From Chalcogen Bonding to S-π Interactions in Hybrid Perovskite Photovoltaics.

The stability of hybrid organic-inorganic halide perovskite semiconductors remains a significant obstacle to their application in photovoltaics. To this end, the use of low-dimensional (LD) perovskites, which incorporate hydrophobic organic moieties, provides an effective strategy to improve their stability, yet often at the expense of their performance. To address this limitation, supramolecular engineering of noncovalent interactions between organic and inorganic components has shown potential by relying on hydrogen bonding and conventional van der Waals interactions. Here, the capacity to access novel LD perovskite structures that uniquely assemble through unorthodox S-mediated interactions is explored by incorporating benzothiadiazole-based moieties. The formation of S-mediated LD structures is demonstrated, including one-dimensional (1D) and layered two-dimensional (2D) perovskite phases assembled via chalcogen bonding and S-π interactions, through a combination of techniques, such as single crystal and thin film X-ray diffraction, as well as solid-state NMR spectroscopy, complemented by molecular dynamics simulations, density functional theory calculations, and optoelectronic characterization, revealing superior conductivities of S-mediated LD perovskites. The resulting materials are applied in n-i-p and p-i-n perovskite solar cells, demonstrating enhancements in performance and operational stability that reveal a versatile supramolecular strategy in photovoltaics.

Establishment and characterization of cMYB-expressing human salivary adenoid cystic carcinoma cell lines (UM-HACC-14, UM-HACC-6) and matching patient-derived xenograft model (UM-PDX-HACC-14).

OBJECTIVE: Limited availability of authentic human adenoid cystic carcinoma (ACC) cell lines has hindered progress in understanding mechanisms underpinning the biology of this disease and the development of safe and effective therapies. STUDY DESIGN: Surgical human ACC specimens (UM-HACC-6, UM-HACC-14) were dissociated into single cell suspensions and cultured in fibronectin-coated flasks. Alternatively, tumor fragments were transplanted subcutaneously into female immunodeficient (SCID) mice to establish patient-derived xenograft tumors (PDX; UM-PDX-HACC-14). RESULTS: Both ACC cell lines showed continuous growth in monolayers for over 100 passages. Total RNA-Seq, RT-PCR, and FISH analysis revealed that both are MYB-NFIB fusion negative. Western blots revealed passage-dependent expression of E-Cadherin, PCNA, p63, phospho-c-MYB, and NFIB. Both, UM-HACC-14 and UM-HACC-6 cells exhibited tumorigenic potential when injected orthotopically into mouse submandibular glands. CONCLUSION: UM-HACC-14, patient-matching UM-PDX-HACC-14, and the UM-HACC-6 cell line are new, authenticated preclinical models of ACC that are well suited for mechanistic and developmental therapeutics studies.

Genome-wide association studies with experimental validation identify a protective role for B lymphocytes against chronic post-surgical pain.

BACKGROUND: Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood. METHODS: A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types. RESULTS: We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia. CONCLUSIONS: These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.

Evaluation of Postoperative Efficacy and Safety of Celecoxib in Children Hospitalized After Adenotonsillectomy.

