.

There is an unmet need for novel and efficacious therapeutics for regenerating injured articular cartilage in progressive osteoarthritis (OA) and/or trauma. Mesenchymal stem cells (MSCs) are particularly promising for their chondrogenic differentiation, local healing environment modulation, and tissue- and organism-specific activity; however, despite early in vivo success, MSCs require further investigation in highly-translatable models prior to disseminated clinical usage. Large animal models, such as canine, porcine, ruminant, and equine models, are particularly valuable for studying allogenic and xenogenic human MSCs in a human-like osteochondral microenvironment, and thus play a critical role in identifying promising approaches for subsequent clinical investigation. In this mini-review, we focus on [1] considerations for MSC-harnessing studies in each large animal model, [2] source tissues and organisms of MSCs for large animal studies, and [3] tissue engineering strategies for optimizing MSC-based cartilage regeneration in large animal models, with a focus on research published within the last 5 years. We also highlight the dearth of standard assessments and protocols regarding several crucial aspects of MSC-harnessing cartilage regeneration in large animal models, and call for further research to maximize the translatability of future MSC findings.

Human Innate Lymphoid Cells in Influenza Infection and Vaccination.

Influenza is a highly contagious respiratory virus that causes mild to severe respiratory illness, as well as death, and remains a serious threat to human health. Annual vaccination is the most cost-effective way to control influenza; however, the vaccine does not provide protection against emerging strains with epidemic and pandemic potential. Several antivirals have been developed to treat influenza but there is a rapid emergence of antiviral resistant strains. Therefore, there is an urgent need to understand the virus and its interactions with the host immune system so that novel strategies can be developed for prophylactic and therapeutic interventions. Innate lymphoid cells (ILCs), a family of immune cells present in the peripheral circulation and in mucosal tissues, play an important role in regulation of tissue homeostasis, inflammation, and immunity. This review examines the current understanding and therapeutic potential of ILCs during influenza virus infection in humans.

Overcoming Communication Barriers: An evaluation of communication devices for healthcare providers wearing powered air-purifying respirators (PAPRs).

Introduction: The COVID-19 pandemic has resulted in an increased use of Powered Air Purifying Respirators (PAPRs), by health care providers to mitigate the risk of viral transmission, especially for aerosol-generating procedures. In this study, we evaluate communication devices that could be used concurrently with PAPRs to promote improved communication. Methods: We tested two devices, a Bluetooth earpiece and a throat microphone that operated over mobile networks, against a control scenario in a simulated operating room environment with participants donning PAPRs. Participants read a short paragraph to each other, transcribed short phrases, and evaluated the scenarios according to speech intelligibility, ease of use, and comfort. Results: There were 30 participants of varying PAPR experience. The Bluetooth headset had the most accurate transcriptions, followed by control, and lastly the neckpiece (94.7%vs 88.4%vs 76%, p<0.001). Conclusion: Communication devices have the potential to bridge but also worsen communications barriers between providers donning PAPRs.

Survival outcomes following modern multidisciplinary management of oral squamous cell carcinoma in Australia.

OBJECTIVE: Oral squamous cell carcinoma (SCC) has been traditionally described as a highly lethal disease. This study aims to provide updated multi-institutional data on the survival of patients with oral SCC in Australia. STUDY DESIGN: Retrospective survival analysis was performed between 2008 and 2016. All new patients with oral SCC treated with curative intent were recruited from 2 high-volume Australian head and neck oncology centers. Outcomes were measured in overall survival (OS), disease-specific survival (DSS), disease-free survival, and salvage rates for recurrences. RESULTS: Survival analysis included 771 patients with oral SCC. Five-year OS and DSS were 66.1% and 79.7%, respectively. Stage I and II oral SCC had significantly better survival than higher stages. Five-year OS and DSS for patients with stage I SCC were 79.7% and 93.4%, respectively, and for patients with stage IVB they were 37.9% and 54.3%, respectively. Two hundred forty-nine patients had disease recurrence (32.3%), with 66 patients (26.5% remaining disease free post salvage treatment. CONCLUSION: Survival outcomes for oral SCC among Australian patients have improved, possibly due to advances in multidisciplinary care. Early detection of oral SCC leads to highly favorable prognosis; there is therefore an opportunity for routine oral cancer screening to be performed by community health practitioners with the aim of improving survival from oral SCC.

OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages.

BACKGROUND: Hyperamyloidosis in the brain is known as the earliest neuropathological change and a unique etiological factor in Alzheimer's disease (AD), while progressive neurodegeneration in certain vulnerable brain regions forms the basis of clinical syndromes. It is not clear how early hyperamyloidosis is implicated in progressive neurodegeneration and what factors contribute to the selective brain vulnerability in AD. METHODS: Bioinformatics and experimental neurobiology methods were integrated to identify novel factors involved in the hyperamyloidosis-induced brain vulnerability in AD. We first examined neurodegeneration-specific gene signatures from sporadic AD patients and synaptic protein changes in young transgenic AD mice. Then, we systematically assessed the association of a top candidate gene with AD and investigated its mechanistic role in neurodegeneration. FINDINGS: We identified the ovary-orientated protein OCIAD1 (Ovarian-Carcinoma-Immunoreactive-Antigen-Domain-Containing-1) as a neurodegeneration-associated factor for AD. Higher levels of OCIAD1, found in vulnerable brain areas and dystrophic neurites, were correlated with disease severity. Multiple early AD pathological events, particularly Aß/GSK-3ß signaling, elevate OCIAD1, which in turn interacts with BCL-2 to impair mitochondrial function and facilitates mitochondria-associated neuronal injury. Notably, elevated OCIAD1 by Aß increases cell susceptibility to other AD pathological challenges. INTERPRETATION: Our findings suggest that OCIAD1 contributes to neurodegeneration in AD by impairing mitochondria function, and subsequently leading to neuronal vulnerability, and synaptic damages. FUNDING: Ting Tsung & Wei Fong Chao Foundation, John S Dunn Research Foundation, Cure Alzheimer's Fund, and NIH R01AG057635 to STCW.

Treatment for oral squamous cell carcinoma: Impact of surgeon volume on survival.

BACKGROUND: The volume-outcome relationship is a well-known phenomenon in surgical oncology. The aim of this study was to quantify the impact of surgeon volume on the treatment outcome of oral squamous cell carcinoma (OSCC) patients. METHODS: All new OSCC cases treated with curative intent between 2008 and 2013 were included. A heterogeneous set of predictor variables was collected, including patient, tumour and treatment factors. The outcomes of interest were recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS). To investigate the cut-off in surgeon volume, the number of OSCC resections was analysed in multiplies of 5 cases per annum according to DSS, using univariable regression analysis. RESULTS: 534 cases were recruited. Independently, the negative predictors for patient survival were age, perineural invasion, worsening tumour staging, and extracapsular spread. High-volume surgeon was determined to be most significant at 20 cases per annum and significantly associated with improved RFS (HR: 0.67), OS (HR: 0.44), and DSS (HR: 0.39). CONCLUSIONS: Results from this study support the rationalisation of OSCC management at high-volume centres and in the hands of experienced surgeons for better patient survival. Head and neck surgeons should perform a minimum of 20 OSCC cases per year to maintain competency in OSCC ablation.

Physical properties and cytotoxicity of antimicrobial dental resin adhesives containing dimethacrylate oligomers of Ciprofloxacin and Metronidazole.

