Prevalence, phenomenology, and impact of misophonia in a nationally representative sample of U.S. adults.

Misophonia is characterized by decreased tolerance for and negative reactions to certain sounds and associated stimuli, which contribute to impairment and distress. Research has found that misophonia is common in clinical, college, and online samples; yet, fewer studies have examined rates of misophonia in population-based samples. The current study addresses limitations of prior research by investigating misophonia prevalence, phenomenology, and impairment in a large, nationally representative sample of adults in the United States. Probability-based sampling was used to administer a survey to a representative sample of U.S. households. Data were adjusted with poststratification weights to account for potential sampling biases and examined as weighted proportions to estimate the outcomes. The sample included 4,005 participants (51.5% female; 62.5% White). Sensitivity to misophonia sounds was reported by 78.5% of the sample, and 4.6% reported clinical levels of misophonia. Results demonstrated significant demographic differences in misophonia symptom severity. Specifically, significantly higher misophonia symptoms were observed for participants who identified as female, less than 55 years old, less than a high school education, never married, lower income, and those working part time, compared to each of the respective comparison groups. Those with clinically significant misophonia symptoms reported that symptoms often onset in childhood and adolescence, were persistent, and contributed to severe impairment in at least one life domain. These findings provide a prevalence estimate of misophonia in the general population of the United States and inform our understanding of who is affected by misophonia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Psychometric Properties of the Short Scale Anxiety Sensitivity Index Among Adults with Chronic Respiratory Disease.

Approximately one-third of adults with chronic respiratory disease (CRD) have comorbid depressive and anxiety disorders; yet these disorders are often unrecognized in this patient population. Transdiagnostic processes such as anxiety sensitivity (AS) are useful for identifying mechanisms underlying psychological and heath conditions. The Short-Scale AS Index (SSASI) is a brief self-report measure of AS which has potential clinical utility among CRD populations to evaluate psychological distress and inform comprehensive care. The present study investigated the psychometric properties of the SSASI among adults with CRDs. Participants were recruited from a web-based panel of adults with CRDs (n = 768; 49.3% female; 57.8% White) including adults with asthma only (n = 230), COPD only (n = 321), or co-occurring asthma and COPD (n = 217). Participants completed a battery of self-report questionnaires assessing psychological and medical symptoms. Analyses were conducted to examine the factor structure and measurement invariance across CRD groups. Convergent validity and criterion validity of the SSASI were assessed within each group. Results supported partial measurement invariance across CRD groups. The SSASI demonstrated high reliability, convergent validity, and criterion validity with each CRD group. Findings from this study and existing work indicate that the SSASI is an effective and economical assessment tool for identifying patients CRD who may benefit from psychological interventions to reduce AS.

Immunity to pathogenic fungi in the eye.

Fusarium, Aspergillus and Candida are important fungal pathogens that cause visual impairment and blindness in the USA and worldwide. This review will summarize the epidemiology and clinical features of corneal infections and discuss the immune and inflammatory responses that play an important role in clinical disease. In addition, we describe fungal virulence factors that are required for survival in infected corneas, and the activities of neutrophils in fungal killing, tissue damage and cytokine production.

Invasive pulmonary aspergillosis in a patient with cirrhosis.

Aspergillus molds are ubiquitous environmental molds that can cause devastating invasive infections in immunocompromised patients. These infections often go unrecognized in critically ill patients. This case describes a 68 year-old female resident of a long-term nursing facility with history of dementia, nonalcoholic fatty liver disease with cirrhosis, chronic kidney disease stage III and insulin-dependent type 2 diabetes who presented with vomiting, diarrhea and leg swelling. She developed hypotension and was treated for sepsis but found to have negative routine infectious workup. Chest imaging showed nodular densities and bilateral opacities. She developed acute renal failure and hypoxic respiratory failure followed by acute decompensated cirrhosis with refractory volume overload and hypotension and was eventually transitioned to comfort care measures. Autopsy ultimately showed invasive pulmonary aspergillosis. Here we review the diagnosis and management of invasive fungal infections in critically ill patients without typical risk factors or clinical findings for invasive fungal disease. Invasive fungal infections are frequently missed and carry high mortality rates, therefore warranting consideration in critically ill populations.

Aspergillus fumigatus corneal infection is regulated by chitin synthases and by neutrophil-derived acidic mammalian chitinase.