OBJECTIVE: The choice of optimal analgesia following an adenotonsillectomy is a clinical issue because of the risk of respiratory depression and bleeding. The objective of this study was to assess the effect of celecoxib on opioid use and pain scores in children hospitalized after adenotonsillectomy and to document its adverse effects. METHODS: This retrospective study was conducted in a tertiary care pediatric hospital. We compared a group of subjects aged 1 to 17 years who were prescribed celecoxib and opioids between January 2017 and June 2020 following an adenotonsillectomy during a 3-day or less hospitalization to a group of matched controls for sex, age, and length of stay who were prescribed opioids. RESULTS: A total of 228 patients were identified (76 in the celecoxib + opioids group, 152 in the control group). Opioid use, in oral morphine equivalent daily dose, was lower in the celecoxib + opioids group at 0 to 24 hours of hospitalization (0.15 vs 0.20 mg/kg/day, p = 0.05). Initiating celecoxib within 24 hours of surgery (n = 60) significantly reduced opioid requirement for up to 48 hours compared with controls (0-24 hours: 0.12 vs 0.20 mg/kg/day, p = 0.002; 25-48 hours: 0.02 vs 0.09 mg/kg/day, p = 0.001). A shorter length of stay was observed for patients receiving celecoxib + opioids during the first 24-hour post--operative period (27 vs 32 hours, p = 0.01). With celecoxib use, no significant change in pain scores and occurrence of adverse effects including bleeding was found. CONCLUSIONS: Using celecoxib early after an adenotonsillectomy has reduced both opioid use and duration of hospital stay without increasing adverse effects or bleeding.

The Women's Health Initiative Randomized Trials and Clinical Practice: A Review.

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years. Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up. Conclusions and Relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Nanotechnology for Pain Management.

Introduction: In the context of the current opioid crisis, non-pharmacologic approaches to pain management have been considered important alternatives to the use of opioids or analgesics. Advancements in nano and quantum technology have led to the development of several nanotransporters, including nanoparticles, micelles, quantum dots, liposomes, nanofibers, and nano-scaffolds. These modes of nanotransporters have led to the development of new drug formulations. In pain medicine, new liposome formulations led to the development of DepoFoam™ introduced by Pacira Pharmaceutical, Inc. (Parsippany, NJ, USA). This formulation is the base of DepoDur™, which comprises a combination of liposomes and extended-release morphine, and Exparel™, which comprises a combination of liposomes and extended-release bupivacaine. In 2021, Heron Therapeutics (San Diego, CA, USA) created Zynrelef™, a mixture of bupivacaine and meloxicam. Advancements in nanotechnology have led to the development of devices/patches containing millions of nanocapacitors. Data suggest that these nanotechnology-based devices/patches reduce acute and chronic pain. Methods: Google and PubMed searches were conducted to identify studies, case reports, and reviews of medical nanotechnology applications with a special focus on acute and chronic pain. This search was based on the use of keywords like nanotechnology, nano and quantum technology, nanoparticles, micelles, quantum dots, liposomes, nanofibers, nano-scaffolds, acute and chronic pain, and analgesics. This review focuses on the role of nanotechnology in acute and chronic pain. Results: (1) Nanotechnology-based transporters. DepoDur™, administered epidurally in 15, 20, or 25 mg single doses, has been demonstrated to produce significant analgesia lasting up to 48 h. Exparel™ is infiltrated at the surgical site at the recommended dose of 106 mg for bunionectomy, 266 mg for hemorrhoidectomy, 133 mg for shoulder surgery, and 266 mg for total knee arthroplasty (TKA). Exparel™ is also approved for peripheral nerve blocks, including interscalene, sciatic at the popliteal fossa, and adductor canal blocks. The injection of Exparel™ is usually preceded by an injection of plain bupivacaine to initiate analgesia before bupivacaine is released in enough quantity from the depofoarm to be pharmacodynamically effective. Finally, Zynrelef™ is applied at the surgical site during closure. It was initially approved for open inguinal hernia, abdominal surgery requiring a small-to-medium incision, foot surgery, and TKA. (2) Nanotechnology-based devices/patches. Two studies support the use of nanocapacitor-based devices/patches for the management of acute and chronic pain. A randomized study conducted on patients undergoing unilateral primary total knee (TKA) and total hip arthroplasty (THA) provided insight into the potential value of nanocapacitor-based technology for the control of postoperative acute pain. The results were based on 2 studies, one observational and one randomized. The observational study was conducted in 128 patients experiencing chronic pain for at least one year. This study suggested that compared to baseline, the application of a nanocapacitor-based Kailo™ pain relief patch on the pain site for 30 days led to a time-dependent decrease in pain and analgesic use and an increase in well-being. The randomized study compared the effects of standard of care treatment to those of the same standard of care approach plus the use of two nanocapacitor-based device/patches (NeuroCuple™ device) placed in the recovery room and kept in place for three days. The study demonstrated that the use of the two NeuroCuple™ devices was associated with a 41% reduction in pain at rest and a 52% decrease in the number of opioid refills requested by patients over the first 30 days after discharge from the hospital. Discussion: For the management of pain, the use of nano-based technology has led to the development of nano transporters, especially focus on the use of liposome and nanocapacitors. The use of liposome led to the development of DepoDur™, bupivacaine Exparel™ and a mixture of bupivacaine and meloxicam (Zynrelef™) and more recently lidocaine liposome formulation. In these cases, the technology is used to prolong the duration of action of drugs included in the preparation. Another indication of nanotechnology is the development of nanocapacitor device or patches. Although, data obtained with the use of nanocapacitors are still limited, evidence suggests that the use of nanocapacitors devices/patches may be interesting for the treatment of both acute and chronic pain, since the studies conducted with the NeuroCuple™ device and the based Kailo™ pain relief patch were not placebo-controlled, it is clear that additional placebo studies are required to confirm these preliminary results. Therefore, the development of a placebo devices/patches is necessary. Conclusions: Increasing evidence supports the concept that nanotechnology may represent a valuable tool as a drug transporter including liposomes and as a nanocapacitor-based device/patch to reduce or even eliminate the use of opioids in surgical patients. However, more studies are required to confirm this concept, especially with the use of nanotechnology incorporated in devices/patches.

