Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma, independent of tobacco and alcohol and human papillomavirus.

Over the past decade, there has been a change in the epidemiology of oral cavity squamous cell cancer (OC-SCC). Many new cases of OC-SCC lack the recognized risk factors of smoking, alcohol and human papilloma virus. The aim of this study was to determine if the oral microbiome may be associated with OC-SCC in nonsmoking HPV negative patients. We compared the oral microbiome of HPV-negative nonsmoker OC-SCC(n = 18), premalignant lesions(PML) (n = 8) and normal control patients (n = 12). Their oral microbiome was sampled by oral wash and defined by 16S rRNA gene sequencing. We report that the periodontal pathogens Fusobacterium, Prevotella, Alloprevotella were enriched while commensal Streptococcus depleted in OC-SCC. Based on the four genera plus a marker genus Veillonella for PML, we classified the oral microbiome into two types. Gene/pathway analysis revealed a progressive increase of genes encoding HSP90 and ligands for TLRs 1, 2 and 4 along the controls→PML → OC-SCC progression sequence. Our findings suggest an association between periodontal pathogens and OC-SCC in non smoking HPV negative patients.

Flightin maintains myofilament lattice organization required for optimal flight power and courtship song quality in Drosophila.

The indirect flight muscles (IFMs) of Drosophila and other insects with asynchronous flight muscles are characterized by a crystalline myofilament lattice structure. The high-order lattice regularity is considered an adaptation for enhanced power output, but supporting evidence for this claim is lacking. We show that IFMs from transgenic flies expressing flightin with a deletion of its poorly conserved N-terminal domain (flnΔN62 ) have reduced inter-thick filament spacing and a less regular lattice. This resulted in a decrease in flight ability by 33% and in skinned fibre oscillatory power output by 57%, but had no effect on wingbeat frequency or frequency of maximum power output, suggesting that the underlying actomyosin kinetics is not affected and that the flight impairment arises from deficits in force transmission. Moreover, we show that flnΔN62 males produced an abnormal courtship song characterized by a higher sine song frequency and a pulse song with longer pulses and longer inter-pulse intervals (IPIs), the latter implicated in male reproductive success. When presented with a choice, wild-type females chose control males over mutant males in 92% of the competition events. These results demonstrate that flightin N-terminal domain is required for optimal myofilament lattice regularity and IFM activity, enabling powered flight and courtship song production. As the courtship song is subject to female choice, we propose that the low amino acid sequence conservation of the N-terminal domain reflects its role in fine-tuning species-specific courtship songs.

HIV self-testing in resource-limited settings: regulatory and policy considerations.

HIV self-testing (HIVST) is an emerging HIV testing strategy intended to address challenges of increasing access to preliminary knowledge of serostatus. It offers the potential for tests and testing to reach more people than previously possible, including those who do not seek testing in facilities. With approval of an HIV self-test kit in the USA, increasing evidence from public pilot programs in sub-Saharan Africa showing high acceptability and feasibility, and evidence of the informal sale of rapid HIV test kits in the private sector, options for individuals to access HIV self-testing, as well as consumer-demand, appear to be increasing. More recently WHO and UNAIDS have explored self-testing as an option to achieving greater HIV testing coverage to support global treatment targets. However, for resource-limited settings, technological development, diagnostic device regulation and quality assurance policies are lagging behind. This commentary will examine regulatory and policy issues with HIVST, given its increased prominence as a potential part of the global HIV/AIDS response.

The Financial Implications of Pancreatic Surgery: The Hospital Is the Big Winner, Not the Surgeon!

