Expression of Aberrant MicroRNAs and p16INK4a Associated with HPV (6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 52, 53, and 56) in Oral Dysplasia and Squamous Cell Carcinoma: A Retrospective Study.

OBJECTIVE: A few studies indicate that human papillomavirus (HPV) induces aberrant expression of microRNAs (miRNAs) and correlate this with p16INK4a in oral dysplasia (OD) and oral squamous cell carcinoma (OSCC). Therefore, this study aimed to evaluate the expression of miRNA-21, miRNA-22, and miRNA-224 by q-PCR and the p16 INK4a by immunohistochemical (IHC) as markers for HPV-positive OSCC and OD in comparison to controls as miRNA expression can be altered by the HPV oncogenes and hence can be used as a biomarker for HPV positive cases. MATERIAL AND METHODS: Fifty-two specimens were collected from archived paraffin blocks for patients aged between 19 and 88 (31 males and 21 females) from various oral sites. They were examined by IHC using p16 INK4a, by RT-PCR for the detection of HPV (6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 52, 53, 56), and by q-PCR for the expression of miRNA-21, miRNA-22, and miRNA-224 in positive specimens. RESULTS: Out of the 15 OD, three were positive by both techniques. Meanwhile, 17 out of all OSCC specimens showed intense nuclear and cytoplasmic staining by p16 INK4a, and only 16 were also positive by RT-PCR. However, all control specimens were negative. MiRNA-21, miRNA-22, and miRNA-224 were overexpressed in 3 specimens of OD and 16 of OSCC. CONCLUSION: MiRNA-21, miRNA-22, and miRNA-224, besides p16 INK4a, could be used as indicators for HPV-associated OD and OSCC as their expression is attributed to the HPV oncoprotein. Further studies using follow-up data should be done to correlate it with miRNA overexpression.

Fracture Risk Among Living Kidney Donors 25 Years After Donation.

Importance: Living kidney donors may have an increased risk of fractures due to reductions in kidney mass, lower concentrations of serum 1,25-dihydroxyvitamin D, and secondary increases in serum parathyroid hormone. Objective: To compare the overall and site-specific risk of fractures among living kidney donors with strictly matched controls from the general population who would have been eligible to donate a kidney but did not do so. Design, Setting, and Participants: This survey study was conducted between December 1, 2021, and July 31, 2023. A total of 5065 living kidney donors from 3 large transplant centers in Minnesota were invited to complete a survey about their bone health and history of fractures, and 16 156 population-based nondonor controls without a history of comorbidities that would have precluded kidney donation were identified from the Rochester Epidemiology Project and completed the same survey. A total of 2132 living kidney donors and 2014 nondonor controls responded to the survey. Statistical analyses were performed from May to August 2023. Exposure: Living kidney donation. Main Outcomes and Measures: The rates of overall and site-specific fractures were compared between living kidney donors and controls using standardized incidence ratios (SIRs). Results: At the time of survey, the 2132 living kidney donors had a mean (SD) age of 67.1 (8.9) years and included 1245 women (58.4%), and the 2014 controls had a mean (SD) age of 68.6 (7.9) years and included 1140 women (56.6%). The mean (SD) time between donation or index date and survey date was 24.2 (10.4) years for donors and 27.6 (10.7) years for controls. The overall rate of fractures among living kidney donors was significantly lower than among controls (SIR, 0.89; 95% CI, 0.81-0.97). However, there were significantly more vertebral fractures among living kidney donors than among controls (SIR, 1.42; 95% CI, 1.05-1.83). Conclusions and Relevance: This survey study found a reduced rate of overall fractures but an excess of vertebral fractures among living kidney donors compared with controls after a mean follow-up of 25 years. Treatment of excess vertebral fractures with dietary supplements such as vitamin D3 may reduce the numbers of vertebral fractures and patient morbidity.

Mayo Clinic Consensus Report on Membranous Nephropathy: Proposal for a Novel Classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Ameloblastic fibro-dentinoma: a rare mixed odontogenic tumor case report with review of literature.

