Depression in Patients with Peripheral Artery Disease: An Underdiagnosis with Increased Mortality.

BACKGROUND: Among patients with peripheral artery disease (PAD), depression is diagnosed in 17-25% and negatively impacts wound healing, quality of life, and survival. We hypothesized that depression is underdiagnosed in patients with PAD. Additionally, given the associations between depression and mortality in PAD patients, there is an increased need to investigate the strength of this relationship. The present analysis includes 2 studies to address the following aims: (1) Investigation of the prevalence of concomitant PAD and depression in a cohort from the Southeastern United States, and (2) Examination of the association between depression and all-cause mortality in a cohort of Canadian patients with PAD. METHODS: STUDY 1: From June-August 2022, the Patient Health Questionnaire Module 9 (PHQ-9) was administered to all patients seeking PAD-related care including medical, wound/podiatric, or vascular interventional/surgical treatment, in the University of North Carolina-Chapel Hill Vascular, Wound, and Podiatry clinics. The PHQ-9 assesses symptoms over 2 weeks and is scored 0-27, with higher scores indicating increasingly severe depression. Demographics, primary diagnosis, depression history, and antidepressant prescription were determined through chart review. We compared the proportion of positive depression screenings (PHQ-9 ≥ 5) to known depression. Among those treated for depression, the PHQ-9 score severity was evaluated. T-tests and χ2 tests were used to compare means and proportions. STUDY 2: From July 2015 to October 2016, the Geriatric Depression Scale Short Form was administered to adult patients with PAD undergoing revascularization. The Geriatric Depression Scale Short Form is a self-report measure of depression with a score >5 consistent with depression. The prevalence of depression was determined; primary outcome was all-cause mortality at 6 months. RESULTS: STUDY 1: In 104 PAD patients (mean age 66.6 ± 11.3 years, 37% female), 37% of respondents scored ≥5 on the PHQ-9 survey, indicating at least mild depression. Only 18% of PAD patients had a history of depression, demonstrating a significant difference between the PHQ-9 findings and documented medical history. While depression was underdiagnosed in both men and women, men were more likely to have unrecognized depression (chi-squared statistic = 35.117, df = 1, P < 0.001). Among those with a history of depression, 74% had a current prescription for antidepressant medication, but 57% still had an elevated PHQ-9 score indicating possible undertreatment. STUDY 2: In 148 patients (mean age 70.3 ± 11.0 years, 39% female) the prevalence of screened depression was 28.4%, but only 3.3% had a documented history of depression suggesting significant underdiagnosis. Patients with depression were significantly more likely to die within 6 months of revascularization (9.5% vs. 0.9%; odds ratio 1.48, 95% confidence interval: 1.08 to 2.29). There was no association between depression and risk of length of stay, reintervention, or readmission. CONCLUSIONS: Depression is underdiagnosed and undertreated among patients with PAD, which has grave consequences as it is associated with 1.5 times the odds of mortality within 6 months of revascularization. There is a critical need for more robust screenings and comprehensive mental health treatment for patients with concomitant depression and PAD.

Simplified COI barcoding of blow, flesh, and scuttle flies encountered in medicolegal investigations.

Accurate insect identification is critical to the estimation of time of colonization (TOC) and post-mortem interval (PMI) in medicolegal death investigations. DNA testing is advantageous because it enables the identification of immature specimens that may not be identified based on morphology alone. We describe here a simplified DNA barcoding method for identifying relevant species that may be implemented by forensic genetics laboratories. A cytochrome oxidase (COI) fragment is analyzed after PCR amplification with a single primer set. The method is effective for many species commonly encountered in death investigations in the USA: members of blowfly genera Calliphora, Chrysomya, Cochliomyia, Lucilia, and Phormia; members of the flesh fly genera Blaesoxipha, Oxysarcodexia, Ravinia, and Sarcophaga; and the scuttle fly Megaselia scalaris. We tested the method on specimens with verified identifications and used it to build a collection of reference sequences from specimens collected in Harris County, Texas. We show here the correct identification of larvae, pupae, and pupal exuviae from the medicolegal casework.

Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young.

