The impact of 'cluster maintenance TMS' on irritability occurring in major depressive disorder.

OBJECTIVE: To determine the impact of clustered maintenance transcranial magnetic stimulation (TMS) on irritability occurring in treatment-resistant major depressive disorder (MDD). METHOD: A naturalistic study of 106 courses that includes pre- and posttreatment assessments of subjective and objective depression and a subjective measure of irritability developed for this study. RESULTS: Forty-six participants (35 females), mean age 43.2 years (14.3), completed 106 courses. There was a significant reduction in irritability and depression scores (p < .001). The change in irritability scores was significantly correlated with the change in depression scores, r = .40, p < .001. CONCLUSION: TMS has the capacity to reduce the irritability co-occurring with treatment-resistant MDD, known to be responsive to TMS. This increases the possibility of using TMS in the treatment of irritability co-occurring with other disorders or standing alone (should irritability be categorized as a stand-alone disorder).

Transcranial Magnetic Stimulation (TMS) during pregnancy: a fetal risk factor.

OBJECTIVE: To examine reports of Transcranial Magnetic Stimulation (TMS) during pregnancy for evidence of fetal risk. METHOD: PubMed was used to locate relevant literature for the years 1998-2020 and reference lists were examined for materials not located electronically. RESULTS: Ten reports were located dealing with 67 births over 20 years. Stimulation was applied is all trimesters, at low and high frequency, and as intermittent theta-burst stimulation. No mother or baby experienced a serious event. CONCLUSIONS: Certainty awaits large, standardized studies. However, the available reports provide no evidence that TMS to mother during pregnancy has detrimental effects on the fetus.

US Food and Drug Administration Perspectives on Clinical Mass Spectrometry.

Mass spectrometry-based in vitro diagnostic devices that measure proteins and peptides are underutilized in clinical practice, and none has been cleared or approved by the Food and Drug Administration (FDA) for marketing or for use in clinical trials. One way to increase their utilization is through enhanced interactions between the FDA and the clinical mass spectrometry community to improve the validation and regulatory review of these devices. As a reference point from which to develop these interactions, this article surveys the FDA's regulation of mass spectrometry-based devices, explains how the FDA uses guidance documents and standards in the review process, and describes the FDA's previous outreach to stakeholders. Here we also discuss how further communication and collaboration with the clinical mass spectrometry communities can identify opportunities for the FDA to provide help in the development of mass spectrometry-based devices and enhance their entry into the clinic.

The Effect of Social Isolation on 1-Year Outcomes After Surgical Repair of Low-Energy Hip Fracture.

OBJECTIVES: To evaluate whether social isolation or loneliness is associated with outcomes 1 year after low-energy hip fracture. DESIGN: Prospective inception cohort study. SETTING: Academic level I trauma center. PATIENT SELECTION CRITERIA: Participants were 65 years or older and enrolled 2-4 days after surgery for a first low-energy hip fracture. Exclusion criteria were bilateral or periprosthetic hip fracture, previous hip fracture, non-English speaking, international address, active cancer, stage 4 cancer in the past 5 years, radiation to the hip region, and cognitive impairment. Participants were followed longitudinally for 1 year. OUTCOME MEASURES AND COMPARISONS: The patient-reported outcomes measurement information system (PROMIS)-29 was elicited 2-4 days postoperatively and 1 year later. Patient-reported risk factors included the Lubben Social Networks Scale and the University of California, Los Angeles Loneliness Scale, which were compared with the lower extremity activity scale and PROMIS-29 domains. RESULTS: Three hundred and twenty-five patients were enrolled. Participants had a median age of 81.7 years, were 70.9% female, and were 85.9% White. In total, 31.6% of patients were socially isolated at the time of fracture. At 1 year, 222 of the 291 subjects who were confirmed alive at 1 year provided data. Multivariable linear models were performed separately for each outcome, including lower extremity activity scale and PROMIS-29 domains. Controlling for age, sex, education, and body mass index, those who were socially isolated at the time of fracture had worse PROMIS-29 function (ß = -3.83; P = 0.02) and ability to participate in social roles (ß = -4.17; P = 0.01) at 1 year. Secondary analyses found that prefracture loneliness was associated with clinically meaningfully worse function, anxiety, depression, fatigue, sleep, pain, and ability to participate in social roles at 1 year (all P < 0.01). CONCLUSIONS: Prefracture social isolation was associated with worse outcomes 1 year after surgical repair of low-energy hip fracture. These data suggest loneliness may be more strongly associated with important patient-centric metrics than prefracture social isolation. Given the dearth of modifiable risk factors in this population, future studies are needed to evaluate whether improving social connections could affect outcomes in this rapidly growing demographic. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