Aspergillus fumigatus is an important cause of pulmonary and systemic infections in immune compromised individuals, and of corneal ulcers and blindness in immune competent patients. To examine the role of chitin synthases in Aspergillus corneal infection, we analyzed Aspergillus mutants of chitin synthase family 1 and family 2, and found that compared with the parent strain, the quadruple mutants from both families were more readily killed by neutrophils in vitro, and that both also exhibited impaired hyphal growth in the cornea. Further, inhibition of chitin synthases using Nikkomycin Z enhanced neutrophil killing in vitro and in vivo in a murine model of A. fumigatus corneal infection. Acidic mammalian chitinase (AMCase) is mostly produced by macrophages in asthmatic lungs; however, we now demonstrate that neutrophils are a major source of AMCase, which inhibits hyphal growth. In A. fumigatus corneal infection, neutrophils are the major source of AMCase, and addition of AMCase inhibitors or adoptive transfer of neutrophils from AMCase-/- mice resulted in impaired hyphal killing. Together, these findings identify chitin synthases as important fungal virulence factors and neutrophil-derived AMCase as an essential mediator of host defense.

Potassium conservation is impaired in mice with reduced renal expression of Kir4.1.

To better understand the role of the inward-rectifying K channel Kir4.1 (KCNJ10) in the distal nephron, we initially studied a global Kir4.1 knockout mouse (gKO), which demonstrated the hypokalemia and hypomagnesemia seen in SeSAME/EAST syndrome and was associated with reduced Na/Cl cotransporter (NCC) expression. Lethality by ~3 wk, however, limits the usefulness of this model, so we developed a kidney-specific Kir4.1 "knockdown" mouse (ksKD) using a cadherin 16 promoter and Cre-loxP methodology. These mice appeared normal and survived to adulthood. Kir4.1 protein expression was decreased ~50% vs. wild-type (WT) mice by immunoblotting, and immunofluorescence showed moderately reduced Kir4.1 staining in distal convoluted tubule that was minimal or absent in connecting tubule and cortical collecting duct. Under control conditions, the ksKD mice showed metabolic alkalosis and relative hypercalcemia but were normokalemic and mildly hypermagnesemic despite decreased NCC expression. In addition, the mice had a severe urinary concentrating defect associated with hypernatremia, enlarged kidneys with tubulocystic dilations, and reduced aquaporin-3 expression. On a K/Mg-free diet for 1 wk, however, ksKD mice showed marked hypokalemia (serum K: 1.5 ± 0.1 vs. 3.0 ± 0.1 mEq/l for WT), which was associated with renal K wasting (transtubular K gradient: 11.4 ± 0.8 vs. 1.6 ± 0.4 in WT). Phosphorylated-NCC expression increased in WT but not ksKD mice on the K/Mg-free diet, suggesting that loss of NCC adaptation underlies the hypokalemia. In conclusion, even modest reduction in Kir4.1 expression results in impaired K conservation, which appears to be mediated by reduced expression of activated NCC.

Protein Deiminase 4 and CR3 Regulate Aspergillus fumigatus and ß-Glucan-Induced Neutrophil Extracellular Trap Formation, but Hyphal Killing Is Dependent Only on CR3.

Neutrophil extracellular trap (NET) formation requires chromatin decondensation before nuclear swelling and eventual extracellular release of DNA, which occurs together with nuclear and cytoplasmic antimicrobial proteins. A key mediator of chromatin decondensation is protein deiminase 4 (PAD4), which catalyzes histone citrullination. In the current study, we examined the role of PAD4 and NETosis following activation of neutrophils by A. fumigatus hyphal extract or cell wall ß-glucan (curdlan) and found that both induced NET release by human and murine neutrophils. Also, using blocking antibodies to CR3 and Dectin-1 together with CR3-deficient CD18-/- and Dectin-1-/- murine neutrophils, we found that the ß-glucan receptor CR3, but not Dectin-1, was required for NET formation. NETosis was also dependent on NADPH oxidase production of reactive oxygen species (ROS). Using an antibody to citrullinated histone 3 (H3Cit) as an indicator of PAD4 activity, we show that ß-glucan stimulated NETosis occurs in neutrophils from C57BL/6, but not PAD4-/- mice. Similarly, a small molecule PAD4 inhibitor (GSK484) blocked NET formation by human neutrophils. Despite these observations, the ability of PAD4-/- neutrophils to release calprotectin and kill A. fumigatus hyphae was not significantly different from C57BL/6 neutrophils, whereas CD18-/- neutrophils exhibited an impaired ability to perform both functions. We also detected H3Cit in A. fumigatus infected C57BL/6, but not PAD4-/- corneas; however, we found no difference between C57BL/6 and PAD4-/- mice in either corneal disease or hyphal killing. Taken together, these findings lead us to conclude that although PAD4 together with CR3-mediated ROS production is required for NET formation in response to A. fumigatus, PAD4-dependent NETosis is not required for A. fumigatus killing either in vitro or during infection.