Each year in the United States, thousands of cases of sudden and unexpected deaths of infants, children, and young adults are assigned an undetermined cause of death after postmortem investigation and autopsy. Heritable genetic variants have been suggested as the cause of up to a third of sudden death (SD) cases. Elucidation of the genetic variants involved in SD cases is important to not only help establish cause and manner of death of these individuals, but to also aid in determining whether familial genetic testing should be considered. Previously, these types of postmortem screenings have not been a feasible option for most county medical examiners' and coroners' offices. We sequenced full exons of 64 genes associated with SD in the largest known cohort (351) of infant and young SD decedents using massively parallel sequencing at <$600 per sample. Genetic variants were assessed through literature review and clinical evaluation by a multidisciplinary consortium of experts. Thirteen individuals (3.7%), eight infants (2.8% of those <1 yr of age) and five children/young adults (7.0% of those >1 yr of age), were found to have a reportable genetic variant contributing to SD. These percentages represent an estimate lower than those previously reported. Overall yields and results likely vary between studies due to differences in evaluation techniques and reporting. Additionally, we recommend ongoing assessment of data, including nonreported novel variants, as technology and literature continually advance. This study demonstrates a strategy to implement molecular autopsies in medicolegal investigations of young SD decedents.

Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: optimization studies and demonstration of in vivo efficacy.

Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10 mg/kg, subcutaneous dose.

Discovery of potent, selective, bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model, part I: transformation of selective pyrazolodiazepinone phosphodiesterase 4 (PDE4) inhibitors into selective PDE2 inhibitors.

We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of PDE4 inhibitors, while simultaneously minimizing PDE4 activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like mode in contrast to the cAMP-like binding mode found in PDE4. Structure activity relationship studies coupled with an inhibitor bound crystal structure in the active site of the catalytic domain of PDE2 identified structural features required to minimize PDE4 inhibition while simultaneously maximizing PDE2 inhibition.

The use of diary methods to evaluate daily experiences in first-episode psychosis.

Integrated Coping Awareness Therapy (I-CAT) is an intervention that targets stress reactivity in first-episode psychosis (FEP). This study extends prior outcome research on I-CAT by examining predictors of online daily diary completion among 38 young adults with FEP and treatment group differences in diary ratings. We found no significant predictors of daily diary completion rate and no effect of treatment condition on diary ratings. These results are consistent with Halverson et al. (2021) and suggest that diaries are a valuable method of data collection in FEP.

A comparative analysis of the genetic epidemiology of deafness in the United States in two sets of pedigrees collected more than a century apart.

In 1898, E.A. Fay published an analysis of nearly 5000 marriages among deaf individuals in America collected during the 19(th) century. Each pedigree included three-generation data on marriage partners that included at least one deaf proband, who were ascertained by complete selection. We recently proposed that the intense phenotypic assortative mating among the deaf might have greatly accelerated the normally slow response to relaxed genetic selection against deafness that began in many Western countries with the introduction of sign language and the establishment of residential schools. Simulation studies suggest that this mechanism might have doubled the frequency of the commonest forms of recessive deafness (DFNB1) in this country during the past 200 years. To test this prediction, we collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay. Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children has increased by a factor of more than five in the past 100 years. Additional analysis within our sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920 through 1980). These data are consistent with the increase in the frequency of DFNB1 predicted by our previous simulation studies and provide convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.

Vestibular dysfunction in DFNB1 deafness.

Mutations of GJB2 and GJB6 (connexin-26 and 30) at the DFNB1 locus are the most common cause of autosomal recessive, nonsyndromic deafness. Despite their widespread expression throughout the vestibular system, vestibular dysfunction has not been widely recognized as a commonly associated clinical feature. The observations of vertigo accompanying DFNB1 deafness in several large families prompted our hypothesis that vestibular dysfunction may be an integral, but often overlooked, component of DFNB1 deafness. Our aim was to define the prevalence of vestibular dysfunction in Cases of DFNB1 deafness and Controls with other forms of deafness. We developed and used a survey to assess symptoms of vestibular dysfunction, medical, and family history was distributed to Cases with deafness due to pathogenic GJB2 and/or GJB6 mutations and deaf Controls without DFNB1 deafness. Our results showed: Surveys were returned by 235/515 Cases (46%) with DFNB1 mutations and 121/321 Controls (38%) without these mutations. The mean age of Cases (41) was younger than Controls (51; P < 0.001). Vestibular dysfunction was reported by 127 (54%) of Cases and was present at significantly higher rates in Cases than in deaf Controls without DFNB1 deafness (P < 0.03). Most (63%) had to lie down in order for vertigo to subside, and 48% reported that vertigo interfered with activities of daily living. Vertigo was reported by significantly more Cases with truncating than non-truncating mutations and was also associated with a family history of dizziness. We conclude that vestibular dysfunction appears to be more common in DFNB1 deafness than previously recognized and affects activities of daily living in many patients.

Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment.

Optic atrophy (OA) and sensorineural hearing loss (SNHL) are key abnormalities in several syndromes, including the recessively inherited Wolfram syndrome, caused by mutations in WFS1. In contrast, the association of autosomal dominant OA and SNHL without other phenotypic abnormalities is rare, and almost exclusively attributed to mutations in the Optic Atrophy-1 gene (OPA1), most commonly the p.R445H mutation. We present eight probands and their families from the US, Sweden, and UK with OA and SNHL, whom we analyzed for mutations in OPA1 and WFS1. Among these families, we found three heterozygous missense mutations in WFS1 segregating with OA and SNHL: p.A684V (six families), and two novel mutations, p.G780S and p.D797Y, all involving evolutionarily conserved amino acids and absent from 298 control chromosomes. Importantly, none of these families harbored the OPA1 p.R445H mutation. No mitochondrial DNA deletions were detected in muscle from one p.A684V patient analyzed. Finally, wolframin p.A684V mutant ectopically expressed in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indicating that the mutation is disease-causing. Our data support OA and SNHL as a phenotype caused by dominant mutations in WFS1 in these additional eight families. Importantly, our data provide the first evidence that a single, recurrent mutation in WFS1, p.A684V, may be a common cause of ADOA and SNHL, similar to the role played by the p.R445H mutation in OPA1. Our findings suggest that patients who are heterozygous for WFS1 missense mutations should be carefully clinically examined for OA and other manifestations of Wolfram syndrome.

Fitness among individuals with early childhood deafness: Studies in alumni families from Gallaudet University.

The genetic fitness of an individual is influenced by their phenotype, genotype and family and social structure of the population in which they live. It is likely that the fitness of deaf individuals was quite low in the Western European population during the Middle Ages. The establishment of residential schools for deaf individuals nearly 400 years ago resulted in relaxed genetic selection against deaf individuals which contributed to the improved fitness of deaf individuals in recent times. As part of a study of deaf probands from Gallaudet University, we collected pedigree data, including the mating type and the number and hearing status of the children of 686 deaf adults and 602 of their hearing siblings. Most of these individuals had an onset of severe to profound hearing loss by early childhood. Marital rates of deaf adults were similar to their hearing siblings (0.83 vs. 0.85). Among married individuals, the fertility of deaf individuals is lower than their hearing siblings (2.06 vs. 2.26, p = 0.005). The fitness of deaf individuals was reduced (p = 0.002). Analysis of fertility rates after stratification by mating type reveals that matings between two deaf individuals produced more children (2.11) than matings of a deaf and hearing individual (1.85), suggesting that fertility among deaf individuals is influenced by multiple factors.

Featured Counter-Trafficking Program: RELENTLESS.

This invited article is one of several comprising part of a special issue of Child Abuse and Neglect focused on child trafficking and health. The purpose of each invited article is to describe a specific program serving trafficked children. Featuring these programs is intended to raise awareness of innovative counter-trafficking strategies emerging worldwide and facilitate collaboration on program development and outcomes research. This article describes Relentless, a Berlin-based organization dedicated to providing clinical consultations and trauma informed training for various counter-trafficking organizations and individuals.

Branchio-oto-renal syndrome (BOR): novel mutations in the EYA1 gene, and a review of the mutational genetics of BOR.

Branchio-oto-renal syndrome (BOR) is an autosomal dominant disorder characterized by the association of branchial and external ear malformations, hearing loss, and renal anomalies. The phenotype varies from ear pits to profound hearing loss, branchial fistulae, and kidney agenesis. The most common gene mutated in BOR families is EYA1, a transcriptional activator. Over 80 different disease-causing mutations have been published (www.healthcare.uiowa.edu/labs/pendredandbor/, last accessed 20 November 2007). We analyzed the EYA1 coding region (16 exons) from 435 families (345 at the University of Iowa [UI] and 95 at Boys Town National Research Hospital [BTNRH], including five at both) and found 70 different EYA1 mutations in 89 families. Most of the mutations (56/70) were private. EYA1 mutations were found in 31% of families (76/248) fitting established clinical criteria for BOR and 7% of families with questionable BOR phenotype (13/187). Severity of the phenotype did not correlate with type of mutation nor with the domain involved. These results add considerably to the spectrum of EYA1 mutations associated with BOR and indicate that the BOR phenotype is an indication for molecular studies to diagnose EYA1-associated BOR.

