Pandemic-associated pernio harbors footprints of an abortive SARS-CoV-2 infection.

Elevated pernio incidence was observed during the COVID-19 pandemic. This prospective study enrolled subjects with pandemic-associated pernio in Wisconsin and Switzerland. Because pernio is a cutaneous manifestation of the interferonopathies, and type I interferon (IFN-I) immunity is critical to COVID-19 recovery, we tested the hypothesis that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated IFN-I signaling might underlie some pernio cases. Tissue-level IFN-I activity and plasmacytoid dendritic cell infiltrates were demonstrated in 100% of the Wisconsin cases. Across both cohorts, sparse SARS-CoV-2 RNA was captured in 25% (6/22) of biopsies, all with high inflammation. Affected patients lacked adaptive immunity to SARS-CoV-2. A hamster model of intranasal SARS-CoV-2 infection was used as a proof-of-principle experiment: RNA was detected in lungs and toes with IFN-I activity at both the sites, while replicating virus was found only in the lung. These data support a viral trigger for some pernio cases, where sustained local IFN-I activity can be triggered in the absence of seroconversion.

Central activation of catecholamine-independent lipolysis drives the end-stage catabolism of all adipose tissues.

Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors Acvr1c, G0s2, and Npr3. This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent in vivo neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.

Contrast arthrography of the equine temporomandibular joint.

Background: Disorders of the equine temporomandibular joint (TMJ) cause clinical problems and detailed investigations of this joint are becoming more common. Specialist radiographic projections have the potential to highlight osseous abnormalities; however, the ability to assess the intra-articular soft tissue structures is currently limited to computed tomography (with, or without contrast enhancement) or magnetic resonance imaging. Both modalities are expensive and not readily accessible. Objective: To develop a technique of contrast arthrography of both compartments of the equine TMJ in cadavers and then perform the refined technique in three living horses as a proof-of-principle. Study design: A descriptive, experimental, study. Methods: Contrast arthrography of the discomandibular and discotemporal joint compartments of both TMJs was performed in 12 cadaveric equine heads using needles placed in the caudal pouches of the respective joint compartments. Radiographs were taken using previously published techniques, repeated with the mouth open and after air had been injected into the joints, to perform a double-contrast study. The TMJs of three healthy horses were subsequently examined to determine the validity of the procedure in live animals. Results: Single and double-contrast arthrography allowed delineation of the dorsal and ventral surfaces of the intra-articular disc in addition to filling the rostral and caudal joint pouches of the independent joint compartments. Contrast extravasation was common, and in two instances iatrogenic disc penetration resulted in the false diagnosis of pathologic disc perforation. The techniques were well tolerated in all three live horses. Main limitations: Low number of horses. Conclusion: Contrast arthrography allows interpretation of intra-articular soft tissue structures, but caution is advised in diagnosing intra-articular disc perforation. Even with experience, accessing the discomandibular joint can be challenging.

The homeoprotein HOXB2 limits triple-negative breast carcinogenesis via extracellular matrix remodeling.

Homeobox genes and their encoded DNA-binding homeoproteins are master regulators of development. Consequently, these homeotic elements may regulate key steps in cancer pathogenesis. Here, using a combination of in silico analyses of large-scale patient datasets, in vitro RNAi phenotyping, and in vivo validation studies, we investigated the role of HOXB2 in different molecular subtypes of human breast cancer (BC). The gene expression signatures of HOXB2 are different across distinct BC subtypes due to various genetic alterations, but HOXB2 was specifically downregulated in the aggressive triple-negative subtype (TNBC). We found that the reduced expression of HOXB2 was correlated with the metastatic abilities (epithelial-to-mesenchymal transition) of TNBC cells. Further, we revealed that HOXB2 restrained TNBC aggressiveness by ECM organization. HOXB2 bound to the promoter regions of MATN3 and ECM2 and regulated their transcription levels. Forced expression of HOXB2 effectively prevented TNBC progression and metastasis in a mouse xenograft model. Reduction of HOXB2 and the HOXB2/MATN3/ECM2 transcriptional axis correlated with poor survival in patients with various cancers. Further, we found the long non-coding RNA HOXB-AS1 in complex with SMYD3, a lysine methyltransferase, as an epigenetic switch controlling HOXB2 expression. Overall, our results indicate a tumor-suppressive role of HOXB2 by maintaining ECM organization and delineate potential clinical utility of HOXB2 as a marker for TNBC patients.