The Intersection of Cardiovascular Health and Maternal Health: Portfolio Analysis of Federal Grant Funding 2016-2021.

Background: The United States has high and increasing rates of maternal morbidity and mortality, large proportions of which are related to cardiovascular health (CVH). Methods: We searched for National Institutes of Health (NIH) supported research as well as that of two other Agencies in the U.S. Department of Health and Human Services (DHHS) for fiscal years (FY) 2016-2021. Grants included maternal health conditions or exposures across all pregnancy stages, but excluded grants that focused entirely on birth, neonatal, infant/childhood outcomes. Results were manually curated by reviewing the abstract and specific aims. Grants deemed to be relevant were grouped by category. Results: Between FY 2016-2021, overall Maternal Health grants remained unchanged at an average of 1.4% of total DHHS grant funding. Maternal CVH-specific (MCVH) funding amounted to $278,926,105 for 755 grants, $191,344,649 was for 534 Type-1 grants, representing a twofold increase. Non-NIH DHHS agencies most commonly funded general Maternal Health related to CVH; NIH focused funding classified as hypertensive disorders of pregnancy, maternal morbidity and mortality, obesity, and diabetes. Non-NIH DHSS Agencies most commonly funded clinical applied research. In addition to clinical applied grants, NIH funded substantial proportions of grants classified as basic research, clinical trials, and/or translational. National Heart, Lung, and Blood Institute (NHLBI) MCVH grants studied participants in the pre-partum period (78.5%), followed by the post-partum period (50.5%), with relatively few in pre-pregnancy and peri-partum periods (10.8% and 9.7%, respectively); at the NIH level, the peri-partum period had better representation at 20.3%, whereas the pre-pregnancy period remained low at 9.9%. Conclusions: Federal grant funding for maternal health including MCVH increased at the same rate as its funding for overall research, and represented only 1.4% of overall total funding. The pre-pregnancy period was understudied in overall NIH funding and represents a gap area whereby funding agencies could further foster research advances.

Occlusal Outcomes in Non-Robin Sequence Patients with Isolated Cleft Palate.

