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Genetic regulation of the host susceptibility to Mycobacterium tuberculosis (Mtb) and severity of tuberculosis (TB) infection remain incompletely investigated. Identification of particular genes and involved in TB control and immune reactions regulated by these genes is essential for our understanding of pathogenesis of the disease, discovery of drug targets and rational vaccine development. We have shown that mice of the B10.SM (H2ᵛ) strain are extremely TB susceptible; meanwhile, the general genome structure of this mouse strain and the H2ᵛ haplotype itself are poorly characterized. We selected a pool of Mit genetic markers differentiating B10.SM mice from Chr. 17-congenic mice of the B10 strain by the PCR products motility in the electrophoresis setting. TB susceptibility of B10 mice is much lower than that of B10.SM. In the model of infection triggered by two different dosed of Mtb (100 and 600 CFU per mouse) administered via respiratory tract we demonstrated that B10.SM mice have significantly shorter survival time and significantly higher lung mycobacterial multiplication compared to B10 mice. We demonstrated (intracellular staining and ELISA) that IFNγ production in the lungs of infected mice of the two strains corresponds well to their disease phenotypes. Thus, more resistant B10 mice possess significantly more lung IFNγ-positive CD4⁺ T cells and a higher level of IFNγ secretion. We have established (B10х B10.SM) F1 hybrids and demonstrated that the post-infection phenotypes of survival time, lung mycobacterial multiplication and IFNγ production in these mice are intermediate compared to parental mice. Thus, we deal with the genetic trait with incomplete dominance expression. These data were confirmed in F2 hybrids by segregation genetic analysis. To characterize the phenotype of B10.SM mice in more detail, we vaccinated these mice with the BCG vaccine before TB challenge. Vaccination significantly prolonged survival time, diminished mycobacterial multiplication in the lungs and the degree of lung tissue pathology. Thus, a high level of susceptibility to primary infection did not interfere with BCG vaccination efficacy. We intend to continue genetic and immunologic analyses of TB-hyper-susceptible B10.SM mice. Experimental data regarding the cause of extreme disturbances in protection against infection are prerequisite for our better understanding causality of the wide spectrum of TB manifestations in human populations, as well as for rational search for novel vaccines and medications against TB infection.

Introduction: RET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC. Methods: This situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion–positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay. Results: The most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively). Conclusions: In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.

Abstract Mycobacterium tuberculosis (Mtb) is able to transition into a dormant state, causing the latent state of tuberculosis. Dormant mycobacteria acquire resistance to all known antibacterial drugs and can survive in the human body for decades before becoming active. In the dormant forms of M. tuberculosis, the synthesis of porphyrins and its Zn-complexes significantly increased when 5-aminolevulinic acid (ALA) was added to the growth medium. Transcriptome analysis revealed an activation of 8 genes involved in the metabolism of tetrapyrroles during the Mtb transition into a dormant state, which may lead to the observed accumulation of free porphyrins. Dormant Mtb viability was reduced by more than 99.99% under illumination for 30 min (300 J/cm2) with 565 nm light that correspond for Zn–porphyrin and coproporphyrin absorptions. We did not observe any PDI effect in vitro using active bacteria grown without ALA. However, after accumulation of active cells in lung macrophages and their persistence within macrophages for several days in the presence of ALA, a significant sensitivity of active Mtb cells (ca. 99.99%) to light exposure was developed. These findings create a perspective for the treatment of latent and multidrug-resistant tuberculosis by the eradication of the pathogen in order to prevent recurrence of this disease.

Mycobacterium tuberculosis (Mtb) remains a major threat worldwide, although only a fraction of infected individuals develops tuberculosis (TB). TB susceptibility is shaped by multiple genetic factors, and we performed comparative immunological analysis of two mouse strains to uncover relevant mechanisms underlying susceptibility and resistance. C57BL/6 mice are relatively TB-resistant, whereas I/St mice are prone to develop severe TB, partly due to the MHC-II allelic variant that shapes suboptimal CD4+ T cell receptor repertoire. We investigated the repertoires of lung-infiltrating helper T cells and B cells at the progressed stage in both strains. We found that lung CD4+ T cell repertoires of infected C57BL/6 but not I/St mice contained convergent TCR clusters with functionally confirmed Mtb specificity. Transcriptomic analysis revealed a more prominent Th1 signature in C57BL/6, and expression of pro-inflammatory IL-16 in I/St lung-infiltrating helper T cells. The two strains also showed distinct Th2 signatures. Furthermore, the humoral response of I/St mice was delayed, less focused, and dominated by IgG/IgM isotypes, whereas C57BL/6 mice generated more Mtb antigen-focused IgA response. We conclude that the inability of I/St mice to produce a timely and efficient anti-Mtb adaptive immune responses arises from a suboptimal helper T cell landscape that also impacts the humoral response, leading to diffuse inflammation and severe disease.