Atovaquone Impairs Growth of Aspergillus and Fusarium Keratitis Isolates by Modulating Mitochondrial Function and Zinc Homeostasis.

Purpose: Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc for fungal growth, we examined the effect of atovaquone, a ubiquinone analog that disrupts zinc homeostasis, on fungal growth in vitro and in vivo. Methods: In vitro: Aspergillus and Fusarium germinating conidia were incubated overnight with atovaquone, and hyphal growth was measured by fluorimetry. In vivo: C57BL/6 mouse corneas were infected with Aspergillus or Fusarium conidia. Atovaquone was added topically and corneal opacification and fungal growth were quantified. Results: Atovaquone has antifungal activity against Aspergillus and Fusarium clinical isolates, with Fusarium species being more sensitive to atovaquone than Aspergillus species. Atovaquone also reduced labile intracellular zinc levels and increased the sensitivity of Aspergillus to metal shock. Atovaquone reduced vacuolar acidification, which regulates storage of intracellular free zinc, and also acted synergistically with voriconazole and itraconazole to kill hyphae. Furthermore, mitochondrial potential and ATP production were reduced in both Aspergillus and Fusarium following atovaquone treatment. Finally, topical application of atovaquone to the ocular surface significantly inhibited fungal growth and corneal opacification in murine models of fungal keratitis. Conclusions: These studies demonstrate that atovaquone has pronounced in vitro and in vivo antifungal activity against filamentous fungi by disrupting both metal homeostasis and mitochondrial function, and therefore has potential as a novel antifungal agent.

Inclusion/exclusion criteria in late life depression antidepressant efficacy trials.

OBJECTIVE: The generalizability of antidepressant efficacy trials (AETs) has been questioned. No studies have examined the inclusion/exclusion criteria used in placebo-controlled studies of late life depression and compared them to the criteria used in non-late life AETs. METHOD: We conducted a comprehensive literature review of placebo-controlled AETs published from January, 1995 through December, 2014. We compared the inclusion/exclusion criteria used in the 18 studies of late life depression to those used in non-late life depression. RESULTS: There were nine inclusion/exclusion criteria that were used in more than half of the late life depression AETs: minimum severity on a symptom severity scale (100.0%), significant suicidal ideation (77.8%), psychotic features during the current episode of depression or history of a psychotic disorder (94.4%), history of bipolar disorder (77.8%), diagnosis of alcohol or drug abuse or dependence (83.3%), presence of a comorbid nondepressive, nonsubstance use Axis I disorder (55.6%), episode duration too short (66.7%), and an insufficient score on a cognitive screen (88.3%) or the presence of a cognitive disorder (55.6%). There were some differences between the late life and non-late life depression studies-use of a screening measure of cognitive functioning, presence of a cognitive disorder such as dementia, and the minimum depression severity cutoff score required at baseline. CONCLUSIONS: The inclusion/exclusion criteria in AETs of late life depression were generally similar to the criteria used in non-late life depression AETs. Copyright © 2016 John Wiley & Sons, Ltd.

The Psychiatric Inclusion and Exclusion Criteria in Placebo-Controlled Monotherapy Trials of Bipolar Depression: An Analysis of Studies of the Past 20 Years.