OBJECTIVES: 1. To assess the skeletal class occlusion and lateral cephalometry in children with isolated cleft palates (non-Robin sequence) and 2. to identify associations between these findings and pre-palatoplasty cleft palate measurements. STUDY DESIGN: Retrospective cohort study. SETTING: North American Institutional Tertiary Paediatric Center. PATIENTS: Our cleft database was reviewed, and patients were included if they had an isolated cleft palate without a Robin Sequence diagnosis, had a Furlow palatoplasty and had available per operative cleft palate measurements and available lateral cephalogram between 6 and 8 years old. Thirty-two patients matched to inclusion criteria. INTERVENTION: Furlow's Palatoplasty. MAIN OUTCOME AND MEASURES: Cleft size at palatoplasty, cephalometric measurements and skeletal occlusal classes were analysed. ANOVA was used to test the association between cephalometric measurements and occlusal classes. Results are presented as means with a 95% confidence interval. The association between cleft measurements and cephalometric parameters was tested with Spearman Correlation (rs). RESULTS: The skeletal occlusal outcome at 7 years old for this series of patients was: Class I: 19%; Class II: 59% and Class III: 22%. No single cleft measurement at palatoplasty was predictive of the skeletal occlusal outcome. A larger hard palate cleft was associated with a shorter antero-posterior maxilla. CONCLUSIONS: The skeletal occlusal class outcomes were similar to those found in a previous study in the literature. The occlusal prognosis appears to be better than in patients with Robin Sequence or with an associated cleft lip. No preoperative measurement was found to be associated with the occlusal outcome.

Tailoring p-Type Behavior in ZnO Quantum Dots through Enhanced Sol-Gel Synthesis: Mechanistic Insights into Zinc Vacancies.

The synthesis and control of properties of p-type ZnO is crucial for a variety of optoelectronic and spintronic applications; however, it remains challenging due to the control of intrinsic midgap (defect) states. In this study, we demonstrate a synthetic route to yield colloidal ZnO quantum dots (QD) via an enhanced sol-gel process that effectively eliminates the residual intermediate reaction molecules, which would otherwise weaken the excitonic emission. This process supports the creation of ZnO with p-type properties or compensation of inherited n-type defects, primarily due to zinc vacancies under oxygen-rich conditions. The in-depth analysis of carrier recombination in the midgap across several time scales reveals microsecond carrier lifetimes at room temperature which are expected to occur via zinc vacancy defects, supporting the promoted p-type character of the synthesized ZnO QDs.

Impact of the 4th of August Beirut explosion mass casualty incident on a university hospital microbial Flora.

BACKGROUND: Following the Beirut explosion, our university hospital received at least 350 casualties. Subsequently, infection control standard practices were compromised. Concerns for Multi-Drug Resistant Organisms (MDROs) infections in injured patients and a resulting hospital outbreak were raised. The objectives of the study were to compare the rate of hospital growing MDROs 6 months before and 6 months after the Beirut explosion, to identify emerging microorganisms and to evaluate the change in surgical infection prevention practices. METHODS: This is a retrospective chart review of patients with hospital acquired infections (HAI) admitted to the hospital before and after the Beirut explosion. The study was conducted between February 4, 2020 and January 4, 2021. Excluded patients were those transferred from other hospitals and those with community acquired infections. The primary outcome was to identify the rate of growing MDROs post explosion. The secondary outcomes were identifying antibiotics used for surgical prophylaxis in patients requiring surgeries and patients diagnosed with a HAI. Therefore, patients were divided in three groups. Control group included patients admitted with explosion-related injuries on that same day. Patients admitted and between February 4 and August 4 and diagnosed with HAI were compared to those admitted post August 4 with explosion-related HAI and to patients diagnosed with non-explosion-related HAI between August 4 and January 4, 2021. An estimated rate of 18-22% MDRO was needed to achieve a statistical significance with 80% power and 0.05 α. Pearson Chi square test was used to analyze the primary outcome. RESULTS: A total of 82 patients with 150 cultures were included in this study. Data showed an increase in the rate of MDRO after the explosion with 37.1% of the cultures taken before the explosion and 53.1% after the explosion (p = 0.05). When comparing the types of HAI in both groups, culture sites were significantly different between pre- and post-explosion patients (p = 0.013). However, both groups had similar types of microbes (p = 0.996) with an increase in candida related infections. CONCLUSION: These findings confirmed that the Beirut explosion impact on antimicrobial resistance was similar to combat zone incidence, where an increase in MDROs rate such as Escherichia coli (E.Coli) and Stenotrophomonas maltophilia, in addition to the increase in candida related infections.

