Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function.

Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinson's disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVM's potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.

Evaluating human papillomavirus testing, prevalence, and association with prognosis in head and neck squamous cell carcinoma by subsite: A national cancer database study.

PURPOSE: To compare human papillomavirus (HPV) testing, prevalence, and association with prognosis between head and neck squamous cell carcinoma (HNSCC) subsites. MATERIALS AND METHODS: This study utilized the National Cancer Database (NCDB) to identify patients diagnosed with HNSCC between 2010 and 2017. Rates of HPV testing, HPV-positivity, and changes in these rates over time were measured by subsite. The impact of HPV-positivity on overall survival across six head and neck subsites was assessed using multivariable-adjusted Cox proportional hazards analysis. RESULTS: A total of 121,550 patients were included. Of this cohort, 87,575 (72.1%) were tested for HPV, with the oropharynx (55,049/64,158; 85.8%) displaying the highest rates of testing and the sinonasal tract (1519/2853; 53.2%) displaying the lowest testing rates. Of the 86,136 with a definitive result, 46,878 (54.4%) were HPV-positive, with the oropharynx (40,313/54,205; 74.4%) displaying the highest rates of HPV-positivity and the oral cavity (1818/11,505; 15.8%) displaying the lowest. HPV-positive malignancy was associated with significantly improved adjusted overall survival in the oropharynx (HR = 0.42 [95% CI: 0.43-0.47]), oral cavity (HR = 0.86 [95% CI: 0.79-0.95]), sinonasal tract (HR = 0.63 [95% CI: 0.48-0.83]), larynx (HR = 0.78 [95% CI: 0.71-0.87]), and hypopharynx (HR = 0.56 [95% CI: 0.48-0.66]), but not the nasopharynx (HR = 0.93 [95% CI: 0.77-1.14]). CONCLUSION: HPV testing rates were significantly lower in non-oropharyngeal subsites. This is relevant as HPV-associated disease displayed significantly improved overall survival in both the oropharynx and four of five non-oropharyngeal subsites. While validation with prospective studies is necessary, these findings may warrant HPV testing in all HNSCC subsites.

Early feeding after free flap reconstruction of the oral cavity: A systematic review and meta-analysis.

BACKGROUND: Traditionally, patients undergoing free flap reconstruction for oral cavity defects have been given nothing by mouth for 6-14 days post-operatively due to concern for orocutaneous fistula development. METHODS: Multiple databases were screened for studies assessing the rate of orocutaneous fistula formation in early (≤5 days) versus late (>5 days) feeding groups following oral cavity free flap reconstruction. Fixed- and random-effects meta-analyses were used. RESULTS: One randomized controlled trial, one prospective cohort, and three retrospective cohort studies were included. The early feeding group displayed no significant increase in orocutaneous fistula formation (RD = -0.02, p = 0.06) or free flap failure (RD = -0.01, p = 0.39), with a significantly shorter hospital length of stay (mean difference [days] = -2.43, p < 0.01). CONCLUSIONS: While further prospective trials are necessary, initiation of oral intake before post-operative day 5 may be appropriate in properly selected patients following oral reconstruction.

The Use of Deep Learning Software in the Detection of Voice Disorders: A Systematic Review.

OBJECTIVE: To summarize the use of deep learning in the detection of voice disorders using acoustic and laryngoscopic input, compare specific neural networks in terms of accuracy, and assess their effectiveness compared to expert clinical visual examination. DATA SOURCES: Embase, MEDLINE, and Cochrane Central. REVIEW METHODS: Databases were screened through November 11, 2023 for relevant studies. The inclusion criteria required studies to utilize a specified deep learning method, use laryngoscopy or acoustic input, and measure accuracy of binary classification between healthy patients and those with voice disorders. RESULTS: Thirty-four studies met the inclusion criteria, with 18 focusing on voice analysis, 15 on imaging analysis, and 1 both. Across the 18 acoustic studies, 21 programs were used for identification of organic and functional voice disorders. These technologies included 10 convolutional neural networks (CNNs), 6 multilayer perceptrons (MLPs), and 5 other neural networks. The binary classification systems yielded a mean accuracy of 89.0% overall, including 93.7% for MLP programs and 84.5% for CNNs. Among the 15 imaging analysis studies, a total of 23 programs were utilized, resulting in a mean accuracy of 91.3%. Specifically, the twenty CNNs achieved a mean accuracy of 92.6% compared to 83.0% for the 3 MLPs. CONCLUSION: Deep learning models were shown to be highly accurate in the detection of voice pathology, with CNNs most effective for assessing laryngoscopy images and MLPs most effective for assessing acoustic input. While deep learning methods outperformed expert clinical exam in limited comparisons, further studies integrating external validation are necessary.