Characteristics of obese children aged 1-4 years at a referral clinic.

OBJECTIVE: To describe characteristics and indicators of nutritional status of young, obese children. STUDY DESIGN: Medical records of 135 children aged 1-4 years seen in an urban referral setting between January 2000 and June 2006 were reviewed. Characteristics associated with severe obesity [percent ideal body weight (%IBW) > or = 160%] were determined. Relationships between %IBW, weight-for-height Z score (WHZ), body mass index (BMI) and BMI Z score (BMIZ) were evaluated. Receiver operating characteristic analyses evaluated BMI values classifying severe and moderate (140-159% IBW) obesity. RESULTS: Children were: 41% male, 71% Hispanic, 76% Medicaid/uninsured, 64% ever breastfed, had median BMI of 25.0 kg/m2 and median %IBW of 159. Fifty-two percent of mothers had BMI > or = 30 kg/m2. Severely obese children more frequently had an obese mother, birthweight > or = 4 kg, were older, male, never breastfed and reported higher juice intake. WHZ and BMIZ were lowest at 4 years; BMI and %IBW were lowest at 1 year. %IBW and BMI were highly correlated. BMI > or = 22.2 kg/ m2 indicated moderate obesity (sensitivity = 0.90, specificity = 0.93), and BMI > or = 25.0 kg/m2 indicated severe obesity (sensitivity = 0.97, specificity = 0.92). CONCLUSION: Few current health behaviors and many family or past risk factors were associated with degree of obesity. %IBW and BMI may be the most useful nutritional status measures to track progress in young, obese children.

Causes of fever in adults on the Thai-Myanmar border.

A hospital-based study was conducted along the Thai-Myanmar border to provide greater knowledge of the causes of febrile illness and to determine what zoonotic and vector-borne emerging infectious diseases might be present. A total of 613 adults were enrolled from June 1999 to March 2002. Cases were classified based on clinical findings and laboratory results. An etiologic diagnosis was made for 48% of subjects. Malaria was the most common diagnosis, accounting for 25% of subjects, with two-thirds Plasmodium falciparum. Serologic evidence for leptospirosis was found in 17% of subjects. Other etiologic diagnoses included rickettsial infections, dengue fever, and typhoid. The most frequent clinical diagnoses were nonspecific febrile illness, respiratory infections, and gastroenteritis. Clinical associations were generally not predictive of etiologic diagnosis. Apparent dual diagnoses were common, particularly for malaria and leptospirosis. Findings have been used to modify treatment of unspecified febrile illness in the area.

Effective teamwork and communication mitigate task saturation in simulated critical care air transport team missions.

BACKGROUND: Critical Care Air Transport Teams (CCATTs) are a critical component of the United States Air Force evacuation paradigm. This study was conducted to assess the incidence of task saturation in simulated CCATT missions and to determine if there are predictable performance domains. METHODS: Sixteen CCATTs were studied over a 6-month period. Performance was scored using a tool assessing eight domains of performance. Teams were also assessed during critical events to determine the presence or absence of task saturation and its impact on patient care. RESULTS: Sixteen simulated missions were reviewed and 45 crisis events identified. Task saturation was present in 22/45 (49%) of crisis events. Scoring demonstrated that task saturation was associated with poor performance in teamwork (odds ratio [OR] = 1.96), communication (OR = 2.08), and mutual performance monitoring (OR = 1.9), but not maintenance of guidelines, task management, procedural skill, and equipment management. We analyzed the effect of task saturation on adverse patient outcomes during crisis events. Adverse outcomes occurred more often when teams were task saturated as compared to non-task-saturated teams (91% vs. 23%; RR 4.1, p < 0.0001). CONCLUSIONS: Task saturation is observed in simulated CCATT missions. Nontechnical skills correlate with task saturation. Task saturation is associated with worsening physiologic derangements in simulated patients.

Psychometric properties of a valuations scale for the Marijuana Effect Expectancies Questionnaire.