BACKGROUND: Concerns about the generalizability of pharmacotherapy efficacy trials to "real-world" patients have been raised for more than 40 years. Almost all of this literature has focused on treatment studies of major depressive disorder (MDD). OBJECTIVE: The aim of the study was to review the psychiatric inclusion and exclusion criteria used in placebo-controlled trials that assessed the efficacy of medications for bipolar depression (bipolar disorder efficacy trials [BDETs]) and compare the criteria used in BDETs with those used in efficacy trials of antidepressants to treat MDD (antidepressant efficacy trials [AETs]). METHODS: We searched the MEDLINE, Embase, and PsycINFO databases for articles published from January 1995 through December 2014. We identified 170 placebo-controlled AETs and 22 BDETs published during these 20 years. Two of the authors independently reviewed each article and completed a pre-specified information extraction form listing the psychiatric inclusion and exclusion criteria used in the study. RESULTS: Six inclusion/exclusion criteria were used in at least half of the BDETs: minimum severity on a depression symptom severity scale, significant suicidal ideation, diagnosis of alcohol or drug use disorder, presence of a comorbid nondepressive, nonsubstance use Axis I disorder, current episode of depression being too long, and absence of current manic symptoms. BDETs were significantly less likely than AETs to exclude patients with a history of psychotic features/disorders, borderline personality disorder, and post-traumatic stress disorder and more likely to exclude individuals who scored too low on the first item of the Hamilton Depression Rating Scale. Nearly two-thirds of the BDETs placed an upper limit on the duration of the current depressive episode, three times higher than the rate in the AETs. There was no difference on other variables between the AETs and BDETs. CONCLUSIONS: Similar to treatment studies of nonbipolar MDD, the treatment studies of bipolar depression frequently excluded patients with comorbid psychiatric and substance use disorders and insufficient severity of depressive symptoms as rated on standardized scales. These findings indicate that concerns about the generalizability of data from trials of recently approved medications for the treatment of bipolar depression are as relevant as the concerns that have been raised about studies of antidepressants for nonbipolar depression.

Variability in the substance use disorder exclusion criterion in antidepressant efficacy trials.

BACKGROUND: Substance use disorders are the most commonly excluded psychiatric disorder in antidepressant efficacy trials (AETs). In a recent review of AETs we noticed variability in the definition of the substance use disorder exclusion criterion. In the present report we examined in greater detail the variability in defining the substance use disorder exclusion criterion, the potential impact of this variability on excluding patients from an AET, and whether the definition of the criterion has changed in the past 20 years. METHODS: We identified 170 AETs published during the past 20 years and compared the studies published during the past 5 years (n=56) to the studies published during the 15 prior years (n=114). RESULTS: Substance abuse was more frequently used as an exclusion criterion than substance dependence. Six time frames have been used as the basis of exclusion, the most frequent being the past 12 months. The time frame had a greater impact on the number of patients who would be excluded than the abuse/dependence distinction. The definition of the substance use exclusion criterion was no different in the studies of the past 5 years compared to the prior 15 years. LIMITATIONS: A limitation of the present analysis is that it was based on published placebo-controlled studies of antidepressants. CONCLUSION: Studies varied in whether abuse or dependence was the basis of exclusion, whether alcohol or illicit drugs or both were the basis of exclusion, and the time frame of the disorders' presence. We raise the question of whether the routine exclusion of patients with a substance use disorder should be reflected in a product's label.

Symptom Severity and the Generalizability of Antidepressant Efficacy Trials: Changes During the Past 20 Years.

The most commonly used inclusion/exclusion criterion in antidepressant efficacy trials (AETs) is a minimum score on a symptom severity scale. In the present study, we reviewed placebo-controlled AETs published during the past 20 years to determine whether there has been a change in the symptom severity inclusion criterion threshold subsequent to publications that highlighted the unrepresentativeness of the depressed patients studied in AETs. We identified 170 AETs published during the past 20 years and compared the studies published during the past 5 years (2010-2104, n = 56) with the studies published during the previous 15 years (n = 114). The symptom severity threshold for inclusion has increased in the more recent cohort of studies. On the 17-item Hamilton Depression Rating Scale, almost half of the studies of the past 5 years used a cutoff of 22 or greater to select patients versus less than one-fifth of the studies during the previous 15 years (44.0% vs 17.5%; χ(2) = 7.4; P < 0.01). Similarly, the cutoff on the Montgomery-Asberg Depression Rating Scale required for study inclusion has been higher in studies of the past 5 years with approximately three-quarters of the recent studies using a cutoff of at least 25, in contrast to one-quarter of the older studies (76.2% vs 25.0%; χ(2) = 8.2; P < 0.01). A significantly higher percentage of patients in our clinical practice would be excluded on the basis of the severity thresholds of the past 5 years (59.3 ± 13.5 vs 49.0 ± 15.1; t121 = 3.1; P < 0.005). These findings suggest that the results of AETs may not be applicable to less severely depressed patients who make up at least half of the patients treated in routine clinical practice. Questions are raised about the Food and Drug Administration labeling of antidepressants.