Artificial intelligence (A.I.) in dental curricula: Ethics and responsible integration.

The use of artificial intelligence (AI) is deeply embedded in all aspects of our daily lives, promoting efficiency and safety in routine tasks at home and work. Likewise, dentistry is rapidly exploring new uses of AI for image analysis, electronic health records, and clinical decision-making. The accelerating advancement of AI and its application in dentistry demands dental education conscientiously integrate AI into curricula and equip graduates to use it ethically and responsibly in practice. The approach must be threefold: instill knowledge of the basic algorithms and appropriate application of AI, discuss its limitations/biases, and examine current and potential ethical challenges in practice. Furthermore, dental education must protect the public from intentional and unintentional harm introduced by AI. Therefore, the purpose of this perspective paper is to discuss various considerations for integrating AI into the dental curriculum, prioritizing patient safety by ensuring knowledgeable, safe, and ethical application by future providers.

Factors Affecting Participation in Telerehabilitation Using Transcranial Direct Current Stimulation for Patients with Poststroke Paralysis in South Korea.

Background: The coronavirus disease 2019 pandemic has expanded noncontact health care systems worldwide. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technology that enables treatment monitoring under remote supervision. We investigated the factors affecting patients' decision to participate in telerehabilitation (TR) using tDCS for motor function recovery after suffering a stroke. Materials and Methods: Four medical institutions surveyed 156 patients with poststroke paralysis. The participants were asked whether they would participate in TR therapy using tDCS in the future. We performed logistic regression analysis to examine the factors-demographic data, stroke characteristics, arm function, gait, and cognitive function-that influenced participants' decisions. Results: Of the participants, 66% (103/156) reported that they would participate in TR using tDCS in the future. Participants' monthly salary was a single significant independent factor influencing their decision to participate. Those earning greater than 5 million KRW (4,000 USD) were more likely to engage in TR via tDCS than those earning less than 1 million KRW (800 USD). The most common barriers to participation in telemedicine included the preference for face-to-face treatment and unfamiliarity. The expected medical expenses of TR using tDCS were 46,154 KRW (37 USD) per session. Conclusions: Most participants with poststroke paralysis responded positively to TR using tDCS for hand function recovery. For telemedicine to work effectively in a situation wherein face-to-face rehabilitation is impossible, prior discussion at the governmental level is essential for determining medical finances.

Third dose of an mRNA COVID-19 vaccine for patients with multiple myeloma.

We have reported that IgG antibody responses following two mRNA COVID-19 vaccinations are impaired among patients with multiple myeloma (MM). In the current study, sixty-seven patients with MM were tested for anti-spike IgG antibodies 0-60 days prior to their first vaccination, 14-28 days following the second dose, and both before and 14-28 days after their third dose of the mRNA-1273 or BNT162b2 vaccines. After the first two doses, most patients' (93 %) antibody levels declined to ineffective levels (<250 BAU/mL) prior to their third dose (D3). D3 elicited responses in 84 % of patients (61 % full response and 22 % partial response). The third vaccination increased antibody levels (average = 370.4 BAU/mL; range, 1.0-8977.3 BAU/mL) relative to just prior to D3 (average = 25.0 BAU/mL; range, 1.0-683.8 BAU/mL) and achieved higher levels than peak levels after the first two doses (average = 144.8 BAU/mL; range, 1.0-4,284.1 BAU/mL). D3 response positively correlated with mRNA-1273, a > 10-fold change from baseline for the two-dose series, switching from BNT162b2 to mRNA-1273 for D3, and treatment with elotuzumab and an immunomodulatory agent. Lower antibody levels prior to D3, poorer overall response to first two doses, and ruxolitinib or anti-CD38 monoclonal antibody treatment negatively correlated with D3 response. Our results show encouraging activity of the third vaccine, even among patients who failed to respond to the first two vaccinations. The finding of specific factors that predict COVID-19 antibody levels will help advise patients and healthcare professionals on the likelihood of responses to further vaccinations.