Evaluating depth of invasion across oral cavity subsites as part of the AJCC 8th edition T staging criteria for oral cavity squamous cell carcinoma.

BACKGROUND: The prognostic impact of depth of invasion (DOI) in American Joint Committee on Cancer 8th edition TNM staging for oral cavity squamous cell carcinoma (OCSCCa) across oral cavity subsites is unknown. METHODS: Overall survival of patients with pT1-4a OCSCCa in the National Cancer Database (2010-2017), stratified by tumor size and DOI across eight oral cavity subsites, was evaluated using multivariable-adjusted Cox proportional hazards modeling. RESULTS: When stratified by tumor size ≤2 cm and >2 cm, DOI >5 mm and DOI >10 mm were only associated with worse overall survival, respectively, for tumors of the oral tongue (Tumor size ≤2 cm, DOI >5 mm v DOI ≤5 mm: HR: 1.31, 95% CI: 1.12-1.53, p < 0.001; Tumor size >2 cm, DOI >10 mm v DOI ≤10 mm: HR: 1.15, 95% CI: 1.01-1.30, p = 0.03). DOI >5 mm and DOI >10 mm was not prognostic for any other tumor location. CONCLUSIONS: These findings suggest that the current staging schema for DOI in OCSCCa may not be prognostic across all oral cavity subsites.

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus-Associated Oropharyngeal Cancer.

Importance: There is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue-modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials. Objective: To establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting. Design, Setting, and Participants: This retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy. Main Outcomes and Measures: Per-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing. Results: Of 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days. Conclusions and Relevance: This cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay's performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

Association between polychlorinated biphenyl exposure and thyroid hormones: a systematic review and meta-analysis.

Purpose: To conduct a comprehensive meta-analysis investigating the association between polychlorinated biphenyl (PCB) exposure and serum thyroid hormone levels among adults. Methods: Eleven studies met inclusion criteria for analysis following systematic search of PubMed, Embase, and Scopus databases. Of these, 7 studies measured exposure by the total sum of PCB congeners (∑PCB), 1 study measured individual PCB congener levels, and 3 studies measured both ∑PCB levels and PCB congener levels. Correlation coefficients (r) were extracted from each study. Summary estimates were calculated for ∑PCB levels and PCB congeners reported by 2 or more studies: PCB 28, 52, 101, 105, 118, 138, 153, and 180, using random effects model. Results: Significant negative correlation was found between ∑PCBs and T3 (r: -0.09; 95% CI: -0.17, -0.02) and FT3 (r: -0.24; 95% CI: -0.36, -0.12). Congener-specific analysis found T3 to be negatively correlated with PCB-153 (r: -0.19; 95% CI: -0.34, -0.03) and PCB-180 (r: -0.14; 95% CI: -0.26, -0.01), whereas TSH was positively correlated with PCB-105 (r: 0.15; 95% CI: 0.02, 0.28). Conclusions: The present study is the first meta-analysis to investigate the association between PCB exposure and thyroid hormone dysfunction among adults. Results suggest a significant association between PCB exposure and thyroid hormone dysregulation.

The Impact of Socioeconomic Status on the Clinical Outcomes of COVID-19; a Retrospective Cohort Study.

There have been limited data assessing the influence of disadvantaged socioeconomic status (SES) on the incidence and clinical outcomes of COVID-19 patients within the diverse communities of the United States. Here, we aim to investigate the association between poverty level, as an indicator of SES, and COVID-19 related clinical outcomes including hospitalization and all-cause mortality. This retrospective cohort study included 3528 patients with laboratory confirmed COVID-19 seen at a large New York City health system between March 1, 2020 and April 1, 2020. Data for neighborhood level poverty was acquired from the American Community Survey 2014-2018 and defined as the percent of residents in each ZIP code whose household income was below the federal poverty threshold (FPT): 0% to < 20% below FPT (low poverty) and > 20% below FPT (high poverty). COVID-19 positive patients who resided in high poverty areas were significantly younger, had a higher prevalence of comorbidities and were more likely to be of female gender or a racial minority when compared to individuals living in low poverty areas. Residence in a high poverty area was not associated with an increased risk of COVID-19 related hospitalization and was found to be associated with a decreased risk of in-hospital mortality. This study suggests the existence of an unequal socioeconomic gradient in the demographic and clinical presentation of COVID-19 patients including differences in age, gender and race between poverty groups. Further studies are needed to fully assess the intersectionality of SES with the COVID-19 pandemic.