Background: High-volume pancreatic surgery centers require a significant investment in expertise, time, and resources to achieve optimal patient outcomes. A detailed understanding of the economics of major pancreatic surgery is limited among many clinicians and hospital administrators. A greater consideration of these financial aspects may in fact have implications for enhancing clinical care and for a broader sustainability of high-volume pancreatic surgery programs. Methods: In this retrospective observational study, patients who underwent pancreaticoduodenectomy (PD), total pancreatectomy, or distal pancreatectomy at one academic medical center during the fiscal year 2021 were evaluated. Detailed hospital charges and professional fees were obtained for patients using the Qlik perioperative database. Clinical data for the study cohort were gathered from a prospectively maintained, IRB-approved pancreatic surgery database. Charges for the 91-day perioperative period were included. A P < 0.05 was considered significant. Results: During the study period, 159 evaluable patients underwent 1 of 3 designated pancreatic resections included in the analysis. Ninety-seven patients (61%) were diagnosed with adenocarcinoma and 70% (n = 110) underwent PD. The total charges (combined professional and hospital charges) for the cohort encompassing the entire perioperative period were $20,661,759. The median charge per patient was $130,306 (interquartile range [IQR], $34,534). The median direct cost of care was $23,219 (IQR, $6321) and the median contribution margin per case was $10,092 (IQR, $22,949). The median surgeon professional fee charges were $7700 per patient (IQR, $1296) as compared to $3453 (IQR, $1,144) for professional fee receipts (45% of the surgeon charge). The differences between the professional fee charges and receipts per patient were also considerable for other health care professionals such as anesthesiologists ($4945 charges vs $1406 receipts [28%]) and pathologists ($3035 charges vs $680 receipts [22%]). The surgeon professional fees were only 6% of the total charges, while the professional fees for anesthesiology and pathology were 4% and 2% of the total charges, respectively. Supply charges were 3% of the total charges. Longer operative time was correlated with increased hospital and anesthesia charges, without a significant increase in surgeon charges (P < 0.001, P < 0.001, and P = 0.2, respectively). Male sex, diabetes, and low serum albumin correlated with greater total hospital charges (P = 0.01, P = 0.01, and P = 0.03, respectively). Conclusions: The role of the surgeon in the perioperative clinical care of major pancreatic resection patients is crucial and important and is by no means limited to the operative day. Nevertheless, in the context of the current US health care system, the reimbursement to the surgeon in the form of professional fees is a relatively small fraction of the total health care receipts for these patients. This imbalance necessitates a substantial financial partnership between hospitals and their pancreatic surgery units to ensure the long-term viability of these programs.

Nuclear receptor corepressor 1 levels differentially impact the intracellular dynamics of mutant thyroid hormone receptors associated with resistance to thyroid hormone syndrome.

Thyroid hormone receptor α1 (TRα1) undergoes nucleocytoplasmic shuttling and mediates gene expression in response to thyroid hormone (T3). In Resistance to Thyroid Hormone Syndrome α (RTHα), certain TRα1 mutants have higher affinity for nuclear corepressor 1 (NCoR1) and may form stable complexes that are not released in the presence of T3. Here, we examined whether NCoR1 modulates intranuclear mobility and nuclear retention of TRα1 or RTHα-associated mutants in transfected human cells, as a way of analyzing critical structural components of TRα1 and to further explore the correlation between mutations in TRα1 and aberrant intracellular trafficking. We found no significant difference in intranuclear mobility, as measured by fluorescence recovery after photobleaching, between TRα1 and select RTHα mutants, irrespective of NCoR1 expression. Nuclear-to-cytoplasmic fluorescence ratios of RTHα mutants, however, varied from TRα1 when NCoR1 was overexpressed, with a significant increase in nuclear retention for A263V and a significant decrease for A263S and R384H. In NCoR1-knockout cells, nuclear retention of A263S, A263V, P389R, A382P, C392X, and F397fs406X was significantly decreased compared to control (wild-type) cells. Luciferase reporter gene transcription mediated by TRα1 was significantly repressed by both NCoR1 overexpression and NCoR1 knockout. Most RTHα mutants showed minimal induction regardless of NCoR1 levels, but T3-mediated transcriptional activity was decreased for R384C and F397fs406X when NCoR1 was overexpressed, and also decreased for N359Y in NCoR1-knockout cells. Our results suggest a complex interaction between NCoR1 and RTHα mutants characterized by aberrant intracellular localization patterns and transcriptional activity that potentially arise from variable repressor complex stability, and may provide insight into RTHα pathogenesis on a molecular and cellular level.

