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IMPORTANCE: Clinical guidelines recommend cognitive behavioral therapy (CBT) as a treatment for tinnitus. However, patient response to CBT is variable, and currently, there are no known predictors of response to CBT treatment for tinnitus. OBJECTIVE: To identify the clinical predictors of patient response to CBT for treatment of tinnitus. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary cohort analysis of a single-arm clinical study including adults with chronic bothersome tinnitus recruited from Washington University School of Medicine in St Louis (Missouri) from September 2019 to February 2023. Participants completed an 8-week group CBT program with a licensed clinical psychologist. Each week consisted of 2.5 hours of CBT, amounting to 20 hours of total CBT participation, primarily delivered through a virtual platform. Conjunctive consolidation was used to create a predictive classification system for response to CBT based on tinnitus bother and anxiety levels. MAIN OUTCOME AND MEASURE: Response to CBT was predefined as a 13-point or greater decrease in the Tinnitus Functional Index (TFI) survey score. RESULTS: The study sample included 88 adult patients (median [IQR] age, 59 [49-66] years; 47 [53%] females and 41 [47%] males) with chronic bothersome tinnitus, of whom 53 (60%) had at least 13-point decrease in TFI and were considered to be responders. In univariable and multivariable logistic regression analyses, high to moderate anxiety level and severe tinnitus bother were associated with treatment response (adjusted odds ratio: anxiety, 3.33; 95% CI, 0.90-12.30; tinnitus bother, 12.08; 95% CI, 1.48-98.35). The clinical stratification system showed good predictive and discriminative ability (χ2 for linear trend = 20.0; C statistic = 0.75; 95% CI, 0.65-0.85). CONCLUSIONS AND RELEVANCE: The findings of this study show that assessment of bother and anxiety levels in patients with tinnitus may be useful for identifying those who are more likely to respond to CBT. Before incorporation into clinical practice, future research should externally validate this finding in a separate population.

IMPORTANCE: Approximately 150 million individuals in the US snore in the absence of obstructive sleep apnea (primary snoring), but few studies have examined the efficacy of treatments for snoring or evaluated the effect of snoring in sleeping partners. OBJECTIVE: To evaluate the efficacy of 2 treatments for primary snoring. DESIGN, SETTING, AND PARTICIPANTS: This pilot randomized clinical trial that included a convenience sample of people who snore without sleep apnea and their sleeping partner who underwent 4 weeks of snoring treatment was conducted at an academic medical center between October 3, 2022, and July 3, 2023. INTERVENTIONS: Fifty couples were randomized to either use a mandibular advancement device (MAD) or receive combined airway and positional therapy (CAPT; external nasal dilator, nasal saline lavage with mometasone, mouth taping, and lateral positional therapy). MAIN OUTCOME AND MEASURE: Percentage of sleeping partners who reported that their partner’s snoring was either very much improved or much improved (responder) on the Clinical Global Impression of Improvement scale. RESULTS: A total of 42 dyads completed the study; 23 (55%) were randomized to MAD and 19 (45%) to CAPT. Among people who snore, 26 (62%) were female, and the mean (SD) age was 48 (14) years. Of 23 dyads randomized to MAD, 21 people who snore (91%) were rated by the sleeping partner as a responder, while 11 of the 19 dyads (58%) randomized to CAPT were rated by the sleeping partner as responder, resulting in a difference of 33 percentage points (95% CI, 8-58) and a number needed to treat of 3. Of the 10 participants who were withdrawn, 4 were withdrawn due to adverse effects of the treatment that were evenly distributed between the MAD (n = 2) and CAPT (n = 2) groups. CONCLUSION AND RELEVANCE: The results of this randomized clinical trial showed that the MAD may be more effective than CAPT for treating primary snoring, while both treatment options were found to reduce primary snoring. Physicians should have a patient-centered discussion to determine which treatment is best for individual patients with primary snoring, weighing convenience, adverse effects, and cost as factors. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05756647

To assess ocular microvasculature changes using optical coherence tomography angiography (OCTA) in pediatric patients with inflammatory bowel disease (IBD). Patients (aged 6–18 years) with IBD were recruited between September 2021 and May 2023. All eligible participants underwent comprehensive clinical assessment and laboratory investigation. Patients with functional gastrointestinal disorders served as the controls. This study assessed specific IBD phenotypes, disease duration, clinical and endoscopic activity indices, laboratory markers, and medication histories. OCTA was utilized to evaluate ocular microvasculature changes in both groups. A total of 63 children (mean age 12.9 ± 3.3 years) were enrolled, comprising 38 in the IBD group (16 ulcerative colitis, 22 Crohn's disease, and 25 in the control group). Most patients in the IBD group were in remission or had mild‐to‐moderate disease activity at enrollment. Analysis of the OCTA results revealed significant differences in the choroidal luminal area and total choroidal area between the IBD and control groups. The study identified distinct ocular microvasculature changes in pediatric IBD patients through OCTA, suggestive of potential systemic endothelial dysfunction. These findings underscore the utility of OCTA in evaluating microvascular alterations associated with pediatric IBD, offering insights into potential systemic complications linked to inflammation in IBD patients. Inflammatory bowel diseases (IBD) encompass systemic inflammation due to immune and nonimmune cell activation leading to microvascular endothelial damage.Endothelium plays a crucial role in various physiological processes like vasoconstriction/vasodilation, coagulation, and leukocyte migration.IBD patients often exhibit early endothelial dysfunction in the gut microvascular system. Inflammatory bowel diseases (IBD) encompass systemic inflammation due to immune and nonimmune cell activation leading to microvascular endothelial damage. Endothelium plays a crucial role in various physiological processes like vasoconstriction/vasodilation, coagulation, and leukocyte migration. IBD patients often exhibit early endothelial dysfunction in the gut microvascular system. Optical coherence tomography angiography has been used for the first time in children to evaluate endothelial dysfunction in pediatric IBD.The study identified distinct ocular microvasculature changes in pediatric IBD patients and a significant inverse correlation between platelet count and choroidal vasculature.The findings suggest a potential link between ocular microvascular alterations and systemic endothelial dysfunction in pediatric IBD emphasizing that IBD‐related inflammation goes beyond the gut, impacting the microvasculature system of the eye. Optical coherence tomography angiography has been used for the first time in children to evaluate endothelial dysfunction in pediatric IBD. The study identified distinct ocular microvasculature changes in pediatric IBD patients and a significant inverse correlation between platelet count and choroidal vasculature. The findings suggest a potential link between ocular microvascular alterations and systemic endothelial dysfunction in pediatric IBD emphasizing that IBD‐related inflammation goes beyond the gut, impacting the microvasculature system of the eye.

