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Background The objective was to examine functional connectivity linked to the auditory system in patients with bothersome tinnitus. Activity was low frequency (< 0.1 Hz), spontaneous blood oxygenation level-dependent (BOLD) responses at rest. The question was whether the experience of chronic bothersome tinnitus induced changes in synaptic efficacy between co-activated components. Functional connectivity for seed regions in auditory, visual, attention, and control networks was computed across all 2 mm 3 brain volumes in 17 patients with moderate-severe bothersome tinnitus ( Tinnitus Handicap Index: average 53.5 ± 3.6 (range 38-76)) and 17 age-matched controls. Results In bothersome tinnitus, negative correlations reciprocally characterized functional connectivity between auditory and occipital/visual cortex. Negative correlations indicate that when BOLD response magnitudes increased in auditory or visual cortex they decreased in the linked visual or auditory cortex, suggesting reciprocally phase reversed activity between functionally connected locations in tinnitus. Both groups showed similar connectivity with positive correlations within the auditory network. Connectivity for primary visual cortex in tinnitus included extensive negative correlations in the ventral attention temporoparietal junction and in the inferior frontal gyrus and rostral insula - executive control network components. Rostral insula and inferior frontal gyrus connectivity in tinnitus also showed greater negative correlations in occipital cortex. Conclusions These results imply that in bothersome tinnitus there is dissociation between activity in auditory cortex and visual, attention and control networks. The reciprocal negative correlations in connectivity between these networks might be maladaptive or reflect adaptations to reduce phantom noise salience and conflict with attention to non-auditory tasks.

Objective To share a single institutional experience with clinical research on COVID‐related olfactory dysfunction (OD). Data Source/Method Narrative review of published original data and ongoing clinical trials on COVID‐related OD at Washington University from 2020 to 2023. Results There were three new diagnostic‐/patient‐reported outcome measures developed and tested. We report five clinical trials of interventions for COVID‐related olfactory disorders: combined Visual‐Olfactory Training (VOLT) with patient‐preferred scents versus standard olfactory training (VOLT trial), oral gabapentin versus placebo (Gabapentin for the Relief of Acquired Chemosensory Experience trial), nasal theophylline irrigations versus placebo (Smell Changes and Efficacy of Nasal Theophylline trial), stellate ganglion block (single‐arm), and mindfulness‐based stress reduction (MBSR) versus lifestyle intervention (MBSR trial). Conclusions Initial intervention trials for COVID‐related OD have shown potential for improving subjective and objective olfactory outcomes. However, there remains no gold standard treatment that definitively outperforms placebo in controlled trials. Therefore, continued investigation of novel therapeutic strategies for COVID‐related OD is necessary to maximize olfactory outcomes for affected patients. Key points There are several potential interventions for COVID‐related olfactory disorders, however, more evidence is needed to establish the most effective treatment strategies for olfactory outcomes.

Epidemiological studies have associated certain human disease outcomes with particular killer cell Ig-like receptor (KIR) and HLA genotypes. However, the functional explanation for these associations is poorly understood, because the KIRs were initially described as natural killer (NK) cell inhibitory receptors with specificity for HLA molecules on their cellular targets. Yet resolution of infections is often associated with genotypic pairing of inhibitory KIRs with their cognate HLA ligands. Recent studies in mice indicate a second role for MHC-specific inhibitory receptors, i.e., self-MHC recognition confers functional competence on the NK cell to be triggered through their activation receptors, a process termed licensing. As a result, licensed NK cells with self-MHC-specific receptors are more readily activated as compared with unlicensed NK cells without self-MHC-specific receptors. Such results predict that human NK cells may undergo a similar process. Here, we examined the human NK cell subset expressing KIR3DL1, the only known KIR specific for HLA-Bw4 alleles. The KIR3DL1⁺ subset in normal donors with two HLA-B-Bw4 genes displayed increased responsiveness to tumor stimulation compared with the KIR3DL1⁺ subset from individuals with only one or no Bw4 genes. By contrast, NK cells lacking KIR3DL1 showed no differences. Therefore, these data indicate that particular KIR and HLA alleles are associated with more responsive NK cells, strongly suggesting that human NK cells are also subjected to NK cell licensing, and providing a potential functional explanation for the influence of KIR and HLA genes in disease as well as interindividual differences in NK cell potency.