Oral Microbiome in Nonsmoker Patients with Oral Cavity Squamous Cell Carcinoma, Defined by Metagenomic Shotgun Sequencing.

Objectives: Smoking is the commonest cause of oral cavity squamous cell carcinoma (OC-SCC), but the etiology of OC-SCC in nonsmokers is unknown. Our primary goal was to use metagenomic shotgun sequencing (MSS) to define the taxonomic composition and functional potential of oral metagenome in nonsmokers with OC-SCC. Methods: We conducted a case-control study with 42 OC-SCC case and 45 control nonsmokers. MSS was performed on DNA extracted from mouthwash samples. Taxonomic analysis and pathway analysis were done using MetaPhlAn2 and HUMAnN2, respectively. Statistical difference was determined using the Mann-Whitney test controlling false discovery rate. Results: There was no significant difference in age, sex, race, or alcohol consumption between OC-SCC and control patients. There was a significant difference in beta diversity between OC-SCC and controls. At the phylum level, Bacteroidetes and Synergistetes were overly represented in OC-SCC while Actinobacteria and Firmicutes were overly represented in controls. At the genus level, Fusobacterium was overly represented in OC-SCC compared with controls, while Corynebacterium, Streptococcus, Actinomyces, Cryptobacterium, and Selenomonas were overly represented in controls. Bacterial pathway analysis identified overrepresentation in OC-SCC of pathways related to metabolism of flavin, biotin, thiamin, heme, sugars, fatty acids, peptidoglycans, and tRNA and overrepresentation of nucleotides and essential amino acids in controls. Conclusions: The oral microbiome in nonsmoker patients with OC-SCC is significantly different from that of nonsmoker control patients in taxonomic compositions and functional potentials. Our study's MSS findings matched with previous 16S-based methods in taxonomic differentiation but varied greatly in functional differentiation of microbiomes in OC-SCC and controls.

A Contemporary Review of Immune Checkpoint Inhibitors in Advanced Clear Cell Renal Cell Carcinoma.

The use of checkpoint inhibitors in advanced and metastatic renal cell carcinomas (RCCs) has rapidly evolved over the past several years. While immune-oncology (IO) drug therapy has been successful at resulting in improved responses and survival, combination therapies with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors have further improved outcomes. This article reviews the landmark trials that have led to the approval of IO therapies, including the Checkmate 214 trial and combination IO/VEGF TKI therapies with Checkmate 9ER, CLEAR, and Keynote-426, and it includes a discussion on promising therapies moving in the future.

Flexible fiber-based CO2 laser vs monopolar cautery for resection of oral cavity lesions: A single center randomized controlled trial assessing pain and quality of life following surgery.