Wnt/ß-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication.

Adenoid cystic carcinoma (ACC) is one of the most common malignant salivary gland tumors. ACC is composed of myoepithelial and epithelial neoplastic cells which grow slowly and have a tendency for neural invasion. The long term prognosis is still relatively poor. Although several gene abnormalities, such as fusions involving MYB or MYBL1 oncogenes and the transcription factor gene NFIB, and overexpression of KIT have been reported in ACC, their precise functions in the pathogenesis of ACC remain unclear. We recently demonstrated that the elevated expression of Semaphorin 3A (SEMA3A), specifically expressed in myoepithelial neoplastic cells, might function as a novel oncogene-related molecule to enhance cell proliferation through activated AKT signaling in 9/10 (90%) ACC cases. In the current study, the patient with ACC whose tumor was negative for SEMA3A in the previous study, revisited our hospital with late metastasis of ACC to the cervical lymph node eight years after surgical resection of the primary tumor. We characterized this recurrent ACC, and compared it with the primary ACC using immunohistochemical methods. In the recurrent ACC, the duct lining epithelial cells, not myoepithelial neoplastic cells, showed an elevated Ki-67 index and increased cell membrane expression of C-kit, along with the expression of phosphorylated ERK. Late metastasis ACC specimens were not positive for ß-catenin and lymphocyte enhancer binding factor 1 (LEF1), which were detected in the nuclei of perineural infiltrating cells in primary ACC cells. In addition, experiments with the GSK-3 inhibitor revealed that ß-catenin pathway suppressed not only KIT expression but also proliferation of ACC cells. Moreover, stem cell factor (SCF; also known as KIT ligand, KITL) induced ERK activation in ACC cells. These results suggest that inactivation of Wnt/ß-catenin signaling may promote C-kit-ERK signaling and cell proliferation of in metastatic ACC.

Standardizing nomenclature in regional anesthesia: an ASRA-ESRA Delphi consensus study of upper and lower limb nerve blocks.

BACKGROUND: Inconsistent nomenclature and anatomical descriptions of regional anesthetic techniques hinder scientific communication and engender confusion; this in turn has implications for research, education and clinical implementation of regional anesthesia. Having produced standardized nomenclature for abdominal wall, paraspinal and chest wall regional anesthetic techniques, we aimed to similarly do so for upper and lower limb peripheral nerve blocks. METHODS: We performed a three-round Delphi international consensus study to generate standardized names and anatomical descriptions of upper and lower limb regional anesthetic techniques. A long list of names and anatomical description of blocks of upper and lower extremities was produced by the members of the steering committee. Subsequently, two rounds of anonymized voting and commenting were followed by a third virtual round table to secure consensus for items that remained outstanding after the first and second rounds. As with previous methodology, strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement. RESULTS: A total of 94, 91 and 65 collaborators participated in the first, second and third rounds, respectively. We achieved strong consensus for 38 names and 33 anatomical descriptions, and weak consensus for five anatomical descriptions. We agreed on a template for naming peripheral nerve blocks based on the name of the nerve and the anatomical location of the blockade and identified several areas for future research. CONCLUSIONS: We achieved consensus on nomenclature and anatomical descriptions of regional anesthetic techniques for upper and lower limb nerve blocks, and recommend using this framework in clinical and academic practice. This should improve research, teaching and learning of regional anesthesia to eventually improve patient care.