OBJECTIVES/GOALS: The primary aim is to evaluate the efficacy of a Mandibular Advancement Device (MAD) vs conservative treatment for adults with non-apneic snoring, as measured by the sleeping partner. The secondary aim is to evaluate the effectiveness of treatment of snoring on the sleeping partner’s sleep quality. METHODS/STUDY POPULATION: We plan to enroll 60 pairs of primary snorers and their sleeping partners in our randomized clinical trial. Snorers will be randomized to either 4 weeks of conservative therapy, consisting of nightly Mometasone nasal rinse, breathe-rite strips, mouth taping, and lateral positional therapy, or 4 weeks of Mandibular Advancement Device therapy (MAD). 30 pairs of snorers and their partners will be in each arm. At follow up the primary outcome measure, the Clinical Global Impression of Improvement Scale (CGI-I), will be assessed by the sleeping partner to evaluate the response to snoring treatment. RESULTS/ANTICIPATED RESULTS: To date, there is no study reporting the rate of response in participants using MAD in Primary Snoring. Due to lack of preliminary data and effect size, we hypothesize that the rate of the responders in the MAD group will be 20% higher than the rate of responders in the active control group based on literature studies and preliminary results. A responder will be classified as someone whose sleeping partner rates on the CGI-I scale that the snoring was much improved or very much improved. MAD has been shown previously to be an effective therapy at treating sleep apnea and reducing snoring, and we anticipate it will continue to be so for patients who do not have sleep apnea. DISCUSSION/SIGNIFICANCE: Snoring is a nearly ubiquitous problem that prevents restful sleep for spouses of snorers, which is known to have detrimental health effects. Yet it does not have scientifically proven treatments. Our study will evaluate these treatments in an effort to improve the health of the sleeping partners.

BACKGROUND:To develop evidence-based treatment guidelines for Chiari malformation type 1 (CM-1), preoperative prognostic indices capable of stratifying patients for comparative trials are needed. OBJECTIVE:To develop a preoperative Chiari Severity Index (CSI) integrating the clinical and neuroimaging features most predictive of long-term patient-defined improvement in quality of life (QOL) after CM-1 surgery. METHODS:We recorded preoperative clinical (eg, headaches, myelopathic symptoms) and neuroimaging (eg, syrinx size, tonsillar descent) characteristics. Brief follow-up surveys were administered to assess overall patient-defined improvement in QOL. We used sequential sequestration to develop clinical and neuroimaging grading systems and conjunctive consolidation to integrate these indices to form the CSI. We evaluated statistical significance using the Cochran-Armitage test and discrimination using the C statistic. RESULTS:Our sample included 158 patients. Sequential sequestration identified headache characteristics and myelopathic symptoms as the most impactful clinical parameters, producing a clinical grading system with improvement rates ranging from 81% (grade 1) to 58% (grade 3) (P = .01). Based on sequential sequestration, the neuroimaging grading system included only the presence (55% improvement) or absence (74% improvement) of a syrinx ≥6 mm (P = .049). Integrating the clinical and neuroimaging indices, improvement rates for the CSI ranged from 83% (grade 1) to 45% (grade 3) (P = .002). The combined CSI had moderately better discrimination (c = 0.66) than the clinical (c = 0.62) or neuroimaging (c = 0.58) systems alone. CONCLUSION:Integrating clinical and neuroimaging characteristics, the CSI is a novel tool that predicts patient-defined improvement after CM-1 surgery. The CSI may aid preoperative counseling and stratify patients in comparative effectiveness trials. ABBREVIATIONS:CM-1, Chiari malformation type 1CSI, Chiari Severity IndexQOL, quality of life

•Quantified the risks and burden of SPMN among survivors of potential HPV-associated cancers.•The risk and burden of SPMN was high overall.•1-in-12 survivors of potentially HPV-associated cancers developed SPMN.•SPMNs were predominantly in the aero-digestive tract and other HPV-associated sites.•Finding calls for strategies that prevent or detect SPMN early in cancer survivors. Since the number of cancer survivors is increasing, it is imperative that we better understand the long-term consequences of these survivors. We assessed the risk of developing a second primary malignant neoplasm (SPMN) after an index potentially-HPV-associated cancers (P-HPV-AC). We constructed a population-based cohort of patients with P-HPV-AC using Surveillance, Epidemiology, and End Results registry data (2000–2015). We limited patients to those with invasive P-HPV-AC [cervical, vagina, vulva, penile, anal, and oropharynx] based on the International Classification of Diseases for Oncology, 3rd edition. Excess SPMN risks were calculated based on standardized incidence ratios (SIRs) and excess absolute risks (EARs) per 10,000 person-years at risk (PYR). A total of 105,644 patients with an index P-HPV-AC were identified, and 7.8 % developed a SPMN. In all P-HPV-AC patients, the overall SIR was 1.73 (95 % CI: 1.69–1.77) and EAR of 70.72 per 10,000 PYR. All index P-HPV-AC sites showed statistically significant increases in the risk of SPMN, except for anal cancer among men, compared with the general population. The greatest increase in risk of SPMN was observed among patients diagnosed with an index P-HPV-oropharyngeal cancer (SIR = 1.83; 95 % CI, 1.70–1.82 and SIR = 2.29; 95 % CI, 2.12–2.47 for men and women, respectively). Men developed SPMN mostly in aero-digestive tract whiles women developed SPMN both in aero-digestive tract and other HPV-associated cancer sites. P-HPV-AC survivors experienced excess risk of SPMN. These findings have the potential to affect future surveillance practices and improve preventive healthcare for survivors of P-HPV-ACs.