A Case Series Study of Weekly or Fortnightly Transcranial Magnetic Stimulation (TMS) in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is frequently chronic and relapsing. The use of maintenance or continuation transcranial magnetic stimulation (TMS) has received clinical and some research support. OBJECTIVE: To conduct a case series study to report the outcomes of once-weekly (OW) or once-fortnightly (OF) continuation TMS in a real-life setting. METHODS: We offered OW or OF TMS sessions to patients with MDD in remission or partial remission/relapse. RESULTS: Ten patients received OW TMS and four received OF TMS, for 8 to 46 weeks. No patients in either group who were in remission or partial remission at baseline experienced a relapse. Improvements in HAMD6 and CGI-S scores were statistically significant or of borderline significance for the total sample and the OW group. CONCLUSIONS: This naturalistic, open-label observational study indicates that OW TMS is effective as maintenance therapy in MDD, while also offering some support for OF TMS maintenance in preventing relapse.

Transcranial Magnetic Stimulation (TMS) for Major Depressive Disorder-Modus Operandi!

Background: Transcranial magnetic stimulation (TMS) is effective in the management of treatment resistant major depressive disorder (MDD) and has recently become widely available. Our aim was to explore the literature for evidence of the mechanism of action. Method: We examined our own accumulating TMS library, the reference lists of all available papers and used a search engine to collect information. We collated and examined this information under relevant heading. Results: TMS produces a large number of physiological changes including site of stimulation neurochemical, brain wave and blood flow effects, and distant structure effects including neurotransmitter effects and volume increase. TMS also corrects generalized and local functional connectivity (FC) abnormalities which are a feature of MDD. Conclusion: TMS produces a range of physiological changes. It is unclear which of these underpin its antidepressant. It is likely more than one work synergistically to this end-almost certainly the capacity to correct MDD induced FC abnormalities makes a strong antidepressant contribution.

Aspergillus tanneri sp. nov., a new pathogen that causes invasive disease refractory to antifungal therapy.

The most common cause of invasive aspergillosis (IA) in patients with chronic granulomatous disease (CGD) is Aspergillus fumigatus followed by A. nidulans; other aspergilli rarely cause the disease. Here we review two clinical cases of fatal IA in CGD patients and describe a new etiologic agent of IA refractory to antifungal therapy. Unlike typical IA caused by A. fumigatus, the disease caused by the new species was chronic and spread from the lung to multiple adjacent organs. Mycological characteristics and the phylogenetic relationship with other aspergilli based on the sequence analysis of Mcm7, RPB2, and Tsr1 indicated that the new species, which we named as A. tanneri, belongs to Aspergillus section Circumdati. The species has a higher amphotericin B, voriconazole, and itraconazole MIC and causes more chronic infection in CGD mice than A. fumigatus. This is the first report documenting IA in CGD patients caused by a species belonging to the Aspergillus section Circumdati that is inherently resistant to azoles and amphotericin B. Unlike the results seen with many members of Aspergillus section Circumdati, ochratoxin was not detected in filtrates of cultures grown in various media. Our phenotypic and genetic characterization of the new species and the case reports will assist future diagnosis of infection caused by A. tanneri and lead to more appropriate patient management.

One Hundred Courses of Cluster Maintenance Transcranial Magnetic Stimulation (CM TMS)-A Clinical Audit Study.

