A comprehensive study of psychological well-being and traditional Chinese medicine constitutions among model workers in Beijing.

Background: Body constitution is the foundation of Traditional Chinese Medicine (TCM), and model workers consist of a special group of workers within China. This study aims to research the relationship between the physical body constitutions based on TCM and the mental health of model workers. Methods: We recruited 314 model workers from Beijing Rehabilitation Hospital to conduct the questionnaires such as SCL-90 and CCMQ to investigate if there is an association between mental health status and TCM body constitutions. We performed a Partial Least Squares Path Modeling (PLS path modeling). Results: Our path model results revealed associations between different TCM constitution types and SCL scores, which serve as indicators of psychological well-being. Our research findings demonstrate a strong correlation between the Balanced constitution and elevated levels of psychological well-being, with a path coefficient of -0.503. In contrast, the other eight constitutional types exhibit path coefficients exceeding 0.3, indicating a tendency toward lower levels of psychological well-being. We also investigated the intricate connections between various TCM constitutional types and both mild and severe psychological well-being. Conclusion: In conclusion, the Balanced constitution continues to be closely associated with higher levels of psychological well-being, while the remaining eight body constitution types are consistently linked to lower levels of psychological well-being.

Examining timing of periorbital interventions in patients with upper division facial paralysis.

BACKGROUND: Facial paralysis is a life-altering condition that may arise from various etiologies, ranging from trauma to malignancy. Permanent facial paralysis may occur secondary to facial nerve sacrifice or irreversible damage to the nerve. In these particularly devastating cases, protection and maintaining function of the eye is paramount. There are many effective lagophthalmos corrective surgical procedures available for these patients. While placement of eyelid weights and lid tightening surgeries are the cornerstone of eyelid rehabilitation, limited information exists on whether the timing of eyelid interventions in the setting of permanent facial paralysis impact outcomes, including need for revision surgery. METHODS: A single-center retrospective chart review was performed for patients with irreversible facial paralysis treated with an upper eyelid weight between 2013 to 2022. Electronic health records were acquired to obtain facial paralysis etiology, associated clinical characteristics, the type of intervention, and the timing of intervention. Patients were classified as immediate if the eyelid weight operation occurred within 29 days of the initial facial paralysis and delayed if the surgery occurred 30 days or more after initial presentation. Outcomes were assessed in terms of revision procedures and surgical complications. RESULTS: There were 70 patients in total, with 35 patients in the immediate category and 35 patients in the delayed category. The most common etiology related to parotid gland pathology, and 58.6% of patients had facial paralysis from cancer-related surgeries. There were no significant differences in revision rates (p < 0.208) or in the types of procedures (p = 0.077) between the two groups. The complication rates also did not differ significantly between groups; however, there were only complications in the delayed intervention group. CONCLUSIONS: These findings suggest there is no difference in postoperative complications between groups, including the need for revision surgeries when comparing groups with immediate or delayed intervention. Thus, treatment plans should be customized based on patient and provider preferences.

Role of 18F-FDG PET/CT in the management of head and neck cancer patients with persistent cervical lymphadenopathy following chemoradiation.

BACKGROUND: We aim to describe the management and outcomes of patients with persistent lymphadenopathy (LAD) after primary chemoradiation for head and neck squamous cell carcinoma (HNSCC) based on post-treatment PET/CT results. METHODS: Retrospective chart review was conducted of all patients who underwent primary concurrent chemoradiation for HNSCC at a tertiary care center from 2010 to 2022 and had persistent post-treatment LAD. RESULTS: Nearly 62% of patients were managed conservatively, and 27.0% underwent neck dissection. PET-positive patients were more likely to undergo neck dissection than PET-negative patients (p = 0.042). Positive predictive value (PPV) and negative predictive values (NPV) of PET/CT in detecting residual disease in the neck were 48.0% and 73.7%, respectively. CONCLUSIONS: PPV and NPV of PET/CT for detecting residual neck disease in patients with post-treatment LAD was lower than those of HNSCC patients with and without persistent LAD reported in other studies.

Peptide Blockers of PD-1-PD-L1 Interaction Reinvigorate PD-1-Suppressed T Cells and Curb Tumor Growth in Mice.