IMPORTANCE: This study reports the impact of laser surgery on quality of life in patients with oral cavity lesions. OBJECTIVE: To compare postoperative pain and quality of life in patients treated with flexible fiberoptic CO2 laser vs electrocautery in patients with oral cavity precancerous lesions and early stage cancers. DESIGN: Randomized controlled trial. SETTING: Single center. PARTICIPANTS: Patients with premalignant oral cavity lesions and early stage oral cancer. INTERVENTION: Patients were randomized to have surgical resection using either flexible fiber carbon dioxide laser (Laser) or electrocautery (EC). The patients were then followed over a period of 28 days to assess for outcomes including pain, quality of life, performance status, return to work, and return to diet. Quality of life was measured by the University of Washington Quality of Life (UWQOL) questionnaire and the performance status score (PSS). MAIN OUTCOME MEASURE: The primary endpoint for this study was the numerical pain rating on postoperative day (POD) 7. RESULTS: Sixty-two patients were randomized (32 laser and 30 electrocautery). Lesions excised were carcinoma in 30(48%), dysplasia in 31(50%) and benign in 1(2%). There was no difference in the location of lesion, size of lesion, defect size, type of closure, resection time, and blood loss between Laser and EC arms. Patients who had Laser had less pain compared to EC (mean pain score on POD 7 L = 2.84 vs EC = 3.83, P = 0.11). better UW QOL scores and PSS scores, quicker return to normal diet (median days L = 26.0 vs EC = 28.5, P = 0.17) and faster return to work (median days L = 13.0 vs EC = 16.5, P = 0.14). However, these results were not statistically significant. CONCLUSION: There was a trend for patients treated with laser to have less pain and better quality of life scores but these result were not statistically significant. Based on the actual observed difference, a large multicenter RCT with 90 patients in each arm is required to determine the clinical relevance of our results.

Case control study comparing the HPV genome in patients with oral cavity squamous cell carcinoma to normal patients using metagenomic shotgun sequencing.

The aim of this study was to carry out a case control study comparing the HPV genome in patients with oral cavity squamous cell carcinoma (OC-SCC) to normal patients using metagenomic shotgun sequencing. We recruited 50 OC-SCC cases which were then matched with a control patient by age, gender, race, smoking status and alcohol status. DNA was extracted from oral wash samples from all patients and whole genome shotgun sequencing performed. The raw sequence data was cleaned, reads aligned with the human genome (GRCH38), nonhuman reads identified and then HPV genotypes identified using HPViewer. In the 50 patients with OC-SCC, the most common subsite was tongue in 26 (52%). All patients were treated with primary resection and neck dissection. All but 2 tumors were negative on p16 immunohistochemistry. There were no statistically significant differences between the cases and controls in terms of gender, age, race/ethnicity, alcohol drinking, and cigarette smoking. There was no statistically significant difference between the cancer samples and control samples in the nonhuman DNA reads (medians 4,228,072 vs. 5,719,715, P value = 0.324). HPV was detected in 5 cases (10%) of OC-SCC (genotypes 10, 16, 98) but only 1 tumor sample (genotype 16) yielded a high number of reads to suggest a role in the etiology of OC-SCC. HPV was detected in 4 control patients (genotypes 16, 22, 76, 200) but all had only 1-2 HPV reads per human genome. Genotypes of HPV are rarely found in patients with oral cancer.

A systematic review of the voice-tagging hypothesis of speech-in-noise perception.

The voice-tagging hypothesis claims that individuals who better represent pitch information in a speaker's voice, as measured with the frequency following response (FFR), will be better at speech-in-noise perception. The hypothesis has been provided to explain how music training might improve speech-in-noise perception. This paper reviews studies that are relevant to the voice-tagging hypothesis, including studies on musicians and nonmusicians. Most studies on musicians show greater f0 amplitude compared to controls. Most studies on nonmusicians do not show group differences in f0 amplitude. Across all studies reviewed, f0 amplitude does not consistently predict accuracy in speech-in-noise perception. The evidence suggests that music training does not improve speech-in-noise perception via enhanced subcortical representation of the f0.

High School Students' College Outcomes in a Dual Enrollment Program, 1998-2015.

AIMS: This paper examines the college outcomes of dual-enrolled high school health science careers' students from 1998 to 2015. METHODS: For this retrospective descriptive evaluation of the program, the university requested from the National Student Clearinghouse (NSC) data on 6,831 students who had earned college credit through the Rutgers high school program. Descriptive statistics were used for analysis using Excel. RESULTS: Final dataset had 5,315 students, with 3,339 students who had been in college long enough to graduate. Of the 2,358 (71%) who had graduated from college, 62% (1,470) completed their associates or bachelor's degrees within 2 or 4 years, while an additional 25% (581) finished their respective degrees within 3 to 6 years. Students attending 2-year colleges had a 42% overall, on-time graduation rate, and students attending 4-year colleges had a 95% graduation rate. One or more health professions degrees were earned by 36% (862) of graduated students. DISCUSSION: College degree completion rates of these students are better than national performance and many students entered health careers. This paper adds to the literature on design and outcomes of dual high school/college enrollment at a time when states are expanding these partnerships.