To share a single institutional experience with clinical research on COVID‐related olfactory dysfunction (OD). Narrative review of published original data and ongoing clinical trials on COVID‐related OD at Washington University from 2020 to 2023. 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). 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. 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.

IMPORTANCE: Despite the aggressive progression of fulminant acute invasive fungal sinusitis (AIFS), data on prognostic factors have been disparate, hindering the development of a staging system. A composite staging system may improve prognostication for patient counseling and conduct of clinical research. OBJECTIVE: To identify prognostically important factors in AIFS and to incorporate the factors into a comprehensive Functional Severity Staging System and Clinical Severity Staging System. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included adult patients diagnosed with pathology-proven AIFS from June 1, 1992, to December 31, 2022, at Washington University Medical Center and Barnes-Jewish Hospital, a tertiary care center in St Louis, Missouri. Data were analyzed from April to July 2023. MAIN OUTCOME AND MEASURES: Sequential sequestration and conjunctive consolidation was used to develop a composite staging system to predict 6-month overall survival. RESULTS: Of 71 patients with pathology-proven AIFS over the 30-year period, the median (range) age of the cohort was 56 (19-63) years, and there were 47 (66%) male patients. The median (range) follow-up time was 2 (0-251) months. There were 28 patients alive within 6 months, for a 39% survival rate. Symptoms, comorbidity burden, and presence and duration of severe neutropenia were associated with 6-month survival and were consolidated into a 3-category Clinical Severity Staging System with 6-month survival of 75% for stage A (n = 16), 41% for stage B (n = 27), and 18% for stage C (n = 28). The discriminative power of the composite staging system was moderate (C statistic, 0.63). CONCLUSION AND RELEVANCE: This cohort study supports the clinical importance of symptomatology, comorbidity burden, and prolonged severe neutropenia at the time of AIFS presentation. The composite clinical staging system may be useful for clinicians when counseling patients with AIFS and conducting clinical research.

Background The University of Pennsylvania Smell Identification Test is widely used to measure change in olfactory function, but a minimal clinically important difference (MCID) has not been well-established. A study published in 1997 regarding patients with head trauma reported an MCID of 4 but did not detail the methods used in the calculation.Objective To validate the MCID for UPSIT in patients with postviral, sinusitis, and procedure-associated olfactory loss.Methods This was a secondary analysis of prospectively collected data from 5 clinical research studies related to olfactory function. Three studies included subjects with COVID-19-related olfactory dysfunction, one with chronic sinusitis subjects, and one with subjects undergoing transsphenoidal surgery. All subjects had completed a baseline and follow-up UPSIT, baseline and follow-up Clinical Global Impression-Severity (CGI-Severity), and a follow-up CGI-Improvement. Both distribution- and anchor-based methods were used to determine the MCID of UPSIT. Distribution-based method calculated MCID using half standard deviation of baseline UPSIT and delta UPSIT scores. Clinical-anchor method determined MCID by comparing delta UPSIT scores between consecutiveCGI-I clinical categories ranging from very much better to very much worse.Results The study population comprised 295 subjects. Subjects had a mean (SD) baseline UPSIT score of 27 (7.5), and follow-up score of 28 (7.9), and a mean UPSIT change of 0.6 (5.8). Half the baseline UPSIT SD was 3.75 and half the delta UPSIT SD was 2.9. With the anchor-based approach, an MCID of 4 was defined as clinically meaningful by exploring the relationship between delta UPSIT and CGI-Improvement. Using a more conservative approach based on the MCID values identified from both methods, we determined that a change of 4 or greater is the appropriate MCID for UPSIT.Conclusion Investigators in the future should use 4 as MCID for UPSIT and report the percentage of study subjects who achieve a clinically meaningful difference.Level of Evidence III.