Role of the NeuroCuple™ Device for the Postoperative Pain Management of Patients Undergoing Unilateral Primary Total Knee and Hip Arthroplasty: A Pilot Prospective, Randomized, Open-Label Study.

BACKGROUND: The potential effectiveness of the non-pharmacological and nanotechnology-based NeuroCuple™ device in reducing postoperative surgical pain and opioid consumption remains unknown. METHODS: This randomized controlled open-label study was conducted in patients undergoing a primary unilateral total knee or total hip arthroplasty. In the recovery room, patients were randomized to receive either standard of care (control group) or standard of care plus two NeuroCuple™ devices. The outcome variables included pain and opioid consumption (oral morphine equivalent, OME in milligrams). RESULTS: A total of 69 patients were randomized to either the NeuroCuple™ group (n = 38) or the control group (n = 31). Use of the NeuroCuple™ devices was associated with a significant 34% reduction in pain at rest (means of area under the curve: 6.3 vs. 9.5; p = 0.018) during postoperative days 1-3. Opioid consumption was reduced by 9%. More importantly, use of the NeuroCuple™ devices reduced the number of patients requesting an opioid prescription following discharge from the hospital by 52% (26% vs. 55%, p = 0.016). CONCLUSIONS: Our data suggest that the NeuroCuple™ device may be an effective non-pharmacological alternative to opioids to manage postoperative pain following unilateral arthroplasty due to its ability to reduce postoperative opioid use.

CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas.

Background: CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4/6i could be considered for treating these advanced thyroid cancers. Methods: We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation/viability assays. Treatment of cell lines with CDK4/6i and combination with BRAF/MEK inhibitors (dabrafenib/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays. Results: CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19/20 PDTC, 16/23 ATC and 18/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels, which were associated with proliferative activity. Absence of CDK4 phosphorylation in cell lines was associated with CDK4/6i insensitivity. RB1 defects (the primary cause of intrinsic CDK4/6i resistance) were not found in 5/7 tumors without detectable phosphorylated CDK4. A previously developed 11-gene expression signature identified the likely unresponsive tumors, lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib by completely and permanently arresting proliferation. These combinations prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Conclusion: Our study supports further clinical evaluation of CDK4/6i and their combination with anti-BRAF/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.

SuRxgWell: study protocol for a randomized controlled trial of telemedicine-based digital cognitive behavioral intervention for high anxiety and depression among patients undergoing elective hip and knee arthroplasty surgery.