Ruxolitinib and methylprednisolone for treatment of patients with relapsed/refractory multiple myeloma.

Although Janus kinase (JAK) inhibitors have demonstrated efficacy for treating autoimmune disorders and myeloproliferative neoplasms, their efficacy in treating other types of cancer has not been clearly demonstrated. We evaluated oral ruxolitinib (15 mg twice daily) with oral methylprednisolone (40 mg every other day) for multiple myeloma (MM) patients with progressive disease who had received a proteasome inhibitor, lenalidomide, glucocorticosteroids and three or more prior regimens. All of the planned 29 patients had been enrolled with follow-up until 28 April 2022. Median lines of prior therapy were 6 (range 3-12). Cytogenetics and fluorescent in situ hybridization were evaluable in 28 patients; 9 (32%) and 17 (70%) patients showed high-risk cytogenetics and/or 1q+, respectively. The overall response rate was 31%. The median duration of response was 13.1 (range 2.8-22.0) months. Median progression-free survival rate was 3.4 (range 0.5-24.6) months, Overall, the treatment was well tolerated. The combination of ruxolitinib and methylprednisolone demonstrated significant clinical activity among previously heavily-treated MM patients, and responses were achieved among patients who had high-risk cytogenetics. This is the first clinical study to show activity of JAK inhibitors in combination with steroids for MM patients and expands the potential use of these drugs to those with cancers other than myeloproliferative neoplasms.

The JAK1/2 inhibitor ruxolitinib downregulates the immune checkpoint protein B7H3 in multiple myeloma.

We hypothesized that ruxolitinib may inhibit the immune checkpoint protein, B7H3; and, thus, investigated its effects on this immune inhibitor using multiple myeloma (MM) cell lines, bone marrow (BM) mononuclear cells from MM patients and human MM LAGλ -1A xenografts. Ruxolitinib reduced B7H3 gene and protein expression and increased IL-2 and CD8 gene expression. These results suggest that ruxolitinib inhibition of B7H3 may restore exhausted T-cell activity in the MM BM tumor microenvironment.

A phase 1 study of ruxolitinib, steroids and lenalidomide for relapsed/refractory multiple myeloma patients.

Ruxolitinib with lenalidomide and dexamethasone shows anti-myeloma effects in vitro and in vivo. MUC1 leads to lenalidomide resistance in multiple myeloma (MM) cells, and ruxolitinib blocks its expression. Thus, ruxolitinib may restore sensitivity to lenalidomide. A phase I trial was conducted to determine the safety and efficacy of ruxolitinib with lenalidomide and methylprednisolone for patients with relapsed/refractory (RR)MM who had been treated with lenalidomide, steroids and a proteasome inhibitor and showed progressive disease at study entry. A traditional 3 + 3 dose escalation design was used to enroll subjects in four cohorts. Subjects received ruxolitinib twice daily, lenalidomide daily on days 1-21 of a 28 day cycle and methylprednisolone orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Forty-nine patients were enrolled. The median age was 64 years and they had received a median of six prior treatments including lenalidomide and steroids to which 94% were refractory. No dose limiting toxicities occurred. The CBR and ORR were 49% and 36%, respectively. All responding patients were refractory to lenalidomide. Grade 3 or 4 adverse events (AEs) included anemia (17%), decreased lymphocyte count (15%), and hypophosphatemia (10%). Most common serious AEs included sepsis (9.8%) and pneumonia (7.8%). This Phase I trial demonstrates that a JAK inhibitor, ruxolitinib, can overcome refractoriness to lenalidomide and steroids for patients with RRMM. These results represent a promising novel therapeutic approach for treating MM. NCT03110822.

Ambient carbon monoxide correlates with mortality risk of hemodialysis patients: comparing results of control selection in the case-crossover designs.