IMPORTANCE: There is a paucity of large-scale prospective studies evaluating the risk of developing head and neck cancer (HNC) associated with smoking, drinking, and dietary habits. OBJECTIVE: To determine the association of smoking, drinking, and dietary habits with the risk of developing HNC. DESIGN, SETTING, AND PARTICIPANTS: A nested cohort survival analysis of Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial participants was performed. Participants were between 55 and 74 years of age and recruited at 10 centers across the US from November 1993 to July 2001. Participants who developed HNC were matched with controls based on demographics and family history of HNC for analysis of smoking habits; for the analysis of drinking and dietary habits, matching was performed on smoking status and duration in addition to demographics and family history of HNC. Data analysis was performed from January to November 2023. EXPOSURES: Smoking, drinking, and dietary habits. MAIN OUTCOME AND MEASURE: Diagnosis of HNC. RESULTS: In total, 139 926 participants (51% female; mean [SD] age, 62.6 [5.4] years) were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.1 (10.3-13.6) years, 571 of whom developed HNC. HNC risk associated with smoking increased the closer the proximity of the head and neck subsite to the lungs, with the greatest risk associated with smoking observed in laryngeal cancer (current smoker hazard ratio [HR], 9.36; 95% CI, 5.78-15.15 compared to a nonsmoker). For analysis of drinking and dietary habits, 94 466 participants were included in the analysis of smoking habits with a median (IQR) follow-up time of 12.2 (10.5-13.6) years, 264 of whom developed HNC. HNC risk increased with heavy drinking (HR, 1.85; 95% CI, 1.44-2.38) and decreased with consumption of whole grains (HR, 0.78; 95% CI, 0.64-0.94/oz per day), whole fruits (HR, 0.90; 95% CI, 0.82-0.98/cup per day), and overall healthy eating, as scored by Healthy Eating Index 2015 (HR, 0.87; 95% CI, 0.78-0.98/10 points). CONCLUSIONS AND RELEVANCE: In this nested cohort study, the risk of HNC associated with smoking was higher for subsites that were closer to the lungs; heavy drinking was associated with greater HNC risk, while healthy eating was associated with a modest reduction in HNC risk.

Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum–pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum–pemetrexed would improve overall survival in patients with pleural mesothelioma.

IMPORTANCE: The COVID-19 pandemic affected millions of people and has become a dominant etiology of olfactory dysfunction (OD). No interventions with definitive clinical utility exist. Gabapentin represents a potential therapy for COVID-19–induced OD. OBJECTIVE: To evaluate the efficacy of oral gabapentin on olfactory function and olfaction-related quality of life in patients with COVID-19–induced OD. DESIGN, SETTING, AND PARTICIPANTS: This pilot double-blinded, placebo-controlled randomized clinical trial (RCT) was conducted at Washington University School of Medicine in St Louis from January 7, 2022, to February 3, 2023. Adults with at least 3 months of OD after COVID-19 infection were eligible for inclusion. Participants with a history of other causes of OD or contraindications to gabapentin were excluded. INTERVENTION: Patients were randomized 1:1 to oral gabapentin or placebo. All patients underwent titration to a maximum tolerable dose, which was maintained during an 8-week fixed-dose (FD) phase then tapered off. Participants were monitored for 4 weeks following cessation of study medication. MAIN OUTCOMES AND MEASURES: Outcomes were assessed following the 8-week FD phase and 4 weeks after taper completion. The primary outcome measure was the response rate determined by subjective improvement in OD on the Clinical Global Impression of Improvement (CGI-I) after the FD phase. Other subjective and objective measures of olfactory function were also assessed as secondary outcome measures. RESULTS: Sixty-eight participants were enrolled (34 randomized to each arm), a total of 44 participants completed the FD period and 20 (45.4%) reported response to treatment with at least slight improvement in olfaction from baseline. Of those randomized, 51 (75%) were women and 56 were White (82%) with a mean (SD) age of 43 (13.5) years. Baseline demographic features including age, sex, and race and ethnicity were not significantly different between the groups. Of the 18 participants in the gabapentin group, 8 (44%) were responders and of the 26 participants in the placebo group, 12 (46%) reported response to treatment (percent difference, 1.7%; 95% CI, −31.6% to 28.2%). Mixed-model analysis of all secondary outcome measures demonstrated no clinically meaningful or statistically significant difference between the gabapentin and placebo groups throughout the trial. There were no serious adverse events. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, gabapentin was not associated with statistically significant or clinically meaningful benefit over placebo and likely is not an efficacious therapy for COVID-19–induced OD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05184192

Photodynamic therapy (PDT) is a noninvasive therapeutic approach for the treatment of skin cancer and diseases. 5-Aminolevulinic acid is a prodrug clinically approved for PDT. Once internalized by cancer cells, it is rapidly metabolized to the photosensitizer protoporphyrin IX, which under the proper light irradiation, stimulates the deleterious reactive oxygen species (ROS) production and leads to cell death. The high hydrophilicity of 5-aminolevulinic acid limits its capability to cross the epidermis. Lipophilic derivatives of 5-aminolevulinic acid only partly improved skin penetration, thus making its incorporation into nanocarriers necessary. Here we have developed and characterized 5-aminolevulinic acid loaded invasomes made of egg lecithin, either 1,2-dilauroyl-sn-glycero-3-phosphocholine or 1,2-dioleoyl-sn-glycero-3-phosphocholine, and the terpene limonene. The obtained invasomes are highly thermostable and display a spherical morphology with an average size of 150 nm and an encapsulation efficiency of 80%; moreover, the ex vivoepidermis diffusion tests established that nanovesicles containing the terpene led to a much higher skin penetration (up to 80% in 3 h) compared to those without limonene and to the free fluorescent tracer (less than 50%). Finally, in vitro studies with 2D and 3D human cell models of melanoma proved the biocompatibility of invasomes, the enhanced intracellular transport of 5-aminolevulinic acid, its ability to generate ROS upon irradiation, and consequently, its antiproliferative effect. A simplified scaffold-based 3D skin model containing melanoma spheroids was also prepared. Considering the results obtained, we conclude that the lecithin invasomes loaded with 5-aminolevulinic acid have a good therapeutic potential and may represent an efficient tool that can be considered a valid alternative in the topical treatment of melanoma and other skin diseases.