BACKGROUND: Ameloblastic fibro-dentinoma is considered a rare, benign, mixed odontogenic tumor that occurs mainly in the posterior mandible in the 1st-2nd decade of life. Although the clinical behavior of Ameloblastic fibro-dentinoma is similar to that of ameloblastic fibroma, there is a debate about whether Ameloblastic fibro-dentinoma is a developing hamartomatous odontoma or a separate neoplastic odontogenic tumor like ameloblastic fibroma. However, it is important to understand the histopathogenesis of this rare tumor. CASE PRESENTATION: A case report presenting an 11-year-old male child with a swelling in the posterior mandible. Radiographic examination revealed a multilocular lesion with mixed radiodensity related to the impacted lower left second premolar tooth. Incisional biopsy was done, and microscopic examination revealed cords and nests of odontogenic follicles lined by ameloblast-like cells and central stellate reticulum-like cells in the primitive ecto-mesenchymal stroma with areas of dentinoid material and osteodentin. The diagnosis was ameloblastic fibro-dentinoma. Surgical excision of the lesion was done, and the patient was followed up for 1 year without evidence of recurrence. CONCLUSION: Reporting such a rare entity clarifies the debate about its nature and the importance of early diagnosis of lesions that are associated with unerupted teeth showing how it is effective in early management and prognosis.

Mandibular small cell osteosarcoma: a case report and review of literature.

BACKGROUND: Small cell osteosarcoma is an extremely rare histopathological variant of conventional osteosarcoma. Due to nonspecific symptoms, most osteosarcomas of the jaws are misdiagnosed as periapical abscesses and mistreated by teeth extraction and drainage. CASE PRESENTATION: We report, to our knowledge, the seventh case of small cell osteosarcoma in gnathic sites affecting the mandible of an old female with history of a large painful swelling related to the right mandibular molar area for 2 months. Cone-beam computed tomography scan showed an osteolytic lesion related to the lower molar area with involvement of the inferior alveolar nerve. An incisional biopsy was taken, and after histopathological examination and immunohistochemical staining, a diagnosis of small cell osteosarcoma was reached. Hemi-mandibulectomy was performed by a maxillofacial surgeon. No clinical evidence for recurrence was noted until manuscript writing. CONCLUSION: Accurate diagnosis is very important, and general practitioners should be aware of this entity considering that small cell osteosarcoma has a poor prognosis when compared to conventional osteosarcoma.

A randomized controlled trial of preemptive rituximab to prevent recurrent focal segmental glomerulosclerosis post-kidney transplant (PRI-VENT FSGS): protocol and study design.

Background: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease requiring kidney transplantation and can recur in the allograft in 30-80% of recipients resulting in reduced graft survival. Plasmapheresis has shown efficacy in treating some cases of recurrent FSGS but isolated plasmapheresis has not demonstrated efficacy in preventing recurrent FSGS. Rituximab has had anecdotal success in preventing recurrence in a single center study but has not been studied in combination with plasmapheresis for preventing FSGS recurrence. Methods: We are conducting a randomized, controlled, multicenter clinical trial of adult and pediatric kidney transplant recipients with primary FSGS to assess whether plasmapheresis in combination with rituximab prevents recurrent disease post-transplantation. Discussion: Rituximab combined with plasmapheresis is a promising, novel therapy to prevent recurrent FSGS, a disease with limited therapeutic options and no consensus guidelines for prevention or treatment. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03763643, identifier NCT03763643.

A Single-Center Retrospective Evaluation of Decision-Making and Factors Motivating Hand Transplant Candidates.

INTRODUCTION: Advancements in vascularized composite allotransplantation have made hand transplants possible for persons living with upper limb loss. Hand transplantation is not a life-saving procedure, but rather a quality-of-life enhancing procedure; hence the risk of morbidity and mortality must be weighed against improvements in function and appearance. This study explored the decision-making process of patients evaluated for hand transplantation. METHODS/APPROACH: A qualitative case series study using retrospective chart data of evaluations was conducted between January 1, 2011 and February 28, 2020. Notes were extracted and read by three reviewers. Each case was summarized noting similarities and differences. FINDINGS: Nine patients underwent evaluation. Eight were no longer under evaluation and did not receive transplant; one was still undergoing evaluation. Patient motivations for evaluation were dissatisfaction with prostheses or self-image, chronic pain, performing activities of daily living, occupation, burden placed on caregivers, and concerns about overuse of non-affected limbs. Patients chose not to pursue transplantation due to rehabilitation time, immunosuppression, alternative treatments, and social and financial challenges. The clinical team discontinued evaluations due to unmet evaluation requirements, medical contraindications, or treatment alternatives. Different modes of shared decision-making were present depending on the party most heavily featured in the charts as driving decisions. DISCUSSION: This was an examination of shared decision-making with hand transplant candidates who did not proceed to transplant. Reasons for choosing alternative strategies for management were multifactorial. Lessons learned regarding patient motivations and shared decision-making can inform future interventions to better support patients.