BACKGROUND: Growing evidence suggests that environmental air pollution adversely affects kidney health. To date, the association between carbon monoxide (CO) and mortality in patients with end-stage renal disease (ESRD) has not been examined. METHODS: Among 134,478 dialysis patients in the Korean ESRD cohort between 2001 and 2014, 8,130 deceased hemodialysis patients were enrolled, and data were analyzed using bidirectional, unidirectional, and time-stratified case-crossover design. We examined the association between short-term CO concentration and mortality in patients with ESRD. We used a two-pollutant model, adjusted for temperature as a climate factor and for nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and particulate matter less than 10 µm in diameter as air pollution variables other than CO. RESULTS: Characteristics of the study population included age (66.2 ± 12.1 years), sex (male, 59.1%; female, 40.9%), and comorbidities (diabetes, 55.6%; hypertension, 14.4%). Concentration of CO was significantly associated with all-cause mortality in the three case-crossover designs using the two-pollutant model adjusted for SO2. Patients with diabetes or age older than 75 years had a higher risk of mortality than patients without diabetes or those younger than 75 years. CONCLUSION: Findings presented here suggest that higher CO concentration is correlated with increased all-cause mortality in hemodialysis patients, especially in older high-risk patients.

A phase 1/2 study of ixazomib in place of bortezomib or carfilzomib in a subsequent line of therapy for patients with multiple myeloma refractory to their last bortezomib or carfilzomib combination regimen.

Identifying effective combination regimens is a high priority in multiple myeloma (MM), as most patients eventually become refractory to their current treatments. In this study, we investigated whether the proteasome inhibitor (PI) ixazomib could delay disease progression among patients who failed regimens containing another PI, bortezomib or carfilzomib. This phase 1/2, multicenter, open-label, nonrandomized study enrolled patients who were refractory to a previous regimen containing bortezomib or carfilzomib. Patients continued the other anti-MM drugs in the regimen at the same doses and frequencies. Patients with combination regimens with unknown maximum tolerated dose (MTD) of ixazomib were enrolled in phase 1, with ixazomib starting at 3 mg and then dose escalated to 4 mg. Patients on regimens with a known ixazomib MTD were enrolled in phase 2. Primary endpoints were overall response rate (ORR), clinical benefit rate (CBR), adverse events (AEs), and determination of maximum tolerated dose (MTD). Of the 46 patients enrolled, 39 were evaluable for efficacy. ORR and CBR were 12.8% and 17.9%, respectively. Ixazomib appeared to be well tolerated as a replacement for carfilzomib and bortezomib, with 23.9% of patients experiencing at least one grade ≥3 serious adverse event (SAE) and 37.0% experiencing at least one grade ≥3 AE. The most common grade ≥3 AEs were hyponatremia (8.7%), anemia (8.7%), dyspnea (8.7%), thrombocytopenia (6.5%), dehydration (4.3%), and pneumonia (4.3%). The results indicate that ixazomib is not an effective replacement for bortezomib or carfilzomib for patients with MM who have previously relapsed on other bortezomib/carfilzomib-containing regimens.

Development of the Korea-Polyenvironmental Risk Score for Psychosis.

OBJECTIVE: Comprehensive understanding of polyenvironmental risk factors for the development of psychosis is important. Based on a review of related evidence, we developed the Korea Polyenvironmental Risk Score (K-PERS) for psychosis. We investigated whether the K-PERS can differentiate patients with schizophrenia spectrum disorders (SSDs) from healthy controls (HCs). METHODS: We reviewed existing tools for measuring polyenvironmental risk factors for psychosis, including the Maudsley Environmental Risk Score (ERS), polyenviromic risk score (PERS), and Psychosis Polyrisk Score (PPS). Using odds ratios and relative risks for Western studies and the "population proportion" (PP) of risk factors for Korean data, we developed the K-PERS, and compared the scores thereon between patients with SSDs and HCs. In addition, correlation was performed between the K-PERS and Positive and Negative Syndrome Scale (PANSS). RESULTS: We first constructed the "K-PERS-I," comprising five factors based on the PPS, and then the "K-PERS-II" comprising six factors based on the ERS. The instruments accurately predicted participants' status (case vs. control). In addition, the K-PERS-I and -II scores exhibited significant negative correlations with the negative symptom factor score of the PANSS. CONCLUSION: The K-PERS is the first comprehensive tool developed based on PP data obtained from Korean studies that measures polyenvironmental risk factors for psychosis. Using pilot data, the K-PERS predicted patient status (SSD vs. HC). Further research is warranted to examine the relationship of K-PERS scores with clinical outcomes of psychosis and schizophrenia.