A growing body of research suggests that standard group-based models might provide little insight regarding individuals. In the current study, we sought to compare group-based and individual predictors of bothersome tinnitus, illustrating how researchers can use dynamic structural equation modeling (DSEM) for intensive longitudinal data to examine whether findings from analyses of the group apply to individuals. A total of 43 subjects with bothersome tinnitus responded to up to 200 surveys each. In multilevel DSEM, survey items loaded on three factors (tinnitus bother, cognitive symptoms, and anxiety), and results indicated a reciprocal relationship between tinnitus bother and anxiety. In fully idiographic models, the three-factor model fit poorly for two individuals, and the multilevel model did not generalize to most individuals, possibly because of limited power. Research examining heterogeneous conditions, such as tinnitus bother, may benefit from methods such as DSEM that allow researchers to model dynamic relationships.

IMPORTANCE: The number of olfactory dysfunction cases has increased dramatically because of the COVID-19 pandemic. Identifying therapies that aid and accelerate recovery is essential. OBJECTIVE: To determine the efficacy of bimodal visual-olfactory training and patient-preferred scents vs unimodal olfactory training and physician-assigned scents in COVID-19 olfactory loss. DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, single-blinded trial with a 2-by-2 factorial design (bimodal, patient preferred; unimodal, physician assigned; bimodal, physician assigned; unimodal, patient preferred) and an independent control group. Enrollment occurred from February 1 to May 27, 2021. Participants were adults 18 to 71 years old with current olfactory loss defined as University of Pennsylvania Smell Identification Test (UPSIT) score less than 34 for men and less than 35 for women and duration of 3 months or longer. Olfactory loss was initially diagnosed within 2 weeks of COVID-19 infection. INTERVENTIONS: Participants sniffed 4 essential oils for 15 seconds with a 30-second rest in between odors for 3 months. Participants in the physician-assigned odor arms trained with rose, lemon, eucalyptus, and clove. Participants randomized to the patient-preferred arms chose 4 of 24 available scents. If assigned to the bimodal arm, participants were shown digital images of the essential oil they were smelling. MAIN OUTCOMES AND MEASURES: The primary end point was postintervention change in UPSIT score from baseline; measures used were the UPSIT (validated, objective psychometric test of olfaction), Clinical Global Impressions Impression–Improvement (CGI-I; self-report improvement scale), and Olfactory Dysfunction Outcomes Rating (ODOR; olfaction-related quality-of-life questionnaire). RESULTS: Among the 275 enrolled participants, the mean (SD) age was 41 (12) years, and 236 (86%) were female. The change in UPSIT scores preintervention to postintervention was similar between the study arms. The marginal mean difference for change in UPSIT scores preintervention to postintervention between participants randomized to patient-preferred vs physician-assigned olfactory training was 0.73 (95% CI, −1.10 to 2.56), and between participants randomized to bimodal vs unimodal olfactory training was 1.10 (95% CI, −2.92 to 0.74). Five (24%) participants in the control arm had clinically important improvement on UPSIT compared with 18 (53%) in the bimodal, patient-preferred arm for a difference of 29% (95% CI, 4%-54%). Four (19%) participants in the control group self-reported improvement on CGI-I compared with 12 (35%) in the bimodal, patient-preferred arm for a difference of 16% (95% CI, −7% to 39%). The mean change in ODOR score preintervention to postintervention was 11.6 points (95% CI, 9.2-13.9), which was not deemed clinically important nor significantly different between arms. CONCLUSIONS AND RELEVANCE: Based on the change in UPSIT scores, this randomized clinical trial did not show any difference between intervention arms, but when exploring within-patient change in UPSIT as well as self-reported impression of improvement, active interventions were associated with larger improvement than controls with a potential advantage of bimodal intervention. While not definitive, these results suggest that patients with COVID-19 olfactory loss may benefit from bimodal visual-olfactory training with patient-preferred scents. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04710394

In this article, strategies to model thermo-electrochemical mechanisms occurring in Li-ion batteries are introduced. Two models are presented. The first consists in a numerical model suitable for finite-element method (FEM) simulations. The numerical model was validated by comparing simulation results with experimental data. The second model concerns fast and accurate simulations in a SPICE-compatible software package; such a model is denoted by macrocircuit and accounts for the main thermo-electrochemical effects of batteries. The macrocircuit was (i) validated with FEM simulation results and (ii) proven to be effective in simulations of practical circuits based on batteries. Although both the above modeling strategies were applied to a commercial product, they are suitable for batteries in any technology.