Objective: Major depressive disorder (MDD) which comes to transcranial magnetic stimulation (TMS) is prone to relapse. Cluster maintenance (CM) TMS is courses of 5 treatments delivered over 2.5-5 days, separated by monthly or greater non-treatment periods. Our aim was to characterize the outcomes of 100 courses of CM TMS. Method: This was a Quality Assurance/Clinical Audit study. We studied consecutive CM TMS courses provided to private hospital inpatients. Mood was rated (on admission and discharge) using the six-item Hamilton depression rating (HAMD6) and the Clinical Global Impression - Severity (CGI-S) scales. We also applied recent STAR*D criteria which are designed to measure the 'clinical change' expected to impact patient function [16]. Results: For the total sample, using the HAMD6, 83% of courses featured relapse or partial relapse on admission, and 81% featured remission on discharge. Of 46 courses featuring HAMD6 relapse on admission, 74% featured remission on discharge. For the 100 courses the HAMD6 discharge scores were significantly lower than the admission scores (p = 2.0 × 10-24), as were the CGI-S scores (p = 1.8 × 10-25). Using STAR*D criteria for people in relapse or partial relapse on admission, CM TMS provided least a 'clinically meaningful' outcome in 82% of the cases. Conclusion: For courses featuring relapse or partial relapse on admission, CM TMS converted greater than 70% to remission at discharge. It produced statistically significant reductions in HAMD6 and CGI-S scores, and using STAR*D criteria, at least 'clinically meaningful' change was extensively demonstrated. This evidence indicates CM TMS should be readily available to people living with relapsing MDD.

Human Dectin-1 deficiency impairs macrophage-mediated defense against phaeohyphomycosis.

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, ß-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1ß in response to ß-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1ß and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1ß-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi.

Geosmithia argillacea: an emerging cause of invasive mycosis in human chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disorder of the nicotinamide adenine dinucleotide phosphate oxidase that leads to defective production of microbicidal superoxide and other oxidative radicals, resulting in increased susceptibility to invasive infections, especially those due to fungi. METHODS: Geosmithia argillacea was identified from cultured isolates by genomic sequencing of the internal transcribed spacer region. Isolates previously identified as Paecilomyces variotii, a filamentous fungus closely resembling G. argillacea, were also examined. RESULTS: We identified G. argillacea as the cause of invasive mycosis in 7 CGD patients. In 5 cases, the fungus had been previously identified morphologically as P. variotii. All patients had pulmonary lesions; 1 had disseminated lesions following inhalational pneumonia. Infections involved the chest wall and contiguous ribs in 2 patients and disseminated to the brain in 1 patient. Four patients with pneumonia underwent surgical intervention. All patients responded poorly to medical treatment, and 3 died. CONCLUSIONS: We report the first cases of invasive mycosis caused by G. argillacea in CGD patients. G. argillacea infections in CGD are often refractory and severe with a high fatality rate. Surgical intervention has been effective in some cases. G. argillacea is a previously underappreciated and frequently misidentified pathogen in CGD that should be excluded when P. variotii is identified morphologically.

Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems.

RATIONALE: Single-site clinic-based studies suggest an increasing prevalence of pulmonary nontuberculous mycobacteria (NTM) disease, but systematic data are lacking. OBJECTIVES: To describe prevalence and trends for NTM lung disease at four geographically diverse integrated heath care delivery systems in the United States. METHODS: We abstracted mycobacterial culture results from electronic laboratory databases and linked to other datasets containing clinical and demographic information. Possible cases were defined as a single positive NTM pulmonary isolate, and definite cases were defined as two positive sputum cultures, or one positive culture from a bronchoalveolar lavage or lung biopsy. Annual prevalence was calculated using United States census data; average annual prevalence is presented for 2004-2006. Poisson regression models were used to estimate the annual percent change in prevalence. MEASUREMENTS AND MAIN RESULTS: A total of 28,697 samples from 7,940 patients were included in the analysis. Of these, 3,988 (50%) were defined as possible cases, and 1,865 (47%) of these were defined as definite cases. Average annual (2004-2006) site-specific prevalence ranged from 1.4 to 6.6 per 100,000. Prevalence was 1.l- to 1.6-fold higher among women relative to men across sites. The prevalence of NTM lung disease was increasing significantly at the two sites where trends were studied, by 2.6% per year among women and 2.9% per year among men. Among persons aged greater than or equal to 60 years, annual prevalence increased from 19.6 per 100,000 during 1994-1996 to 26.7 per 100,000 during 2004-2006. CONCLUSIONS: The epidemiology of nontuberculous mycobacterial lung disease is changing, with a predominance of women and increasing prevalence at the sites studied.