BACKGROUND: Mood disorders (anxiety, depression), sleep disorders, and catastrophizing lead to increased post-operative pain perception, increase in postoperative opioid consumption, decreased engagement with physical activity, and increased resource utilization in surgical patients. Psychosocial disorders significantly affect postoperative outcome. Unfortunately, studies focused on perioperative psychological assessment and treatment are scarce. We propose to test whether digital cognitive behavioral intervention (dCBI) can help surgical patients. dCBI such as RxWell™ is a proven treatment for mood disorders in medical patients such as reducing depression in patients with inflammatory bowel disease. We hypothesize that RxWell™ will also be effective in surgical patients. This study aims to test whether RxWell™ can improve preoperative mood disorders and subsequently reduce postoperative pain and opioid requirement in patients scheduled for primary total hip and knee arthroplasty (THA, TKA). We named the trial as the SuRxgWell trial. METHODS: This is a randomized, controlled trial that will enroll primary and unilateral THA or TKA patients with anxiety and/or depression symptoms before surgery to receive the SuRxgWell dCBI program and investigate its impact on postoperative outcomes including postoperative pain, anxiety, depression, sleep disorder, and catastrophizing. After signing an informed consent, subjects will be screened using the PROMIS questionnaires, and subjects with a T-score of ≥ 60 on the short Patient-Reported Outcomes Measurement Information System (PROMIS) 4a Anxiety and/or short PROMIS 4a Depression questionnaires will be randomized to either usual care (control group) or the cognitive behavioral intervention, RxWell™, plus usual care (intervention group). The control group will receive information on how to locate tools to address anxiety and depression, whereas the intervention group will have access to SuRxgWell 1 month prior to surgery and up to 3 months after surgery. The allocation will be 3:1 (intervention to control). Investigators will be blinded, but research coordinators approaching patients and research subjects will not. The primary outcome will be day of surgery anxiety or depression symptoms measured with the PROMIS Short Form v1.0 -Anxiety 4a/Depression and Generalized Anxiety Disorder Measure (GAD-7) and Patient Health Questionnaire (PHQ-8). Secondary end points include measuring other health-related quality of life outcomes including sleep disturbance, fatigue, ability to participate in social roles, pain interference, cognitive function, pain catastrophizing, and physical function. Other secondary outcomes include collecting data about preoperative and postoperative pain scores, and pain medication usage, and orthopedic functional recovery at baseline, day of surgery, and 1, 2, and 3 months after the surgery with the Pain Catastrophizing Scale, the Knee injury and Osteoarthritis Outcome Score (KOOS), and Hip injury and Osteoarthritis Outcome Score (HOOS). In addition, subjects will be asked to complete a GAD-7 and PHQ-8 questionnaires bi-weekly (via the RxWell™ app for the interventional group or REDCAP for the control group). Data about postsurgical complications, and resource utilization will also be recorded. We will also receive monthly reports measuring the usage and engagement of RxWell use for each participant randomized to that arm. The primary hypotheses will be assessed with intention-to-treat estimates, and differences in primary outcome will be tested using independent two sample t-tests. This trial is registered to the ClinicalTrials.gov database (NCT05658796) and supported by the DAPM, UPMC Health Plan, and the NIH. DISCUSSION: Our trial will evaluate the feasibility of digital cognitive behavioral intervention as a perioperative tool to improve anxiety and depression before and after major orthopedic surgery in comparison to education. If digital cognitive behavioral intervention proves to be effective, this might have important clinical implications, reducing the incidence of chronic postsurgical pain and improving outcomes.

Stem cells in clinical dentistry.

BACKGROUND: Stem cells are present in most of the tissues in the craniofacial complex and play a major role in tissue homeostasis and repair. These cells are characterized by their capacity to differentiate into multiple cell types and to self-renew to maintain a stem cell pool throughout the life of the tissue. TYPES OF STUDIES REVIEWED: The authors discuss original data from experiments and comparative analyses and review articles describing the identification and characterization of stem cells of the oral cavity. RESULTS: Every oral tissue except enamel, dentin, and cementum contains stem cells for the entire life span. These stem cells self-renew to maintain a pool of cells that can be activated to replace terminally differentiated cells (for example, odontoblasts) or to enable wound healing (for example, dentin bridge in pulp exposures and healing of periodontal tissues after surgery). In addition, dental stem cells can differentiate into functional blood vessels and nerves. Initial clinical trials have shown that transplanting dental pulp stem cells into disinfected necrotic teeth has allowed for the recovery of tooth vitality and vertical and horizontal root growth in immature teeth with incomplete root formation. PRACTICAL IMPLICATIONS: As a consequence of these groundbreaking discoveries, stem cell banks are now offering services for the cryopreservation of dental stem cells. The future use of stem cell-based therapies in the clinic will depend on the collaboration of clinicians and researchers in projects designed to understand whether these treatments are safe, efficacious, and clinically feasible.

Telemedicine-Based Digital Cognitive Behavioral Intervention for Perioperative Anxiety and Depression for Total Knee Arthroplasty.