Introduction: Peripheral venous access for extracorporeal photopheresis (ECP) may be difficult in graft versus host disease (GVHD) patients, because of previous intravenous therapies and multiple peripheral cannulations; in this population of patients, ultrasound guided midline catheters may be an alternative option to central venous access.Methods: In this single-center, prospective preliminary study, we enrolled all consecutive patients with a diagnosis of GVHD and candidate to ECP, over a period of 10 months. We used inserted power injectable, non-valved, polyurethane, 20–25 cm single lumen midline catheters (MC).Results: Sixty-nine ECP procedures were carried out in six patients, using single-lumen MCs for outflow (5Fr in 74% and 4Fr in 26% of cases). For inflow, we used 5Fr or 4Fr MCs, or central venous access devices previously placed for other clinical reasons. There were no catheter-related complications during the entire period of ECP treatment. Mean outflow was significantly higher for 5Fr than for 4Fr MCs (35.8 ± 7.3 vs 29.2 ± 7.8 ml/min; p= 0.0008) and the procedure time was significantly shorter (92.9 ± 9.2 vs 108 ± 13.2 min; p< 0.0001).Conclusion: In GVHD patients, ECP can be performed efficiently and safely using single lumen polyurethane power injectable MCs. The best results are obtained with 5Fr rather than with 4Fr catheters. This strategy of venous access should be implemented in DIVA patients requiring ECP treatments, and probably also in other types of apheresis.

The measurement of the Cosmic Microwave Background (CMB) polarization and the spectral distortions produced on this radiation field by clusters of galaxies (Sunyaev-Zeldovich Effect, SZE) are the current frontiers in cosmology. In this paper, we report on two stratospheric balloon experiments aimed to study the research fields mentioned above. OLIMPO is a mm/submm waves telescope, with 2.6 m primary mirror coupled to four arrays of Kinetic Inductance Detectors (KID), centered at 150, 250, 350, and 460 GHz, to match the SZ spectrum, and operating at 0.3 K. The payload, flown in 2018 producing a very successful technology demonstration, includes a plug-in Differential Fourier-Transform Spectrometer. LSPE (Large Scale Polarization Explorer) is a combined balloon-borne and ground-based program dedicated to the measurement of the CMB polarization at large angular scales. LSPE/SWIPE (Short Wavelength Instrument for the Polarization Explorer), the balloon-borne instrument, includes a refractive telescope with a 50 cm optical aperture feeding three arrays of 330 multi-mode TES bolometers at 145, 210, e 240 GHz. The polarization of the incoming radiation will be modulated by a rotating Half Wave Plate (HWP), that is maintained levitating by an innovative magnetic suspension system. The detectors and the optical elements are cooled at cryogenic temperatures. The cryogenic system is designed to have a duration of 14 days with a flight performed during the polar night, to allow a coverage of a large fraction of the sky. In the paper, we describe the configuration of the two instruments, the modifications to be implemented on OLIMPO for a second scientific flight and the status of the different sub-system for LSPE/SWIPE.

IMPORTANCE: Effect size quantifies the magnitude of the difference or the strength of the association between variables. In clinical research it is important to calculate and report the effect size and the confidence interval (CI) because it is needed for sample size calculation, meaningful interpretation of results, and meta-analyses. OBSERVATIONS: There are many different effect size measures that can be organized into 2 families or groups—d family and r family. The d family includes measures that quantify the differences between groups. The r family includes measures that quantify the strength of the association. Effect sizes that are presented in the same units as the characteristic being measured and compared are known as nonstandardized or simple effect sizes. The nonstandardized effect sizes have the advantage of being more informative, easier to interpret, and easier to evaluate in the light of clinical significance or practical relevance. Standardized effect sizes are unit-less and are helpful for combining and comparing effects of different outcome measures or across different studies (ie, meta-analysis). CONCLUSIONS AND RELEVANCE: The choice of the correct effect size measure depends on the research question, study design, targeted audience, and the statistical assumptions being made. For a complete and meaningful interpretation of results from a clinical research study, the investigator should make clear the type of effect size being reported, its magnitude and direction, degree of uncertainty of the effect size estimate as presented by the CIs, and whether the results are compatible with a clinically meaningful effect.

IMPORTANCE: Patient-reported outcome measures (PROMs) allow clinicians and researchers to assess health-related information from a patient’s perspective. These measures have been used more frequently over the last several decades, but an associated minimal clinically important difference (MCID) is needed to optimize their utility. This narrative review identified the top 100 most-cited otolaryngology-related PROM development and validation publications and assessed the presence and characteristics of the PROMs’ associated MCID. OBSERVATIONS: In this narrative review, a literature search in Scopus and Web of Science was conducted on June 29, 2022, using keywords related to PROM development and validation studies in otolaryngology and reference lists. Studies that met the definition of a PROM and assessed an otolaryngologic disorder or study population were included for full-text review. After full-text review of 188 articles, the top 100 most-cited PROM development and validation publications, resulting in 106 total PROMs, were chosen for review. A total of 39 (37%) of the identified PROMs had an associated MCID. Of those reporting an MCID, 14 (35.9%) used an anchor-based method, 12 (30.8%) used a distribution-based method, 10 (25.6%) used both, and 3 (7.7%) did not specify or used neither method. Rhinology had the greatest number of PROMs with an associated MCID (16 of 24, 66%), and pediatrics had the fewest (1 of 13, 7.7%). The median number of citations of PROMs with an MCID was higher than those without an MCID. CONCLUSIONS AND RELEVANCE: The majority of the most-cited PROMs in otolaryngology lack an associated MCID. These data indicated that there are a multitude of PROMs that have been cited hundreds of times and used for decades without the ability to identify whether a particular change in score on the instrument is clinically meaningful. There is a need to determine and validate MCIDs for commonly used PROMs to aid clinical research and trial interpretation.