Pharmacokinetics of liposomal amphotericin B in pleural fluid.

We report the penetration of liposomal amphotericin B into the pleural fluid of a patient with pulmonary zygomycosis and empyema. The ratio of area under the concentration-versus-time curve in pleural fluid (AUC(pleural fluid)) to that in serum (AUC(serum)) for liposomal amphotericin B over 24 h was 9.4%, with pleural fluid concentrations of 2.12 to 4.91 microg/ml. Given the relatively low level of intrapleural penetration of liposomal amphotericin B, chest tube drainage may be warranted for successful treatment of zygomycotic empyema.

Evaluation of matrix-assisted laser desorption ionization-time of flight mass spectrometry for identification of clinically important yeast species.

We evaluated the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for the rapid identification of yeast species. Using Bruker Daltonics MALDI BioTyper software, we created a spectral database library with m/z ratios of 2,000 to 20,000 Da for 109 type and reference strains of yeast (44 species in 8 genera). The database was tested for accuracy by use of 194 clinical isolates (23 species in 6 genera). A total of 192 (99.0%) of the clinical isolates were identified accurately by MALDI-TOF MS. The MALDI-TOF MS-based method was found to be reproducible and accurate, with low consumable costs and minimal preparation time.

Fusarium proliferatum soft tissue infection at the site of a puncture by a plant: recovery, isolation, and direct molecular identification.

After allogeneic stem cell transplantation, a 49-year-old man developed fever and inflammation at the site of a plant puncture on a finger. A hyalohyphomycete was recovered by incubating the plant spine fragment following surgery. Amplification of the internal transcribed spacer region and 5.8S rRNA, beta-tubulin, and translation elongation factor coding genes identified Fusarium proliferatum, which was confirmed later by culture.

Infections caused by Scedosporium spp.

Scedosporium spp. are increasingly recognized as causes of resistant life-threatening infections in immunocompromised patients. Scedosporium spp. also cause a wide spectrum of conditions, including mycetoma, saprobic involvement and colonization of the airways, sinopulmonary infections, extrapulmonary localized infections, and disseminated infections. Invasive scedosporium infections are also associated with central nervous infection following near-drowning accidents. The most common sites of infection are the lungs, sinuses, bones, joints, eyes, and brain. Scedosporium apiospermum and Scedosporium prolificans are the two principal medically important species of this genus. Pseudallescheria boydii, the teleomorph of S. apiospermum, is recognized by the presence of cleistothecia. Recent advances in molecular taxonomy have advanced the understanding of the genus Scedosporium and have demonstrated a wider range of species than heretofore recognized. Studies of the pathogenesis of and immune response to Scedosporium spp. underscore the importance of innate host defenses in protection against these organisms. Microbiological diagnosis of Scedosporium spp. currently depends upon culture and morphological characterization. Molecular tools for clinical microbiological detection of Scedosporium spp. are currently investigational. Infections caused by S. apiospermum and P. boydii in patients and animals may respond to antifungal triazoles. By comparison, infections caused by S. prolificans seldom respond to medical therapy alone. Surgery and reversal of immunosuppression may be the only effective therapeutic options for infections caused by S. prolificans.

DIY-NAMIC Behavior: A High-Throughput Method to Measure Complex Phenotypes in the Homecage.

Complex behavioral assessment is necessary to comprehensively assess in vivo manipulations in rodent models for neuropsychiatric disorders. Operant behavioral paradigms provide rich datasets and allow for the careful analysis of behavioral phenotypes. However, one major limitation in these studies is the expense and work-load that are required using traditional methods. The equipment for commercial operant boxes can be prohibitively expensive, and the daily experimenter effort and mouse costs required for these studies is extensive. Rodents are generally trained on task-specific paradigms for months, tested every day for 5-7 d/week. Additionally, appetitive paradigms usually require food restriction and are also commonly run in the non-active light phase of the rodent circadian rhythm. These limitations make operant behavioral testing especially difficult during adolescence, a time period of interest with regards to the development of adult-like phenotypes and a high-risk period for the development of neuropsychiatric disorders, including those which involve impulsive behavior. In order to address these issues, we developed an automated, inexpensive, open-source method which allows the implementation of most standard operant paradigms in the homecage of rodents in shorter time frames without food restriction, and with much less experimenter effort. All construction and code for the do-it-yourself Nautiyal Automated Modular Instrumental Conditioning (DIY-NAMIC) system are open source. We demonstrate their utility here by measuring impulsive behavior in a pharmacology experiment, as well as in adolescent mice.