The programmed cell death protein 1 (PD-1) plays a critical role in cancer immune evasion. Blocking the PD-1-PD-L1 interaction by monoclonal antibodies has shown remarkable clinical efficacy in treating certain types of cancer. However, antibodies are costly to produce, and antibody-based therapies can cause immune-related adverse events. To address the limitations associated with current PD-1/PD-L1 blockade immunotherapy, we aimed to develop peptide-based inhibitors of the PD-1/PD-L1 interaction as an alternative means to PD-1/PD-L1 blockade antibodies for anti-cancer immunotherapy. Through the functional screening of peptide arrays encompassing the ectodomains of PD-1 and PD-L1, followed by the optimization of the hit peptides for solubility and stability, we have identified a 16-mer peptide, named mL7N, with a remarkable efficacy in blocking the PD-1/PD-L1 interaction both in vitro and in vivo. The mL7N peptide effectively rejuvenated PD-1-suppressed T cells in multiple cellular systems designed to recapitulate the PD-1/PD-L1 interaction in the context of T-cell receptor signaling. Furthermore, PA-mL7N, a chimera of the mL7N peptide coupled to albumin-binding palmitic acid (PA), significantly promoted breast cancer cell killing by peripheral blood mononuclear cells ex vivo and significantly curbed tumor growth in a syngeneic mouse model of breast cancer. Our work raises the prospect that mL7N may serve as a prototype for the development of a new line of peptide-based immunomodulators targeting the PD-1/PD-L1 immune checkpoint with potential applications in cancer treatment.

The intrinsic substrate specificity of the human tyrosine kinome.

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.

Examining lack of referrals to heart valve specialists as mechanisms of potential underutilization of aortic valve replacement.

BACKGROUND: Recent studies suggest that aortic valve replacement (AVR) remains underutilized. AIMS: Investigate the potential role of non-referral to heart valve specialists (HVS) on AVR utilization. METHODS: Patients with severe aortic stenosis (AS) between 2015 and 2018, who met class I indication for intervention, were identified. Baseline data and process-related parameters were collected to analyze referral predictors and evaluate outcomes. RESULTS: Among 981 patients meeting criteria AVR, 790 patients (80.5%) were assessed by HVS within six months of index TTE. Factors linked to reduced referral included increasing age (OR: 0.95; 95% CI: 0.94-0.97; P < .001), unmarried status (OR: 0.59; 95% CI: 0.43-0.83; P = .002) and inpatient TTE (OR: 0.27; 95% CI: 0.19-0.38; P < .001). Conversely, higher hematocrit (OR: 1.13; 95% CI: 1.09-1.16; P < .001) and eGFR (OR: 1.01; 95% CI: 1.00-1.02; P = .003), mean aortic valve gradient (OR: 1.03; 95% CI: 1.01-1.04; P < .001) and preserved LVEF (OR: 1.59; 95% CI: 1.02-2.48; P = .04), were associated with increased referral likelihood. Moreover, patients assessed by HVS referral as a time-dependent covariate had a significantly lower two-year mortality risk than those who were not (aHR: 0.30; 95% CI: 0.23-0.39; P < .001). CONCLUSION: A substantial proportion of severe AS patients meeting indications for AVR are not evaluated by HVS and experience markedly increased mortality. Further research is warranted to assess the efficacy of care delivery mechanisms, such as e-consults, and telemedicine, to improve access to HVS expertise.

Neoadjuvant Dual Checkpoint Inhibitors vs Anti-PD1 Therapy in High-Risk Resectable Melanoma: A Pooled Analysis.

Importance: Despite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known. Objective: To compare the safety and efficacy of dual checkpoint inhibitors with anti-programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM. Design, Setting, and Participants: In this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM. Interventions: Patients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab. Main Outcomes and Measures: The main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered. Results: Among 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy. Conclusion and Relevance: In this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.

Development of hypothyroidism following hemithyroidectomy: A population-based study.

