Rationale: Among patients with nontuberculous mycobacterial lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. We hypothesize that unidentified factors predispose these individuals to pulmonary nontuberculous mycobacterial disease. Objectives: To compare body morphotype, serum adipokine levels, and whole-blood cytokine responses of patients with pulmonary nontuberculous mycobacteria (pNTM) with contemporary control subjects who are well matched demographically. Methods: We enrolled 103 patients with pNTM and 101 uninfected control subjects of similar demographics. Body mass index and body fat were quantified. All patients with pNTM and a subset of control subjects were evaluated for scoliosis and pectus excavatum. Serum leptin and adiponectin were measured. Specific cytokines important to host-defense against mycobacteria were measured in whole blood before and after stimulation. Measurements and Main Results: Patients with pNTM and control subjects were well matched for age, gender, and race. Patients with pNTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis and pectus excavatum were significantly more prevalent in patients with pNTM. The normal relationships between the adipokines and body fat were lost in the patients with pNTM, a novel finding. IFN-g and IL-10 levels were significantly suppressed in stimulated whole blood of patients with pNTM. Conclusions: This is the first study to comprehensively compare body morphotype, adipokines, and cytokine responses between patients with NTM lung disease and demographically matched controls. Our findings suggest a novel, predisposing immunophenotype that should be mechanistically defined.Keywords: leptin; adiponectin; pectus excavatum; scoliosis; Marfan syndrome Chronic lung disease due to nontuberculous mycobacteria (NTM) is a growing public health concern (1-3). Recent studies estimate the incidence in the United States to be five to six cases per 100,000 and as high as 15.5 cases per 100,000 in persons over 50 years of age (3-5). Because the duration of symptomatic NTM lung disease is often years, the prevalence of disease is estimated to be 10 to 40 cases per 100,000 (1).In the United States, the most common NTM species associated with lung disease are Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium abscessus. Although NTM are widespread in water and soil (6, 7), relatively few persons develop disease. Thus, intact immunity is likely pivotal for protection against NTM.Chronic lung disease is the most common form of NTM infection, manifested by two main radiographic patterns: (i) an upper lobe fibrocavitary pattern that occurs mostly in men with underlying lung disease such as chronic obstructive pulmonary disease (COPD) and (ii) a nodular-bronchiectasis pattern that often involves the right middle lobe and lingula and which appears to be more common in women with no clear risk factors (8)...

Breast and/or ovarian cancer (BOC) are among the most frequently diagnosed forms of hereditary cancers and leading cause of death in India. This emphasizes on the need for a cost-effective method for early detection of these cancers. We sequenced 141 unrelated patients and families with BOC using the TruSight Cancer panel, which includes 13 genes strongly associated with risk of inherited BOC. Multi-gene sequencing was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations. When we considered familial breast cancer cases only, the detection rate increased to 52%. When cases were stratified based on age of diagnosis into three categories, ⩽40 years, 40-50 years and >50 years, the detection rates were higher in the first two categories (44.4% and 53.4%, respectively) as compared with the third category, in which it was 26.9%. Our study suggests that next-generation sequencing-based multi-gene panels increase the sensitivity of mutation detection and help in identifying patients with a high risk of developing cancer as compared with sequential tests of individual genes.

Atopic dermatitis (AD) is characterized by epidermal barrier defects and recurrent microbial skin infections. AD patients with a history of eczema herpeticum (ADEH+) have more severe skin disease and more highly TH2 polarized immune responses as compared to uncomplicated AD (ADEH−). However, the mechanisms linking epidermal barrier defects and viral skin infection are not well understood. Recently, it has been reported that interleukin (IL)-25 may play a role in augmenting TH2 responses. We examined protein expression of IL-25 in the skin biopsies from normal subjects (n=10), ADEH− (n=18), ADEH+ (n=7) and psoriasis (n=9). IL-25 expression was increased in the skin from ADEH−, ADEH+ and psoriasis compared to normal skin, and was significantly greater in lesional ADEH+ skin than in lesional ADEH- skin. Importantly, we demonstrated that IL-25 enhances herpes simplex virus (HSV)-1 and vaccinia virus replication by inhibiting filaggrin expression, and IL-25 acts synergistically with IL-4 and IL-13 to enhance HSV-1 replication in vitro. In contrast, interferon-γ inhibited HSV-1 replication in vitro. Additionally, we demonstrate that filaggrin is a critical protein to inhibit HSV-1 replication because filaggrin small interfering RNA knockdown enhances HSV-1 replication in vitro. Filaggrin breakdown products, however, inhibited HSV-1 replication in vitro.

f Nontuberculous mycobacterial infections caused by Mycobacterium abscessus are responsible for a range of disease manifestations from pulmonary to skin infections and are notoriously difficult to treat, due to innate resistance to many antibiotics. Previous population studies of clinical M. abscessus isolates utilized multilocus sequence typing or pulsed-field gel electrophoresis, but high-resolution examinations of genetic diversity at the whole-genome level have not been well characterized, particularly among clinical isolates derived in the United States. We performed whole-genome sequencing of 11 clinical M. abscessus isolates derived from eight U.S. patients with pulmonary nontuberculous mycobacterial infections, compared them to 30 globally diverse clinical isolates, and investigated intrapatient genomic diversity and evolution. Phylogenomic analyses revealed a cluster of closely related U.S. and Western European M. abscessus subsp. abscessus isolates that are genetically distinct from other European isolates and all Asian isolates. Large-scale variation analyses suggested genome content differences of 0.3 to 8.3%, relative to the reference strain ATCC 19977 T . Longitudinally sampled isolates showed very few single-nucleotide polymorphisms and correlated genomic deletion patterns, suggesting homogeneous infection populations. Our study explores the genomic diversity of clinical M. abscessus strains from multiple continents and provides insight into the genome plasticity of an opportunistic pathogen. N ontuberculous mycobacteria (NTM) represent a diverse group of environmental and pathogenic bacteria that are increasing in clinical prevalence in the United States (1) and other countries (2, 3). NTM are thought to be acquired primarily through environmental exposure (4), as they reside in water, biofilms, and soil environments (5, 6), although a few recent studies provide evidence of possible person-to person transmission among individuals with cystic fibrosis (CF) (7,8). Mycobacterium abscessus is the second most clinically prevalent NTM species in pulmonary NTM infections (1, 9, 10), with Mycobacterium avium complex (MAC) being the most prevalent. M. abscessus infections are challenging to treat because they are innately resistant to many antimicrobials, including some that are effective against Mycobacterium tuberculosis and other mycobacteria (11-13). Acquired antibiotic resistance has been observed in some M. abscessus strains, with mechanisms of resistance ranging from mutational resistance to aminoglycosides (14) to mutational (15) and inducible (16) resistance to macrolides.The current taxonomy of M. abscessus recognizes two subspecies, M. abscessus subsp. abscessus and M. abscessus subsp. bolletii (17), although recent population and comparative genomic studies support the three previously recognized subspecies, i.e., M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii (18)(19)(20)(21). This delineation is important because clinical studies suggest diff...