Detection of HPV related oropharyngeal cancer in oral rinse specimens.

BACKGROUND: The majority of patients diagnosed with oropharyngeal squamous cell cancer (OPSCC) are due to HPV infection. At present, there are no reliable tests for screening HPV in patients with OPSCC. The objective of this study was to assess the Cobas® HPV Test on oral rinse specimens as an early, non-invasive tool for HPV-related OPSCC. METHODS: Oral rinse specimens were collected from 187 patients (45 with OPSCC, 61 with oral cavity SCC (OCSCC) and 81 control patients who had benign or malignant thyroid nodules) treated at MSKCC. The Cobas® HPV Test was used to detect 14 high-risk HPV types in these samples. Performance of the HPV Test was correlated with p16 tumor immunohistochemistry as gold standard. RESULTS: 91.1% of the oropharynx cancer patients had p16 positive tumors compared to 3.3% of oral cavity cancer. Of the 81 control patients, 79 (97.5%) had no HPV in their oral rinse giving a specificity of the HPV test of 98%. For the combined oral cavity oropharynx cancer cohort, the sensitivity, specificity, positive predictive value and negative predictive value of the HPV Test were 79.1%, 90.5%, 85.0% and 86.4% respectively when p16 immunohistochemistry was used as the reference. CONCLUSION: The Cobas® HPV Test on oral rinse is a highly specific and potentially sensitive test for oropharyngeal cancer and may be a potentially useful screening test for early oropharyngeal cancer. IMPACT: We describe an oral rinse test for the detection of HPV related oropharyngeal cancer.

Hemispheric asymmetry in the hierarchical perception of music and speech.

The perception of music and speech involves a higher level, cognitive mechanism that allows listeners to form expectations for future music and speech events. This article comprehensively reviews studies on hemispheric differences in the formation of melodic and harmonic expectations in music and selectively reviews studies on hemispheric differences in the formation of syntactic and semantic expectations in speech. On the basis of this review, it is concluded that the higher level mechanism flexibly lateralizes music processing to either hemisphere depending on the expectation generated by a given musical context. When a context generates in the listener an expectation whose elements are sequentially ordered over time, higher level processing is dominant in the left hemisphere. When a context generates in the listener an expectation whose elements are not sequentially ordered over time, higher level processing is dominant in the right hemisphere. This article concludes with a spreading activation model that describes expectations for music and speech in terms of shared temporal and nontemporal representations. (PsycINFO Database Record

Hemispheric asymmetry in the formation of musical pitch expectations: a monaural listening and probe tone study.

This study investigated hemispheric asymmetry in the formation of musical pitch expectations by combining the monaural listening and probe tone paradigms. On each trial, adult participants heard a short context melody and a single pitch (i.e. a probe tone). Both the context and the probe tone were played in the left or right ear. The context was an ascending major scale or pitches from the major scale in a random order. Following each context, participants rated one of three probe tones for how well it fit with the context they just heard. Probe tones were one of two pitches from the major scale (the tonic or the supertonic) or an out-of-set pitch. Participants provided the highest ratings for the tonic, followed by the supertonic, followed by the out-of-set pitch. Ratings did not differ for the tonic or out-of-set pitch between the two ears, but participants provided lower ratings for the supertonic in the right ear. For the ascending context only, the difference in ratings between the tonic and supertonic was greater in the right ear. These results suggest that the left hemisphere differentiates the stability of pitches in a set by forming temporal expectations for specific, in-set pitches.