OBJECTIVE: Antimicrobial oligomers synthesized from ciprofloxacin (CF) and metronidazole (MN) were investigated for their potential use in dental adhesives. METHODS: Susceptibility of the cariogenic bacterium Streptococcus mutans UA159 to CF, MN, and CF/MN combination was evaluated. Hydrolytic stability and drug release from the oligomers was studied in buffer and simulated human salivary esterase conditions. Cytotoxicity of films with 15wt% drug oligomers co-polymerized with commercial monomers were assessed using human gingival fibroblasts (HGFs). In-house adhesives were prepared and characterized for viscosity. Polymerized films were analysed for gel content and water swelling. Interfacial fracture toughness (KIC) of composites bonded to dentin by either a 2 or 3-step etch-and-rinse approach using the in-house formulated adhesives was measured. RESULTS: The respective minimum inhibitory concentration for CF and MN against S. mutans was 0.7 and 2400µg/mL, with the combination having an additive effect (0.35µg/mL CF with 1200µg/mL MN). Antibiotics were released upon hydrolysis of the oligomers. Films containing the drug oligomers were not cytotoxic against HGFs. Replacing 2-hydroxyethyl methacrylate with the drug oligomers increased the viscosity of the experimental adhesives, reduced gel content, and decreased swelling of films in water. Antimicrobial adhesives demonstrated bonding to dentin with interfacial KIC values comparable to the in-house control in the 2-step application, and with slightly lower KIC values in the 3-step approach. SIGNIFICANCE: The antimicrobial oligomers can be incorporated into dental adhesive systems using formulations that show comparable fracture toughness to commercial materials, and may provide a means to deliver local antimicrobial drug release at the marginal interface.

Postoperative Radiotherapy for Oral Squamous Cell Carcinoma With Histologic Risk Factors: Are We Over-Treating?

PURPOSE: The role of postoperative radiotherapy (PORT) remains controversial for patients with low-risk oral squamous cell carcinoma (OSCC) and adverse histologic features. The aim of this study was to examine the survival benefits in the role of PORT, when compared with surgery alone, among these patients. MATERIALS AND METHODS: In this systematic review, relevant published literature was identified in the PubMed database and eligible studies were included. Predictor variables were perineural invasion (PNI), lymphovascular invasion, and unfavorable grade. The primary outcomes were patient survival and recurrence rates. Because of the heterogeneity and insufficiency of the reported data, quantitative meta-analysis was precluded. Qualitative analysis and pooled analysis on overall survival were performed for study patients. RESULTS: Six eligible studies were included, with a median study period of 10 years. All studies evaluated the role of PORT in pN0 OSCC patients with PNI, and 3 studies evaluated the role of PORT in patients with PNI in isolation. Overall, study patients had similar treatment outcomes between the PORT and non-PORT groups. In the pooled analysis of 325 patients, PORT was not associated with an improved overall survival rate compared with surgery alone (70.3% vs 80.2%, P = .059). CONCLUSIONS: No evidence was found to support the application of PORT given the indication of histologic risk factors alone. The prescription of PORT for PNI, lymphovascular invasion, and unfavorable grading among otherwise low-risk OSCC needs to be approached with caution to avoid the unnecessary harm of radiation exposure.

Synthesis and characterization of Ciprofloxacin-containing divinyl oligomers and assessment of their biodegradation in simulated salivary esterase.

OBJECTIVE: Two leading causes contributing to dental restoration replacement are the marginal breakdown at the composite/dentin interface and secondary caries mediated by bacteria. The objective of the present study was to synthesize oligomers which incorporated enhanced bio-stability but would also be able to generate antimicrobial function if they underwent degradation. METHODS: Stability was incorporated into the oligomers by generating structural features that would physically hinder the availability of hydrolytically sensitive groups in the oligomers. As a proof-of concept for the antibacterial feature, antimicrobial function was achieved by covalently incorporating Ciprofloxacin (CF) into the backbone of cross-linking divinyl oligomers (referred to as EDV and HLH-CFPEG). The hydrolytic stability of the oligomers was studied in simulated human salivary esterase and compared to the commercial monomer 2,2-bis[4(2-hydroxy-3-methacryloxypropoxy)-phenyl]propane (BisGMA). RESULTS: Both drug oligomers were found to be significantly more stable than BisGMA. Upon degradation, both drug oligomers released CF differentially in free form. Polymer synthesis from resin formulations containing 15wt% HLH-CFPEG showed a high degree of vinyl group conversion and gel content, and under hydrolytic conditions showed the release of CF during a 28-day monitoring study period. SIGNIFICANCE: HLH-CFPEG can be used in dental resin adhesive systems for local delivery of CF to the marginal interface. Minimizing the growth of Streptococcus mutans at the marginal site can improve longevity by reducing esterase activity derived specifically from S. mutans.