The ability to identify and characterize not only the protein-protein interactions but also their internal modular organization through network analysis is fundamental for understanding the mechanisms of biological processes at the molecular level. Indeed, the detection of the network communities can enhance our understanding of the molecular basis of disease pathology, and promote drug discovery and disease treatment in personalized medicine. This work gives an overview of recent computational methods for the detection of protein complexes and functional modules in protein-protein interaction networks, also providing a focus on some of its applications. We propose a systematic reformulation of frequently adopted taxonomies for these methods, also proposing new categories to keep up with the most recent research. We review the literature of the last five years (2017-2021) and provide links to existing data and software resources. Finally, we survey recent works exploiting module identification and analysis, in the context of a variety of disease processes for biomarker identification and therapeutic target detection. Our review provides the interested reader with an up-to-date and self-contained view of the existing research, with links to state-of-the-art literature and resources, as well as hints on open issues and future research directions in complex detection and its applications.

IMPORTANCE: Olfactory dysfunction (OD) is an increasingly common and morbid condition, especially given the ongoing COVID-19 pandemic. Thus, the ability to reproducibly measure smell loss–associated quality of life (QOL) and its response to treatment is paramount. OBJECTIVE: To develop and validate a concise and visually appealing smell loss–associated QOL patient-reported outcome measure for OD. DESIGN, SETTING, AND PARTICIPANTS: A secondary analysis of comments to an online survey by 1000 patients with olfactory dysfunction published in 2013 was used as the primary source to generate items of the Olfactory Dysfunction Outcomes Rating (ODOR). In addition, 30 patients with OD enrolled in 2 clinical studies at a tertiary care medical center (Washington University) were asked to identify their main concerns associated with smell loss. And finally, 4 otolaryngologists reviewed the items generated from the online survey and the patients’ interviews to identify any additional items. Prospective study design was used for data collection from the 30 patients and 4 otolaryngologists. Prospective study design was used for survey validation. Validation of the ODOR was performed with 283 patients enrolled in several prospective studies at a single institution that completed the ODOR as an outcome measure. MAIN OUTCOMES AND MEASURES: Item generation and selection were the outcomes of ODOR development. The psychometric and clinimetric measures evaluated for validation were internal consistency, test-retest reliability, face and content validity, concurrent validity, and discriminant validity. Minimal clinically important difference was also determined. RESULTS: The ODOR is a 28-item instrument with each item scored as either no difficulty or very rarely bothered (0) to complete difficulty or very frequently bothered (4) with a total instrument score range of 0 to 112 points. Higher scores indicate higher degree of dysfunction and limitation. Validation in the cohort of 283 patients (mean [SD] age, 47.0 [14.4] years; 198 female participants [73%]; 179 White participants [80%]) revealed that the instrument has high internal consistency (Cronbach α = 0.968), test-retest reliability (r = 0.90 [95% CI, 0.81-0.95]), face validity, content validity, concurrent validity (r = 0.87 [95% CI, 0.80-0.91] compared with the Questionnaire of Olfactory Disorders–Negative Statements; ρ = −0.76 [95% CI, −0.81 to −0.71] compared with a patient-reported symptom severity scale), and divergent validity (mean score difference, −33.9 [95% CI, −38.3 to −29.6] between normosmic patients and hyposmic/anosmic patients). The minimal clinically important difference was 15 points. The estimated time for survey completion was approximately 5 minutes. CONCLUSIONS AND RELEVANCE: In this survey creation and validation study, the ODOR was shown to be a novel, concise, reliable, and valid patient-reported outcome measure of OD-associated QOL. It can be used to measure physical problems, functional limitations, and emotional consequences associated with OD and how they change after a given intervention, which is clinically applicable and particularly pertinent given the growing burden of OD associated with COVID-19.

Calcium phosphates (CaPs) have been recently proposed as a bio- and eco-compatible alternative to UV filters in sunscreens, which are in the spotlight for being associated with health risks for both people and the environment. Here, natural CaPs extracted from fish bones have been tested as a booster of the sun protection factor (SPF), that is, as material working in synergy with UV filters to increase sunscreen UV-shielding efficiency, in combination with three of the most used UV filters, namely, octocrylene (OCR), octinoxate, and padimate-O, at different concentrations (10.0 and 20.0 wt %). The material obtained by calcination at 800 °C (CaP-N) was also enriched with Zn (CaP-Zn) or Mn (CaP-Mn) in an attempt to increase its SPF-boosting abilities. CaP-N and CaP-Zn consisted of a biphasic mixture of hydroxyapatite and beta tricalcium phosphate, while CaP-Mn presented a small quantity of Mn oxides. CaP-N was the most effective at increasing the SPF of the final emulsions, doubling the SPF of the formulation containing 20.0 wt % of OCR from 40.6 to 80.8. The results show that these CaPs, produced according to a circular economy approach, can be used as effective SPF boosters to decrease the concentration of UV filters used in sunscreen, while retaining high SPF values.

Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients undergoing diagnostic or therapeutic procedures that require contrast use and negatively affects the long-term outcomes. Patients with type 2 diabetes mellitus (DM), particularly those who have already developed diabetic nephropathy (DN), are more susceptible to contrast-induced renal damage. Indeed, contrast media amplify some pathological molecular and cellular pathways already in place in the DN setting. In recent years, sodium–glucose cotransporter-2 inhibitors (SGLT2i) have triggered a paradigm shift in managing patients with type 2 DM, reducing cardiovascular and renal adverse events, and slowing DN development. Some evidence also suggests favorable effects of SGLT2i on acute kidney injury despite the initial alarm; however, little data exist regarding CI-AKI. The present review provides an updated overview of the most recent experimental and clinical studies investigating the beneficial effects of SGLT2i on chronic and acute renal injury, focusing on their potential role in the development of CI-AKI. Thus, we aimed to expand the clinicians' understanding by underscoring new opportunities to prevent this complication in the setting of DM, where effective preventive strategies are still lacking.

Nano-enabled agriculture involves researching smart nano-agrochemicals for sustainable farming. Nano-hydroxyapatite (nHAP), a phosphorus-rich compound, has the potential to be used as a fertilizer with reduced environmental impact. This study tests the effectiveness of nHAP produced from waste materials (animal bones) on barley plants (Hordeum vulgare). Two different nHAPs were prepared by thermal treatment of chicken bones at 300 °C and 700 °C (nHAP300and nHAP700, respectively). The nanopowders were then tested in a seed toxicity trial and in a greenhouse pot experiment with barley, using Pseudomonas alloputida, a P-solubilizing bacterium (PSB). The treatments were unfertilized soil, conventional triple superphosphate (TSP), and the nHAP treatments alone. The results indicated that: (i) the nHAP materials had particle sizes of 1 micrometer (nHAP300, due to aggregation) and 50–70 nm (nHAP700), with P contents of 12.8 % and 19.6 %, respectively; (ii) no toxicity was observed on barley seeds, and nHAP300at maximum dose stimulated root length by 45.6 % compared to the control; (iii) compared to conventional P fertilizer TSP, nHAP300and nHAP700stimulated root growth by 7 % and 18 %, respectively; (iv) the fraction of available P produced through nHAP300-PSB (40.6 mg kg−1) was higher than that from TSP (39.2 mg kg−1); (v) ions associated with the nHAP structure supplied supplementary nutrients, predominantly allocated in root tissues. This study provides valuable insights for future investigations to assess the implications of P nano-fertilizations in achieving sustainability in agriculture.

This systematic review aimed at investigating the role that biosecurity can have in preventing or controlling colibacillosis in broiler production. Primary studies with natural or experimental exposure to avian pathogenic Escherichia coli, evaluating any biosecurity measure to prevent or control colibacillosis in broiler chickens with at least one of the following outcomes: feed conversion ratio (FCR), condemnations at slaughter, and mortality due to colibacillosis, were included. A systematic search was carried out in 4 databases according to the Cochrane handbook and reported following the PRISMA 2020 directions. Studies (n = 3,886) were screened in a 2-phase process and data matching the inclusion criteria were extracted. Risk of bias assessment was performed. Four studies reporting biosecurity measures to prevent or control colibacillosis in broiler production were included. In all studies, only disinfection during either the pre-hatching period (n = 3) or the post-hatching period (n = 1) was evaluated as biosecurity measure in broiler production, as well as its effect on FCR (n = 2) and mortality (n = 4) due to colibacillosis. No studies with effects on condemnations at slaughter were found. Due to the heterogeneity of studies in regard to interventions and outcomes, meta-analysis was not carried out. The limited findings of this systematic review do not provide a comprehensive evidence to statistically evaluate the efficacy of biosecurity to prevent or control colibacillosis in broiler production. The scarcity of evidence found suggests that further and deeper investigations on the topic are needed, considering the variety of interventions related to biosecurity.

Adding bevacizumab to erlotinib prolonged progression-free survival (PFS) of patients with EGFR-mutated advanced NSCLC in the Japanese JO25567 trial, but limited data were available in non-Asian patients. BEVERLY is an Italian, multicenter, randomized, phase 3 investigating the addition of bevacizumab to erlotinib as first-line treatment of advanced EGFR-mutated NSCLC.

IMPORTANCE: Recent studies suggest that theophylline added to saline nasal irrigation (SNI) can be an effective treatment for postviral olfactory dysfunction (OD), a growing public health concern during the COVID-19 pandemic. OBJECTIVE: To evaluate the efficacy and safety of theophylline added to SNI compared with placebo for COVID-19–related OD. DESIGN, SETTING, AND PARTICIPANTS: This triple-blinded, placebo-controlled, phase 2 randomized clinical trial was conducted virtually between March 15 and August 31, 2021. Adults residing in Missouri or Illinois were recruited during this time period if they had OD persisting for 3 to 12 months following suspected COVID-19 infection. Data analysis was conducted from October to December 2021. INTERVENTIONS: Saline sinus rinse kits and bottles of identical-appearing capsules with either 400 mg of theophylline (treatment) or 500 mg of lactose powder (control) were mailed to consenting study participants. Participants were instructed to dissolve the capsule contents into the saline rinse and use the solution to irrigate their nasal cavities in the morning and at night for 6 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the difference in the rate of responders between the treatment and the control arms, defined as a response of at least slightly better improvement in the Clinical Global Impression-Improvement scale posttreatment. Secondary outcome measures included changes in the University of Pennsylvania Smell Identification Test (UPSIT), the Questionnaire for Olfactory Disorders, the 36-Item Short Form Health Survey on general health, and COVID-19–related questions. RESULTS: A total of 51 participants were enrolled in the study; the mean (SD) age was 46.0 (13.1) years, and 36 (71%) participants were women. Participants were randomized to SNI with theophylline (n = 26) or to SNI with placebo (n = 25). Forty-five participants completed the study. At the end of treatment, 13 (59%) participants in the theophylline arm reported at least slight improvement in the Clinical Global Impression-Improvement scale (responders) compared with 10 (43%) in the placebo arm (absolute difference, 15.6%; 95% CI, −13.2% to 44.5%). The median difference for the UPSIT change between baseline and 6 weeks was 3.0 (95% CI, −1.0 to 7.0) for participants in the theophylline arm and 0.0 (95% CI, −2.0 to 6.0) for participants in the placebo arm. Mixed-model analysis revealed that the change in UPSIT scores through study assessments was not statistically significantly different between the 2 study arms. Eleven (50%) participants in the theophylline arm and 6 (26%) in the placebo arm had a change of 4 or more points in UPSIT scores from baseline to 6 weeks. The difference in the rate of responders as measured by the UPSIT was 24% (95% CI, −4% to 52%) in favor of theophylline. CONCLUSIONS AND RELEVANCE: This randomized clinical trial suggests that the clinical benefit of theophylline nasal irrigations on olfaction in participants with COVID-19–related OD is inconclusive, though suggested by subjective assessments. Larger studies are warranted to investigate the efficacy of this treatment more fully. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04789499