Given that marijuana remains the most commonly used illicit substance, identification of the role of potentially malleable cognitive factors in marijuana-related behaviors remains an important goal. The Marijuana Effect Expectancies Questionnaire (MEEQ; Schafer & Brown, 1991) assesses marijuana effect expectancies that are differentially related to marijuana use and use-related problems. Evaluation of the desirability of marijuana effect expectancies may provide additional information regarding cognitions related to marijuana use behaviors. The present study examined the psychometric properties of the Marijuana Effect Expectancy Questionnaire-Valuations Scale (MEEQ-V) which was developed for this study to assess the desirability of marijuana effect expectancies. The sample was comprised of 925 (73.0% female) undergraduate participants, 41.9% of whom endorsed lifetime marijuana use and 24.7% of whom reported current (past three-month) use. The MEEQ-V scales demonstrated adequate internal consistency. Most (but not all) MEEQ-V scales were correlated with their corresponding MEEQ scale. There was some support for convergent validity. MEEQ-V scales were differentially related to frequency of marijuana use and use-related problems. Most MEEQ-V scales were related to frequency of marijuana use above and beyond variance attributable to corresponding MEEQ scales. Results suggest that assessment of desirability of marijuana's effects could provide unique and important information about cognitions related to marijuana use behaviors.

DNA testing of sexual assault evidence: the laboratory perspective.

The availability of DNA testing has dramatically changed the way that crimes are investigated. DNA results can link offenders to their crimes, exonerate wrongfully accused individuals, identify mass fatality victims and more. In the case of sexual assault, DNA evidence alone cannot prove that a sexual assault has occurred. DNA analysis can only reveal whether a person's DNA is, or is not, present. In this paper, the authors provide readers with an overview of the advantages and limitations of DNA analysis, the importance of proper evidence collection, the technologies available, and the amount of sample needed for testing. Through proper evidence collection and quality laboratory services, the full value of DNA will be realized.

Compound heterozygosity for dominant and recessive GJB2 mutations: effect on phenotype and review of the literature.

Mutations in GJB2 (which encodes the gap-junction protein connexin 26) are the most common cause of genetic deafness in many populations. To date, more than 100 deafness-causing mutations have been described in this gene. The majority of these mutations are inherited in an autosomal recessive manner, but approximately 19 GJB2 mutations have been associated with dominantly inherited hearing loss. One, W44C, was first identified in two families from France. We subsequently described a family in the United States with the same mutation. In these families, W44C segregates with a dominantly inherited, early-onset, progressive, sensorineural deafness that is worse in the high frequencies. Since that report, we have tested additional family members and identified two siblings who are compound heterozygous for the W44C and K15T mutations. Their father, the original proband, is heterozygous for the dominant W44C mutation, and their mother is compound heterozygous for two recessively inherited mutations, K15T and 35delG. Both children have a profound, sensorineural deafness and use manual communication, in contrast to their parents and other relatives whose hearing losses are less severe and who can communicate orally. The difference in phenotype may be a result of the disruption of different functions of the gap-junction protein by the two mutations, which have an additive effect.

NSD1 analysis for Sotos syndrome: insights and perspectives from the clinical laboratory.

PURPOSE: Sotos syndrome is a genetic disorder characterized primarily by overgrowth, developmental delay, and a characteristic facial gestalt. Defects in the NSD1 gene are present in approximately 80% of patients with Sotos syndrome. The goal of this study was to determine the incidence of NSD1 abnormalities in patients referred to a clinical laboratory for testing and to identify clinical criteria that distinguish between patients with and without NSD1 abnormalities. METHODS: Deletion or mutation analysis of the NSD1 gene was performed on 435 patients referred to our clinical genetics laboratory. Detailed clinical information was obtained on 86 patients with and without NSD1 abnormalities, and a clinical checklist was developed to help distinguish between these two groups of patients. RESULTS: Abnormalities of the NSD1 gene were identified in 55 patients, including 9 deletions and 46 mutations. Thus, in the clinical laboratory setting, deletions were found in 2% and mutations in 21% of samples analyzed, because not all patients had both tests. Thirty-three previously unreported mutations in the NSD1 gene were identified. Clinical features typically associated with Sotos syndrome were not found to be significantly different between individuals with and without NSD1 abnormalities. The clinical checklist developed included poor feeding, increased body mass index, and enlarged cerebral ventricles, in addition to the typical clinical features of Sotos syndrome, and was able to distinguish between the two groups with 80% sensitivity and 70% specificity. CONCLUSIONS: The dramatic decrease in the frequency of finding NSD1 abnormalities in the clinical laboratory is likely because of the heterogeneity of the patient population. Our experience from a diagnostic laboratory can help guide clinicians in deciding for whom NSD1 genetic analysis is indicated.