Maximizing Solid Organ and Face Transplant Procurement Team Coordination: The Posterior Tibial Artery Flap as an Ideal Sentinel Flap.

Face transplantation became a reality with the first case performed in 2005. Facial tissue allograft procurement is technically complex and time-intensive. Brain-dead deceased donors are frequently, if not always, multiorgan donors. Every effort should be made during face allograft recovery to minimize any risk to the recovery of lifesaving solid organs. Some programs require the procurement of a myofascial vascularized skin graft to function as a sentinel flap allowing frequent monitoring for rejection without negatively impacting the esthetics of the face graft. Up till now, the flap used has been the radial forearm flap. Procuring the radial forearm flap places the procuring team in close proximity to the head and torso, where the face recovery and the solid organ recovery teams would require unhindered access. Here, we present the posterior tibial artery flap as an alternative flap that would provide benefits to the coordination of the multiple teams working to procure organs from a deceased donor.

Physiological Age by Artificial Intelligence-Enhanced Electrocardiograms as a Novel Risk Factor of Mortality in Kidney Transplant Candidates.

BACKGROUND: Mortality risk assessment before kidney transplantation (KT) is imperfect. An emerging risk factor for death in nontransplant populations is physiological age as determined by the application of artificial intelligence to the electrocardiogram (ECG). The aim of this study was to examine the relationship between ECG age and KT waitlist mortality. METHODS: We applied a previously developed convolutional neural network to the ECGs of KT candidates evaluated 2014 to 2019 to determine ECG age. We used a Cox proportional hazard model to examine whether ECG age was associated with waitlist mortality. RESULTS: Of the 2183 patients evaluated, 59.1% were male, 81.4% were white, and 11.4% died during follow-up. Mean ECG age was 59.0 ± 12.0 y and mean chronological age at ECG was 53.3 ± 13.6 y. After adjusting for chronological age, comorbidities, and other characteristics associated with mortality, each increase in ECG age of >10 y than the average ECG age for patients of a similar chronological age was associated with an increase in mortality risk (hazard ratio 3.59 per 10-y increase; 95% confidence interval, 2.06-5.72; P < 0.0001). CONCLUSIONS: ECG age is a risk factor for KT waitlist mortality. Determining ECG age through artificial intelligence may help guide risk-benefit assessment when evaluating candidates for KT.

Early post-transplant recurrence of ANCA vasculitis while on belatacept maintenance immunosuppression.

Post-transplant recurrence of ANCA-associated vasculitis (AAV) is infrequent, with recurrence within weeks of transplantation being even rarer. We describe an unusual case of AAV recurrence within 2 weeks post-transplant. Our patient received a deceased donor kidney transplant (KDPI 60%) after 6 years on hemodialysis for end-stage renal disease from AAV. She was induced with thymoglobulin and steroids, and maintained on belatacept, mycophenolate and prednisone. Time-zero biopsy showed acute tubular injury. Due to persistent delayed graft function by post-operative day 14, she underwent repeat biopsy, which showed focal segmental necrotizing and crescentic glomerulonephritis, with positive MPO, PR3 and negative anti-glomerular basement membrane antibodies. As her findings were in keeping with recurrent AAV, she underwent induction with rituximab, prednisone and intravenous immunoglobulin, with repeat rituximab 14 days later because of increasing B-lymphocyte counts. Belatacept was replaced with tacrolimus due to concerns with autoimmunity. Fortunately, renal function began to recover 4 days after treatment. In addition to highlighting potential immunologic mechanisms in AAV and the use of rituximab in post-transplant recurrence, our case suggests that for systemic autoimmune disease, patients maintained on belatacept must be monitored closely for recurrence, particularly in the setting of delayed graft function.

Incorporation of Genetic Studies in the Kidney Transplant Evaluation Clinic: The Value of a Multidisciplinary Approach.