Comorbidity is an important prognostic factor for elderly patients with head and neck cancer. Investigators are faced with the dilemma of selecting the appropriate comorbidity instrument for outcomes research in cancer. The goal of this study was to compare 2 general comorbidity indices with 2 disease-specific indices. The Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database was used to identify 15,493 patients with incident squamous cell carcinomas of the oral cavity, pharynx, and larynx first diagnosed between December 1983 and December 1994. Comorbid ailments were identified through the use of the International Classification of Diseases, 9th edition codes in the Medicare inpatient and outpatient claims for 7131 patients. The overall severity of comorbidity was classified according to 2 general comorbidity indices: the Charlson Comorbidity Index and the Klabunde Index, and 2 disease-specific indices: the Washington University Head and Neck Index and the Head and Neck Cancer Index. Overall survival was the primary end point. Cox proportional hazards analysis was used to assess the performance and discrimination of the comorbidity indices. Results: For each of the 4 comorbidity indices, there was a weak trend of worse survival with higher levels of comorbidity. The 2 general indices performed as well as the 2 disease-specific indices and no instrument clearly performed better than the others. Both the general and disease-specific comorbidity indices provided important prognostic information. The diseasespecific indices did not perform better than the general indices. In this claims-based analysis, there was no apparent advantage to using a disease-specific index when attempting to predict overall survival.

The symptoms of coronavirus disease 2019 (COVID-19) appear to be heterogenous, and the typical course of these symptoms is unknown. Our objectives were to characterize the common trajectories of COVID-19 symptoms and to assess how symptom course predicts other symptom changes as well as clinical deterioration. One hundred sixty-two participants with acute COVID-19 responded to surveys up to 31 times for up to 17 days. Several statistical methods were used to characterize the temporal dynamics of these symptoms. Because 9 participants showed clinical deterioration, we explored whether these participants showed any differences in symptom profiles. Trajectories varied greatly between individuals, with many having persistently severe symptoms or developing new symptoms several days after being diagnosed. A typical trajectory was for a symptom to improve at a decremental rate, with most symptoms still persisting to some degree at the end of the reporting period. The pattern of symptoms over time suggested a fluctuating course for many patients. Participants who showed clinical deterioration were more likely to present with higher reports of severity of cough and diarrhea. The course of symptoms during the initial weeks of COVID-19 is highly heterogeneous and is neither predictable nor easily characterized using typical survey methods. This has implications for clinical care and early-treatment clinical trials. Additional research is needed to determine whether the decelerating improvement pattern seen in our data is related to the phenomenon of patients reporting long-term symptoms and whether higher symptoms of diarrhea in early illness presages deterioration.

BACKGROUND:Outcomes research on Chiari malformation type 1 (CM-1) is impeded by a reliance on small, single-center cohorts. OBJECTIVE:To study the complications and resource use associated with adult CM-1 surgery using administrative data. METHODS:We used a recently validated International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm to retrospectively study adult CM-1 surgeries from 2004 to 2010 in California, Florida, and New York using State Inpatient Databases. Outcomes included complications and resource use within 30 and 90 days of treatment. We used multivariable logistic regression to identify risk factors for morbidity and negative binomial models to determine risk-adjusted costs. RESULTS:We identified 1947 CM-1 operations. Surgical complications were more common than medical complications at both 30 days (14.3% vs 4.4%) and 90 days (18.7% vs 5.0%) postoperatively. Certain comorbidities were associated with increased morbidity; for example, hydrocephalus increased the risk for surgical (odds ratio [OR] = 4.51) and medical (OR = 3.98) complications. Medical but not surgical complications were also more common in older patients (OR = 5.57 for oldest vs youngest age category) and male patients (OR = 3.19). Risk-adjusted hospital costs were $22530 at 30 days and $24852 at 90 days postoperatively. Risk-adjusted 90-day costs were more than twice as high for patients experiencing surgical ($46264) or medical ($65679) complications than for patients without complications ($18880). CONCLUSION:Complications after CM-1 surgery are common, and surgical complications are more frequent than medical complications. Certain comorbidities and demographic characteristics are associated with increased risk for complications. Beyond harming patients, complications are also associated with substantially higher hospital costs. These results may help guide patient management and inform decision making for patients considering surgery. ABBREVIATIONS:CM-1, Chiari malformation type 1ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical ModificationOR, odds ratioSID, State Inpatient Database

Objectives: A common complaint of cancer patients is the experience of cognitive difficulty during and after chemotherapy. We hypothesized that cognitive impairment may result from dysfunction in large-scale brain networks, particularly those involved in attentional control. Methods: Using a case-control design, this study includes women with a history of invasive ductal or lobular triple-negative breast cancer who completed standard adjuvant chemotherapy within 2 years of study entry. Women who reported cognitive impairment by the Global Rating of Cognition question were considered to be cases (n = 15). Women who reported no cognitive impairment were considered to be controls (n = 13). All enrolled participants were eligible for MRI investigation and underwent resting-state functional connectivity MRI. Results: Women who self-reported cognitive impairment were found to have disrupted resting-state functional connectivity, as measured by MRI, when compared to women who did not self-report cognitive impairment. These findings suggest that some women may be more sensitive to the standard treatments for breast cancer and that this increased sensitivity may result in functional connectivity alterations in the brain networks supporting attention and executive function. Conclusions: Neuroimaging analyses confirmed self-reported cognitive deficits in women with breast cancer treated with chemotherapy.