Introduction: Preoperative anxiety and depression have been shown to increase postoperative pain and opioid consumption by up to 50% in patients undergoing primary unilateral Total Knee Arthroplasty (TKA). We hypothesized that the use of a telemedicine-based digital Cognitive Behavioral Intervention program (RxWell®) started one month prior to surgery would control anxiety and depression prior to surgery. Materials and methods: This was a randomized, controlled trial that enrolled patients undergoing primary unilateral TKA. At least a month prior to surgery, patients who gave consent to participate were asked to complete PROMIS® (Patient-Reported Outcomes Measurement Information System) emotional anxiety short form 8a and PROMIS® emotional depression short form-8a questionnaires. Patients with T-scores of ≥ 57 were randomized to either a no intervention (control group) or a RxWell® program (treatment group) for a month prior to surgery. The primary outcome of this proof-of-concept study was the ability of the RxWell® to normalize patients' PROMIS anxiety T scores. Results: T scores for anxiety and depression among patients randomized to the RxWell® group significantly decreased from 64.3 ± 3.0 at the time of randomization to 58.5 ± 2.6 prior to surgery (n=5, p=0.006), whereas no changes in T scores were recorded in the control group (59.4 ± 4.2 at the time of randomization vs. 57.7 ± 6.2; n=6, p=0.559). Conclusion: These preliminary data suggest that the use of a RxWell® program represents an effective approach to control anxiety and depression prior to surgery. In contrast, it seems that in the absence of treatment, anxiety level remains similar over a month prior to surgery.

Can efficacy and safety data from clinical trials of rituximab in RA be extrapolated? Insights from 1984 patients from the AIR-PR Registry.

OBJECTIVES: To investigate whether the efficacy and safety data from drug-registration trials can be extrapolated to real-life RA patients receiving RTX. METHODS: The AIR-PR registry is a French multicentre, prospective cohort of RA patients treated with RTX in a real-life setting. We compared treatment responses at 12 months and serious AEs between eligible and non-eligible patients, by retrieving the eligibility criteria of the three rituximab-registration trials. We determined critical eligibility criteria and modelled the benefit-risk ratio according to the number of fulfilled critical eligibility criteria. RESULTS: Among 1984 RA patients, only 9-12% fulfilled all eligibility criteria. Non-eligible patients had less EULAR response at 12 months (40.3% vs 46.9%, p= 0.044). Critical inclusion criteria included SJC ≥ 4, TJC ≥ 4, CRP ≥ 15 mg/l, and RF positivity. Critical exclusion criteria were age >80 years, RA-associated systemic diseases, ACR functional class IV, other DMARD than methotrexate, and prednisone > 10 mg/day. Only 20.8% fulfilled those critical eligibility criteria. During the first year, serious AEs occurred for 182 (9.2%) patients, (70.3% serious infections) and patients with ≥1 critical exclusion criterion were at higher risk (HR 3.03; 95%CI 2.25-4.06; for ≥ 3 criteria vs 0). The incremental risk-benefit ratio decreased with the number of unmet critical inclusion criteria and of fulfilled exclusion criteria. CONCLUSION: Few real-life RA patients were eligible for the drug-registration trials. Non-eligible patients had lower chance of response, and higher risk of serious AEs. Efficacy and safety data obtained from those trials may not be generalizable to RA patients receiving RTX in real-world clinical practice.

Use of Nanotechnology as an Alternative to Opioids for Post-operative Pain Management Following TKA.

Introduction: In response to the current opioid crisis, there is a great interest to develop non-pharmacologic approaches to post-operative pain management for patients undergoing total knee arthroplasty (TKA). Case Report: We report a case of a patient whose post-operative pain following TKA was managed using the newly designed NeuroCuple™ device, a patch based on the use of nanotechnology. The NeuroCuple™ device was placed above the knee by the patient at home. The use of the NeuroCuple™ device allowed the patient completely avoid the use of any opioids at home. Conclusion: Our report suggests that the use of the NeuroCuple™ device may represent an interesting alternative to opioids for the peri-operative management of pain following a primary, unilateral TKA.