BACKGROUND: Recent studies identified underlying genetic causes in a proportion of patients with various forms of kidney disease. In particular, genetic testing reclassified some focal segmental glomerulosclerosis (FSGS) cases into collagen type 4 (COL4)-related nephropathy. This knowledge has major implications for counseling prospective transplant recipients about recurrence risk and screening biologically related donors. We describe our experience incorporating genetic testing in our kidney transplant multidisciplinary practice. METHODS: Patients' DNA was analyzed using whole exome sequencing for a comprehensive kidney gene panel encompassing 344 genes associated with kidney diseases and candidate genes highly expressed in the kidney. Results were correlated with phenotype by a multidisciplinary committee of nephrologists, renal pathologists, geneticists, and genetic counselors. Between October 2018 and July 2020, 30 recipient and 5 donor candidates completed testing. RESULTS: Among recipient candidates, 24 (80%) carried the diagnosis of FSGS, 2 (6.7%) tubulointerstitial nephritis, and 1 (3.3%) nephrolithiasis, and 3 (10%) had an unknown cause of kidney disease. The yield for pathogenic/likely pathogenic variants was 43.3%, with majority being COL4 variants (53.8%). Among those with FSGS diagnosis, the yield was 10 of 24 (41.6%), with 29% reclassified into a COL4-related nephropathy. Family history of kidney disease was the only clinical characteristic difference between recipients with positive and negative results (76.9 versus 29.4%; P = 0.025). One of 5 donors tested positive for a pathogenic/likely pathogenic variant and was excluded from donation. CONCLUSIONS: We conclude that thoughtful use of genetic testing can be valuable for kidney donor selection and transplant recipient management.

Virtual Surgical Planning and 3D-Printed Surgical Guides in Facial Allotransplantation.

The complex three-dimensional (3D) anatomy in facial allotransplantation creates a unique challenge for surgical reconstruction. Evolution of virtual surgical planning (VSP) through computer-aided design and computer-aided manufacturing has advanced reconstructive outcomes for many craniomaxillofacial indications. Surgeons use VSP, 3D models, and surgical guides to analyze and to trial surgical approaches even prior to entering the operating room. This workflow allows the surgeon to plan osteotomies and to anticipate challenges, which improves surgical precision and accuracy, optimizes outcomes, and should reduce operating room time. We present the development, evolution, and utilization of VSP and 3D-printed guides in facial allotransplantation at our institution, from guide conception to first clinical case.

Education for patients with limb loss or absence: Aging, overuse concerns, and patient treatment knowledge gaps.

The goals of vascular composite allotransplantation (VCA) for hand are to maximize functional status and psychosocial wellbeing and to improve quality of life. Candidates are carefully vetted by transplant programs through an extensive evaluation process to exclude those patients with contraindications and to select those that are most likely to attain functional or quality of life benefit from transplant. Patient choice for any treatment, however, requires that candidates be able to understand the risks, benefits, and alternatives before choosing to proceed. This study aimed to understand patients' knowledge and perceptions about treatment options for hand loss, including hand transplant. This study will be used to inform a standardized education approach and develop conversation aids for use by clinicians and patients throughout the treatment decision process. Ten individuals who had experienced hand amputation or had congenital limb loss were interviewed to better understand previous and current decisions about treatment, experiences in adjusting to their treatment, and perceptions about hand VCA. From this qualitative interview data, four findings emerged: (1) knowledge and education around VCA as a treatment option; (2) adaptation of individuals with limb loss; (3) fear of risk associated with transplantation; (4) issues of aging and overuse injuries to existing limbs. Results suggests that there is opportunity for expanding education about all treatment options for patients with new loss, long-term loss, and congenital limb loss. Establishing a baseline of knowledge about all options-prosthetics, rehabilitative strategies, and VCA-can help patients evaluate their values and goals of treatment. Issues associated with aging, including overuse and injury, and adaptability over the life course should be included in considerations about treatment choices. Data indicate the need for routinely assessing patient preferences about treatment choice so patients can plan for their future as they adapt and age and as technology for treatments change. To assure that thorough information is provided for current and future decision-making, education about treatment choices and selection procedures for VCA should be standardized.

Using team science in vascularized composite allotransplantation to improve team and patient outcomes.