Care Management for Serious Mental Illness: A Systematic Review and Meta-Analysis.

OBJECTIVE: Persons with serious mental illness face adverse psychiatric and medical outcomes, and their care is associated with a large burden of health care costs. Care management, in which assessment, care planning, and care coordination are provided, is a common model of support, yet the evidence supporting its use among psychiatric populations is mixed. A systematic review and a meta-analysis were undertaken to determine the impact of care management on clinical outcomes, acute care utilization, cost, and satisfaction among adults with serious mental illness. METHODS: A multidatabase literature search was performed. Articles were included if they compared standard outpatient care plus care management with standard outpatient care alone for adults with serious mental illness and reported on one or more predefined outcomes. Randomized controlled trials (RCTs) and other study designs were permitted for inclusion in the systematic review. The meta-analysis included only RCTs. RESULTS: For the systematic review, 34 articles representing 28 unique studies were included. Fifteen of these articles, representing 12 unique studies, were included in the meta-analysis, which indicated that care management was associated with small, statistically significant improvements in psychiatric symptoms, overall quality of life (QOL), and mental QOL (Hedges' g range 0.13-0.26). In addition, care management was associated with a small, statistically significant reduction in inpatient psychiatric hospital days (Hedges' g=0.16, p=0.02). CONCLUSIONS: Care management is associated with fewer psychiatric symptoms and greater QOL for persons with serious mental illness. Further work is needed to determine which components of the intervention are associated with effectiveness.

Postoperative Screening With the Modified National Institutes of Health Stroke Scale After Noncardiac Surgery: A Pilot Study.

BACKGROUND: Perioperative stroke is associated with high rates of morbidity and mortality, yet there is no validated screening tool. The modified National Institutes of Health Stroke Scale (mNIHSS) is validated for use in nonsurgical strokes but is not well-studied in surgical patients. We evaluated perioperative changes in the mNIHSS score in noncardiac, non-neurological surgery patients, feasibility in the perioperative setting, and the relationship between baseline cognitive screening and change in mNIHSS score. METHODS: Patients aged 65 years and above presenting for noncardiac, non-neurological surgery were prospectively recruited. Those with significant preoperative cognitive impairment (Montreal Cognitive Assessment score [MoCA] ≤17) were excluded. mNIHSS was assessed preoperatively, on postoperative day (POD) 0, POD 1, and POD 2, demographic data collected, and feedback solicited from participants. Changes in mNIHSS from baseline, time to completion, and relationship between baseline MoCA score and change in mNIHSS score were analyzed. RESULTS: Twenty-five patients were enrolled into the study; no overt strokes occurred. Median mNIHSS score increased between baseline (0 interquartile range [IQR 0 to 1]) and POD 0 (2 [IQR 0 to 3.5]; P<0.001) but not between baseline and POD 1 (0.5 [IQR 0 to 1.5]; P=0.174) or POD 2 (0 [IQR 0 to 1]; P=0.650). Time to complete the mNIHSS at baseline was 3.5 minutes (SD 0.8), increasing to 4.1 minutes (SD 1.0) on POD 0 (P=0.0249). Baseline MoCA score was correlated with mNIHSS score change (P=0.038). Perioperative administration of the mNIHSS was feasible, and acceptable to patients. CONCLUSIONS: Changes in mNIHSS score can occur early after surgery in the absence of overt stroke. Assessment of mNIHSS appears feasible in the perioperative setting, although further research is required to define its role in detecting perioperative stroke.