Risk factors and outcomes of COVID-19 in New York City; a retrospective cohort study.

Coronavirus disease 2019 (COVID-19) is a global pandemic and information on risk factors for worse prognosis is needed to accurately identify patients at risk and potentially provide insight into therapeutic options. In this retrospective cohort study, including 3703 patients with laboratory confirmed COVID-19, we identified risk factors associated with all-cause mortality, need for hospitalization and mechanical ventilation. Male gender was independently associated with increased risk of hospitalization (adjusted odds ratio [ORadj ]: 1.62; 95% confidence interval [95% CI]: 1.38-1.91)), mechanical ventilation (ORadj : 1.35; 95% CI: 1.08-1.69) and death (ORadj : 1.46; 95% CI: 1.17-1.82). Patients > 60 years had higher risk of hospitalization (ORadj : 5.47; 95% CI: 4.29-6.96), mechanical ventilation (ORadj : 3.26; 95% CI: 2.08-5.11) and death (ORadj : 13.04; 95% CI: 6.25-27.24). Congestive heart failure (ORadj: 1.47; 95% CI: 1.06-2.02) and dementia (ORadj : 2.03; 95% CI: 1.46-2.83) were associated with increased odds of death, as well as the presence of more than two comorbidities (ORadj : 1.90; 95% CI: 1.35-2.68). Patients with COVID-19 of older age, male gender, or having more than two comorbidities are at higher risk of hospitalization, mechanical ventilation and death, and should therefore be closely monitored.

Outcomes of Patients With Hypothyroidism and COVID-19: A Retrospective Cohort Study.

Coronavirus diseases (COVID-19) is associated with high rates of morbidity and mortality and worse outcomes have been reported for various morbidities. The impact of pre-existing hypothyroidism on COVID-19 outcomes remains unknown. The aim of the present study was to identify a possible association between hypothyroidism and outcomes related to COVID-19 including hospitalization, need for mechanical ventilation, and all-cause mortality. All patients with a laboratory confirmed COVID-19 diagnosis in March 2020 in a large New York City health system were reviewed. Of the 3703 COVID-19 positive patients included in present study, 251 patients (6.8%) had pre-existing hypothyroidism and received thyroid hormone therapy. Hypothyroidism was not associated with increased risk of hospitalization [Adjusted Odds Ratio (ORadj): 1.23 (95% Confidence Interval (CI): 0.88- 1.70)], mechanical ventilation [ORadj: 1.17 (95% CI: 0.81-1.69)] nor death [ORadj: 1.07 (95% CI: 0.75-1.54)]. This study provides insight into the role of hypothyroidism on the outcomes of COVID-19 positive patients, indicating that no additional precautions or consultations are needed. However, future research into the potential complications of COVID-19 on the thyroid gland and function is warranted.

Shoulder strength and range-of-motion characteristics in bodybuilders.

The purpose of this study was to compare shoulder range-of-motion (ROM) and strength values between bodybuilders and nonbodybuilders. Fifty-four men (29 bodybuilders and 25 nonbodybuilders) between the ages of 21 and 34 years participated in the study. Goniometric measurements were used to assess shoulder flexion and internal and external rotation ROM. Isometric manual muscle tests were performed using a handheld dynamometer. Shoulder flexion, internal and external rotation, abduction, and prone shoulder retraction and elevation strength were tested. Independent t-tests were used to determine levels of statistical significance between the groups. Bodybuilders showed an overall loss of shoulder rotation ROM (166 degrees vs. 180 degrees ) and a significantly decreased internal rotation ROM (-11 degrees ) compared with the control group. Bodybuilders were significantly stronger on all isometric shoulder-strength tests than nonbodybuilders, except for the assessment of lower trapezius strength when expressed as a percentage of body weight. The results of this study indicate that bodybuilders have imbalances regarding strength and ROM at the shoulder that may make them susceptible to shoulder pathology.