Reconstructive allografts using Vascularized Composite Allotransplantation (VCA) are providing individuals living with upper limb loss and facial disfigurement with new opportunities for a sensate, esthetically acceptable, and functional alternative to current treatment strategies. Important research attention is being paid to how best to assess and screen candidates for VCA, measure optimal patient outcomes, and support patient adherence to lifelong behaviors and medical regimens. Far less attention, however, has been dedicated to the team science required for these complex VCA teams to form, prepare, and provide the highest quality clinical and psychosocial care to those receiving VCA. VCA teams are unique in that they require specialized team members whose scope of practice may not otherwise overlap. The team also needs to constantly negotiate balancing patient safety with multiple risks throughout the transplant process. This study aimed to elucidate the team science needed for this highly innovative and complex area of medicine. Using in-depth qualitative interviews with 14 VCA team members and observations at team meetings, we found that careful consideration of team composition, team structure, and organizational commitment (e.g., local culture and team values; investment of resources) influences team performance and patient outcomes, but that to be efficient and truly effective, teams need to commit to developing processes that foster collaboration. These processes are action-oriented (e.g., communication, leadership), strategic (e.g., planning, training) and interpersonal (e.g., conflict management, trust building). Dedication and commitment to team science allows teams to manage conflict under stress and exercise ways to leverage strengths to provide optimal performance or patient psychosocial and clinical outcomes. This study can provide insight into quality improvement efforts for VCA teams and guidance for other transplant programs that wish to consider expansion into VCA.

Guiding Kidney Transplantation Candidates for Effective Weight Loss: A Clinical Cohort Study.

Background: Obesity is increasingly common in kidney transplant candidates and may limit access to transplantation. Obesity and diabetes are associated with a high risk for post-transplant complications. The best approach to weight loss to facilitate active transplant listing is unknown, but bariatric surgery is rarely considered due to patient- and physician-related apprehension, among other factors. Methods: We aimed to determine the magnitude of weight loss, listing, and transplant rates in 28 candidates with a mean BMI of 44.4±4.6 kg/m2 and diabetes treated conservatively for 1 year post weight-loss consultations (group 1). Additionally, we evaluated 15 patients (group 2) who met the inclusion criteria but received bariatric intervention within the same time frame. All patients completed a multidisciplinary weight management consultation with at least 1 year of follow-up. Results: In the conservatively managed group (group 1), the mean weight at the time of initial consultation was 126.5±18.5 kg, and the mean BMI was 44.4±4.6 kg/m2. At 1 year post weight-loss consultation, the mean weight decreased by 4.4±8.2 kg to 122.9±17 kg, and the mean BMI was 43±4.8 kg/m2, with a total mean body weight decrease of 3% (P=0.01). Eighteen patients (64%) did not progress to become candidates for active listing/transplantation during the follow-up time of 4±2.9 years, with 15 (54%) subsequently developing renal failure/diabetes-related comorbidities prohibitive for transplantation. In contrast, mean total body weight decreased by 19% at 6 months post bariatric surgery, and the mean BMI was 34.2±4 and 32.5±3.7 kg/m2 at 6 and 12 months, respectively. Bariatric surgery was strongly associated with subsequent kidney transplantation (HR=8.39 [95% CI 1.71 to 41.19]; P=0.009). Conclusions: A conservative weight-loss approach involving multidisciplinary consultation was ineffective in most kidney transplant candidates with diabetes, suggesting that a more proactive approach is needed.

Post-COVID-19 related osteonecrosis of the jaw (PC-RONJ): an alarming morbidity in COVID-19 surviving patients.

PURPOSE: The recent coronavirus disease (COVID-19) pandemic mainly affects the respiratory system; however, several oral and maxillofacial post-COVID-19 complications have also been observed. This series reports the growing number of osteonecrosis cases associated with post-COVID-19 patients. MATERIALS AND METHODS: This is a retrospective, multi-center case series that reports cases with maxillary osteonecrosis after various periods of SARS-CoV-2 infection in the period between January and August 2021 based on the PROCESS guidelines. RESULTS: Twelve cases were reported with post-COVID-19 manifestation of spontaneous osteonecrosis of the maxillary jaw. Five patients were hospitalized during COVID-19 management and all of the twelve cases had at least one systematic Co-morbidity, and undertake corticosteroids prescription based on the COVID-19 disease treatment protocol. The mean onset of osteonecrosis symptoms appearance was 5.5 ± 2.43 weeks calculated from the day of the negative PCR test. The management was successfully done through surgical debridement and pre and post-operative antibiotics. No anti-fungal medications were prescribed as the fungal culture and the histopathological report were negative. CONCLUSION: Post-COVID-related osteonecrosis of the jaw (PC-RONJ) could be now considered as one of the potential post-COVID-19 oral and maxillofacial complications that occurs unprovokedly and mainly in the maxilla.