The p97 complex participates in the degradation of muscle proteins during atrophy upon fasting or denervation interacting with different protein adaptors. We investigated whether and how it might also be involved in muscle wasting in cancer, where loss of appetite occurs, or amyotrophic lateral sclerosis (ALS), where motoneuron death causes muscle denervation and fatal paralysis. As cancer cachexia models, we used mice bearing colon adenocarcinoma C26, human renal carcinoma RXF393, or Lewis lung carcinoma, with breast cancer 4T1‐injected mice as controls. As ALS models, we employed 129/SvHsd mice carrying the mutation G93A in human SOD1. The expression of p97 and its adaptors was analysed in their muscles by quantitative real‐time polymerase chain reaction (qPCR) and western blot. We electroporated plasmids into muscles or treated mice with disulfiram (DSF) to test the effects of inhibiting p97 and nuclear protein localization protein 4 (Nploc4), one of its adaptors, on atrophy. The mRNA levels of p97 were induced by 1.5‐fold to 2‐fold in tibialis anterior (TA) of all the cachectic models but not in the non‐cachectic 4T1 tumour‐bearing mice (P≤ 0.05). Similarly, p97 was high both in mRNA and protein in TA from 17‐week‐old SOD1G93Amice (P≤ 0.01). Electroporation of a shRNA for murine p97 into mouse muscle reduced the fibre atrophy caused by C26 (P= 0.0003) or ALS (P≤ 0.01). When we interrogated a microarray, we had previously generated for the expression of p97 adaptors, we found Derl1, Herpud1, Nploc4, Rnf31, and Hsp90ab1induced in cachectic TA from C26‐mice (Fold change > 1.2, adjusted P≤ 0.05). By qPCR, we validated their inductions in TA of cachectic and ALS models and selected Nploc4 as the one also induced at the protein level by 1.5‐fold (P≤ 0.01). Electroporation of a CRISPR/Cas9 vector against Nploc4 into muscle reduced the fibre atrophy caused by C26 (P= 0.01) or ALS (P≤ 0.0001). Because DSF uncouples p97 from Nploc4, we treated atrophying myotubes with DSF, and found accumulated mono and polyubiquitinated proteins and reduced degradation of long‐lived proteins by 35% (P≤ 0.0001), including actin (P≤ 0.05). DSF halves Nploc4 in the soluble muscle fraction (P≤ 0.001) and given to C26‐bearing mice limited the body and muscle weight loss (P≤ 0.05), with no effect on tumour growth. Overall, cancer cachexia and ALS seem to display similar mechanisms of muscle wasting at least at the catabolic level. The p97‐Nploc4 complex appears to have a crucial role in muscle atrophy during these disorders and disrupting this complex might serve as a novel drug strategy.

This paper proposes a homoclinic bifurcation control method in a planar system of nonlinear differential equations (x ˙ = f (x) , x ∈ R 2 , f : U ⊂ R 2 ⟶ R 2). The feedback control law is formulated within the framework of Melnikov theory and L p spaces, and it will be called as L p control. Here it is proved that if γ 0 (t) is the homoclinic orbit of the planar system, then f (γ 0 (t)) ∈ L q space (1 ≤ q ≤ ∞). To avoid the transverse intersection of the stable and unstable manifolds of the hilltop saddle, a lot of control laws (u (x) ∈ L p space) have been developed, where each of them can be found by choosing one particular L q space to f (γ 0 (t)) , such that p and q are conjugate exponents, that is, 1 p + 1 q = 1. Furthermore, a procedure to find the control gains is presented. Numerical results show the efficiency of the proposed method in avoiding the homoclinic bifurcation of a classical Duffing system. [ABSTRACT FROM AUTHOR]

OBJECTIVE--In this study, we asked whether a possible quantitative or qualitative deficiency in naturally occurring Foxp[3.sup.+]CD[4.sup.+] regulatory T-cells ([nT.sub.reg]), which display potent inhibitory effects on T-cell functions in vitro and [...]

A 40-year-old woman presented to the emergency department (ED) complaining of sharp, localized right lower quadrant (RLQ) abdominal pain for 1 day associated with vaginal spotting for 1 week. Her [...]