Polymerase chain reaction of secA1 on sputum or oral wash samples for the diagnosis of pulmonary tuberculosis.

BACKGROUND: Nucleic acid amplification tests are sensitive and specific for identifying Mycobacterium tuberculosis in sputum smear-positive populations, but they are less sensitive in sputum smear-negative populations. Few studies have assessed their performance among patients infected with HIV, and no studies have assessed their performance with oral wash specimens, which may be easier to obtain than sputum samples. METHODS: We performed a prospective study involving 127 adults from 2 populations who were undergoing evaluation for respiratory complaints at Mulago Hospital in Kampala, Uganda. We obtained and tested sputum samples for Mycobacterium tuberculosis, and we simultaneously obtained oral wash specimens to test for M. tuberculosis DNA by polymerase chain reaction (PCR) amplification of a novel locus, the secA1 gene. A positive mycobacterial culture of sputum was used to define cases of tuberculosis; we calculated the sensitivity and specificity of the PCR assay with sputum or oral wash specimens in reference to the standard of sputum culture results. RESULTS: Tuberculosis (75 [59%] of 127 patients) and HIV infection (58 [46%] of 126 patients) were both common in the study population. PCR of sputum samples was highly sensitive (sensitivity, 99%; 95% confidence interval, 93%-100%) and specific (specificity, 88%; 95% confidence interval, 77%-96%) for detection of pulmonary tuberculosis and performed well among HIV-infected patients and among patients with negative sputum smear results. PCR of oral wash specimens was less sensitive (sensitivity, 73%; 95% confidence interval, 62%-83%) but also detected a substantial proportion of tuberculosis cases. CONCLUSIONS: PCR targeting the secA1 gene was highly sensitive and specific for identifying M. tuberculosis in sputum samples, independent of smear or HIV infection status. Oral washes showed promise as an easily obtained respiratory specimen for tuberculosis diagnosis. PCR of sputum for detection of the secA1 gene could be a rapid, effective diagnostic tool for tuberculosis referral centers.

Invasive aspergillosis due to Neosartorya udagawae.

BACKGROUND: Invasive aspergillosis (IA) is most commonly caused by the morphospecies Aspergillus fumigatus. However, genetic-based methods indicate that organisms phenotypically identified as A. fumigatus actually constitute a mold complex, designated Aspergillus section fumigati subgenus fumigati. METHODS: Multilocus sequencing and analysis was performed on fungi identified as A. fumigatus from the clinical culture collection maintained at the National Institutes of Health from 2000 through 2008, with a focus on the internal transcribed spacer 1 and 2 regions of ribosomal DNA (rDNA), beta-tubulin, and rodlet A genes. We reviewed the medical records, radiology, and histopathology of corresponding patients. To confirm identification of Neosartorya udagawae isolates, mating studies were performed with reference strains. Antifungal susceptibility testing was performed by broth microdilution and read at 48 hours. RESULTS: Thirty-six cases of infection attributed to A. fumigatus were identified; 4 were caused by N. udagawae (3 in patients with chronic granulomatous disease and 1 in a patient with myelodysplastic syndrome). Disease due to N. udagawae was chronic, with a median duration of 35 weeks, compared with a median duration of 5.5 weeks for patients with chronic granulomatous disease who had infection due to A. fumigatus sensu stricto (P < .05 , Mann-Whitney U test). Infection spread across anatomical planes in a contiguous manner and was refractory to standard therapy. Two of the 4 patients died. N. udagawae demonstrated relatively higher minimum inhibitory concentrations to various agents, compared with those demonstrated by contemporary A. fumigatus sensu stricto isolates. CONCLUSIONS: To our knowledge, this is the first report documenting infection due to N. udagawae. Clinical manifestations were distinct from those of typical IA. Fumigati-mimetics with inherent potential for antifungal resistance are agents of IA. Genetic identification of molds should be considered for unusual or refractory IA.