Problems in the Descriptions of the Psychiatric Inclusion and Exclusion Criteria in Publications of Antidepressant Efficacy Trials: A Qualitative Review and Recommendations for Improved Clarity.

We recently conducted a comprehensive review of the psychiatric inclusion and exclusion criteria used in 170 placebo-controlled antidepressant efficacy trials (AETs) that were published between 1995 and 2014. In conducting this literature review, we identified a number of instances in which the descriptions of the inclusion/exclusion criteria were vague, redundant, or difficult to interpret. In the present article, we describe nine problems we encountered in our literature review. We recommend that future publications follow the examples found in a few studies in which the inclusion/exclusion criteria are clearly defined and listed in a table.

Inclusion/exclusion criteria in placebo-controlled studies of vortioxetine: Comparison to other antidepressants and implications for product labeling.

BACKGROUND: We recently conducted a comprehensive review of the psychiatric inclusion/exclusion criteria used in 170 placebo-controlled antidepressant efficacy trials (AETs) published during the past 20 years and found that the criteria of more recent studies were significantly more restrictive than prior studies. Vortioxetine is the most recently approved medication for the treatment of major depressive disorder (MDD). We compared the inclusion/exclusion criteria of the vortioxetine studies to the criteria used in other AETs, and discuss the broader issue of the generalizability of AETs and the implications this might have for the labeling of antidepressants receiving FDA approval. METHODS: We conducted a comprehensive literature review of placebo-controlled AETs published from January, 1995 through December, 2014. We identified 170 AETs published during this 20 year period and compared the inclusion/exclusion criteria used in the 12 studies of vortioxetine to those used in the nonvortioxetine studies. A second analysis compared vortioxetine to the 3 antidepressants most recently approved prior to vortioxetine (desvenlafaxine, levomilnacipran extended release, vilazodone). RESULTS: Compared to the nonvortioxetine AETs, the vortioxetine studies significantly more often excluded patients with any comorbid Axis I disorder (p<.001) and more often required the current depressive episode to be longer than the DSM minimum symptom duration requirement of 2 weeks (p<.01). The cutoff on the Montgomery Asberg Depression Rating Scale required for inclusion in the vortioxetine studies was higher than the cutoff used in the other AETs (p<.01). LIMITATIONS: A limitation of the present analysis is that it was based on published placebo-controlled studies of antidepressants. CONCLUSION: The inclusion/exclusion criteria in the studies of vortioxetine were more restrictive than the criteria used in other AETs. Inconsistent with FDA guidelines on the labeling of medications, the label of vortioxetine does not include a description of the limits to the group of patients with MDD for whom the medication has been shown to be effective.

Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection.

Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein that possesses antimicrobial activity primarily because of its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectin-deficient S100A9(-/-) mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9(-/-) mice by injecting recombinant calprotectin. Furthermore, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin's antihyphal activity. In contrast to hyphae, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus ∆zafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared with wild-type. Collectively, these studies demonstrate a novel stage-specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin.

Have Treatment Studies of Depression Become Even Less Generalizable? A Review of the Inclusion and Exclusion Criteria Used in Placebo-Controlled Antidepressant Efficacy Trials Published During the Past 20 Years.

OBJECTIVE: To compare the inclusion and exclusion criteria used in antidepressant efficacy trials (AETs) published during the past 5 years with those used in studies published during the previous 15 years. PATIENTS AND METHODS: We conducted a comprehensive literature review of placebo-controlled AETs published from January 1995 through December 2014. We included trials whether or not the medication has received regulatory approval for the treatment of depression. We compared the inclusion and exclusion criteria of studies published during the past 5 years (2010-2014) with those of studies published during the previous 15 years (1995-2009). RESULTS: We identified 170 placebo-controlled AETs published during the past 20 years, 56 of which were published during the past 5 years. The more recent studies were significantly more likely to exclude patients with comorbid Axis I disorders and personality disorders, patients with the episode duration either too long or too short, and patients who had made a suicide attempt in the past. The severity threshold on depression rating scales required for inclusion was higher in the more recent studies. CONCLUSION: The inclusion and exclusion criteria of AETs have become more stringent over the past 5 years, thereby suggesting that AETs may be even less generalizable than they were previously (when concerns about their generalizability had already been raised).