PURPOSE: Hypothyroidism is a known possibility after hemithyroidectomy, with a highly variable incidence in the literature ranging from 8 to 60 %. Incidence of hypothyroidism after hemithyroidectomy was evaluated with a secondary aim to assess incidence in patients with Hashimoto's disease. MATERIALS & METHODS: A retrospective study using the TriNetX global federated research network was performed. We included patients within the last 15 years that were ≥18 years of age and had Current Procedural Terminology codes for hemithyroidectomy. Patients were excluded if they had a total or completion thyroidectomy at any time, a history of thyroid cancer, were preoperatively either on levothyroxine, diagnosed with hypothyroidism, or had a Thyroid Stimulating Hormone ≥ 4 m[IU]/L. We assessed the 3 month incidence of hypothyroidism postoperatively based on the International Classification of Diseases code, TSH ≥ 4 m[IU]/L, or taking levothyroxine after surgery. RESULTS: 6845 patients met the inclusion criteria. Most of the cohort was female (67 %) and white (63 %). The mean age at surgery for this population was 54 ± 14.8 years. During the 15 years of data, we found the 3-month incidence of hypothyroidism following hemithyroidectomy to be 23.58 %. The median time to develop the disease was 41.8 months. A subgroup analysis of those with Hashimoto's revealed a 3-month incidence of 31.1 % of patients developing hypothyroidism after surgery. CONCLUSIONS: This population-based study gives additional insight into the incidence of hypothyroidism after hemithyroidectomy. This will help improve perioperative patient counseling and management.

Kinome and phosphoproteome reprogramming underlies the aberrant immune responses in critically ill COVID-19 patients.

SARS-CoV-2 infection triggers extensive host immune reactions, leading to severe diseases in certain individuals. However, the molecular basis underlying the excessive yet non-productive immune responses in severe COVID-19 remains incompletely understood. In this study, we conducted a comprehensive analysis of the peripheral blood mononuclear cell (PBMC) proteome and phosphoproteome in sepsis patients positive or negative for SARS-CoV-2 infection, as well as healthy subjects, using quantitative mass spectrometry. Our findings demonstrate dynamic changes in the COVID-19 PBMC proteome and phosphoproteome during disease progression, with distinctive protein or phosphoprotein signatures capable of distinguishing longitudinal disease states. Furthermore, SARS-CoV-2 infection induces a global reprogramming of the kinome and phosphoproteome, resulting in defective adaptive immune response mediated by the B and T lymphocytes, compromised innate immune responses involving the SIGLEC and SLAM family of immunoreceptors, and excessive cytokine-JAK-STAT signaling. In addition to uncovering host proteome and phosphoproteome aberrations caused by SARS-CoV-2, our work recapitulates several reported therapeutic targets for COVID-19 and identified numerous new candidates, including the kinases PKG1, CK2, ROCK1/2, GRK2, SYK, JAK2/3, TYK2, DNA-PK, PKCδ, and the cytokine IL-12.

Free Flap Outcomes for Head and Neck Surgery in Patients with COVID-19.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) affects the vascular system, subjecting patients to a hypercoagulable state. This is of particular concern for the success of microvascular free flap reconstruction. This study aims to report head and neck free flap complications in patients with COVID-19 during the perioperative period. We believe these patients are more likely to experience flap complications given the hypercoagulable state. METHODS: This is a multi-institutional retrospective case series of patients infected with COVID-19 during the perioperative period for head and neck free flap reconstruction from March 2020 to January 2022. RESULTS: Data was collected on 40 patients from 14 institutions. Twenty-one patients (52.5%) had a positive COVID-19 test within 10 days before surgery and 7 days after surgery. The remaining patients had a positive test earlier than 10 days before surgery. A positive test caused a delay in surgery for 16 patients (40.0%) with an average delay of 44.7 days (9-198 days). Two free flap complications (5.0%) occurred with no free flap deaths. Four patients (10.0%) had surgical complications and 10 patients had medical complications (25.0%). Five patients (12.5%) suffered from postoperative COVID-19 pneumonia. Three deaths were COVID-19-related and one from cancer recurrence during the study period. CONCLUSION: Despite the heightened risk of coagulopathy in COVID-19 patients, head and neck free flap reconstructions in patients with COVID-19 are not at higher risk for free flap complications. However, these patients are at increased risk of medical complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 2023.

Proteomic and Phosphoproteomic Reprogramming in Epithelial Ovarian Cancer Metastasis.

Epithelial ovarian cancer (EOC) is a high-risk cancer presenting with heterogeneous tumors. The high incidence of EOC metastasis from primary tumors to nearby tissues and organs is a major driver of EOC lethality. We used cellular models of spheroid formation and readherence to investigate cellular signaling dynamics in each step toward EOC metastasis. In our system, adherent cells model primary tumors, spheroid formation represents the initiation of metastatic spread, and readherent spheroid cells represent secondary tumors. Proteomic and phosphoproteomic analyses show that spheroid cells are hypoxic and show markers for cell cycle arrest. Aurora kinase B abundance and downstream substrate phosphorylation are significantly reduced in spheroids and readherent cells, explaining their cell cycle arrest phenotype. The proteome of readherent cells is most similar to spheroids, yet greater changes in the phosphoproteome show that spheroid cells stimulate Rho-associated kinase 1 (ROCK1)-mediated signaling, which controls cytoskeletal organization. In spheroids, we found significant phosphorylation of ROCK1 substrates that were reduced in both adherent and readherent cells. Application of the ROCK1-specific inhibitor Y-27632 to spheroids increased the rate of readherence and altered spheroid density. The data suggest ROCK1 inhibition increases EOC metastatic potential. We identified novel pathways controlled by Aurora kinase B and ROCK1 as major drivers of metastatic behavior in EOC cells. Our data show that phosphoproteomic reprogramming precedes proteomic changes that characterize spheroid readherence in EOC metastasis.

Prognostic significance of time trends in treatment of head and neck squamous cell carcinoma.

PURPOSE: To analyze the impact of demographic, clinical, and management variables on time to treatment initiation (TTI) and overall survival (OS). STUDY DESIGN: Retrospective chart review. MATERIALS AND METHODS: Medical records of patients diagnosed with head and neck cancer from 2018 to 2020 were reviewed. Univariate linear and Cox-regressions identified predictors of TTI and OS. Kaplan Meier (KM) curves assessed the difference in survival by diagnostic year and TTI. RESULTS: 381 patients met eligibility criteria. Median TTI was 35.0 days (IQR: 25.0-49.0). Only 10.8 % of all patients reported any treatment delay, with TTI exceeding 90 days found in 3.7 % of patients. TTI increased with African American race (p = 0.02), ED referrals (p = 0.02), and direct admission status (p = 0.01). When compared to treatment with surgery alone, TTI was shorter in patients undergoing surgery with adjuvant radiation (p = 0.02), adjuvant chemoradiation (p = 0.04), and salvage surgery (p = 0.04). Univariate Cox-regressions found smoking (p = 0.01), direct admission status (p = 0.02), increased duration of symptoms (p = 0.02), placement of PEG tubes (p < 0.01) and tracheostomies (p < 0.01), combination treatment (p < 0.01), and surgery with adjuvant chemoradiation treatment (p = 0.01) to increase mortality risk. Disease characteristics, including tumor size (p < 0.01), presence of nodal disease (p = 0.02), and late-stage disease (p < 0.01), increased mortality risk. TTI and diagnostic year did not impact survival. CONCLUSIONS: Our analysis determined several demographic, referral, and treatment factors impacted TTI. However, increased TTI did not impact survival. Characteristics consistent with advanced disease worsened OS. Despite the pandemic burden, patients diagnosed in 2020 showed no difference in short-term survival compared to prior years.

Loss to Follow-up in Head and Neck Cancer: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: To evaluate the reporting and rates of loss to follow-up (LTFU) in head and neck cancer (HNC) randomized controlled trials based in the United States. DATA SOURCES: Pubmed/MEDLINE, Cochrane, Scopus databases. REVIEW METHODS: A systematic review of titles in Pubmed/MEDLINE, Scopus, and Cochrane Library was performed. Inclusion criteria were US-based randomized controlled trials focused on the diagnosis, treatment, or prevention of HNC. Retrospective analyses and pilot studies were excluded. The mean age, patients randomized, publication details, trial sites, funding, and LTFU data were recorded. Reporting of participants through each stage of the trial was documented. Binary logistic regression was performed to evaluate associations between study characteristics and reporting LTFU. RESULTS: A total of 3255 titles were reviewed. Of these, 128 studies met the inclusion criteria for analysis. A total of 22,016 patients were randomized. The mean age of participants was 58.6 years. Overall, 35 studies (27.3%) reported LTFU, and the mean LTFU rate was 4.37%. With the exception of 2 statistical outliers, study characteristics including publication year, number of trial sites, journal discipline, funding source, and intervention type did not predict the odds of reporting LTFU. Compared to 95% of trials reporting participants at eligibility and 100% reporting randomization, only 47% and 57% reported on withdrawal and details of the analysis, respectively. CONCLUSION: The majority of clinical trials in HNC in the United States do not report LTFU, which inhibits the evaluation of attrition bias that may impact the interpretation of significant findings. Standardized reporting is needed to evaluate the generalizability of trial results to clinical practice.