Resumen: El melasma corresponde a un trastorno pigmentario crónico que se caracteriza por máculas hiperpigmentadas que se localizan principalmente en la cara. Afecta con mayor frecuencia a mujeres en edad fértil y de fototipos oscuros. Se asocia a un importante deterioro de la calidad de vida debido a su ubicación, cronicidad y alto porcentaje de recidiva. Los tratamientos clásicos incluyen agentes tópicos, peelings, láser y tratamientos basados en luz, o una combinación de ellos. Los tratamientos combinados han demostrado ser la mejor solución sea de forma doble o triple. La terapia triple combinada (hidroquinona, tretinoína y corticoides) actualmente muestra ser el tratamiento más efectivo.Dentro de los nuevos tratamientos publicados hasta la fecha, el ácido tranexámico oral ha mostrado resultados favorables en el melasma moderado, severo, recurrente y/o refractario, por lo que se debería considerar como una nueva estrategia terapéutica. Abstract: Melasma is a chronic pigmentary disorder, characterized by hyper-pigmented macules in photo-exposed areas that are located mainly on the face. It more frequently affects women in childbearing age and with darker skin phototypes. It is associated with a significant impact in quality of life because of its location, chronicity and high percentage of relapse.Classical treatments include topical agents, peelings, laser and light based therapies, or a combination of these. Combined treatments have proven to be the best solution, whether double or triple. Hydroquinone alone or a triple combination cream (hydroquinone, tretinoin and corticosteroid) currently have the greatest evidence of efficacy in the treatment of melasma.Among the new treatments published to date, oral tranexamic acid has shown favorable results in moderate, severe, recurrent and/or refractory melasma, and should be considered as a new therapeutic strategy.

We reexamine the characterization of incentive compatible single-parameter mechanisms introduced in Archer and Tardos (2001). We argue that the claimed uniqueness result, called 'Myerson's Lemma' was not well established. We provide an elementary proof of uniqueness that unifies the presentation for two classes of allocation functions used in the literature and show that the general case is a consequence of a little known result from the theory of real functions. We also clarify that our proof of uniqueness is more elementary than the previous one. Finally, by generalizing our characterization result to more dimensions, we provide alternative proofs of revenue equivalence results for multiunit auctions and combinatorial auctions.

Areas with sparse transmission lines are common in regions with high solar energy potential and need voltage support. This may require installing expensive voltage compensators, such as static synchronous compensators (STATCOMs). This expense can increase the cost and decrease the acceptance of large-scale adoption of solar power. Unlike current photovoltaic (PV) inverter controllers, which provide voltage support only during the day, commercially available augmented voltage controllers can provide voltage support at night. We examine whether PV inverters improve nighttime voltage on the grid and how much such an operation would cost compared to a STATCOM. We ran grid contingency analyses on a model for West Texas within the Electric Reliability Council of Texas (ERCOT) jurisdiction under spring and summer conditions to determine if PV inverters can support nighttime voltage under varying reactive power demand. The cost of reactive power has not been defined previously, especially in the context of the United States. Our methods and application provide a way to determine the cost of reactive power for both PV project developers and system planners. Allowing PV inverters to provide reactive power can reduce system costs by millions of dollars, or 4–15 times less costly than installing a STATCOM. We determined inverter voltage support costs by calculating the cost of earlier inverter replacements due to increased reactive power output and voltage controllers. The net system savings argue for ERCOT changing their voltage support policies to incentivize PV plants to provide voltage support at night.

Background: Officers who provide health care make it a priority to ensure the safety of their patients. In healthcare, patient safety is a fundamental principle. Understanding the patient safety culture is one step toward improving patient safety. Patient safety culture is the main foundation of patient safety arrangements that aim to improve the quality of service of healthcare facilities by implementing risk management in all service areas. Purpose: This study aimed to determine the cultural picture of patient safety among health workers in a public hospital in East Lombok. Method: This study was observational and cross-sectional using the Hospital Survey of Patient Safety Culture (HSOPSC) questionnaire designed by the Association of Health Care and Research Quality (AHRQ.) The population of this study were healthcare professionals (doctors, pharmacists, pharmaceutical technical personnel, nurses, and midwives) at Dr R. Soedjono Selong Hospital in East Lombok. Descriptive and inferential statistics were used to adjust frequency distribution tables to identify variable relationship differences. The results analysis followed the guidelines from AHRQ, and univariate analysis was carried out. Results: Among the 250 employees invited to participate, 238 (95.2%) completed the surveys. The dimension with the highest percentage of positive responses was organizational learning - continuous improvement (91.3%), and the dimension with the lowest rate of positive responses was staff management (42.5%). Generally, the patient safety culture in health workers at Dr R, Soedjono belongs to the strong category (70.34%). Conclusion: Building a strong patient safety culture is essential to improve service quality.

IntroductionTo dissect the role of the part of the H2 complex comprised of the MHC-II genes in the control of tuberculosis (TB) infection, we previously established a panel of recombinant congenic mouse strains bearing different segments of the H2j haplotype on the B6 (H2b) genetic background. Fine genetic mapping, gene sequencing and assessment of TB phenotypes resulted in identification of the H2-Ab gene as a major factor of TB control.MethodsWe further narrowed the MHC-II H2j interval by spotting a new recombination event, sequencing newly established DNA configuration and establishing a mouse strain B6.I-103 in which j/b recombination occurred within the coding sequence of the H2-Ab gene.ResultsUnexpectedly, a novel H2-Aαb/AβjE0 haplotype provided exclusively high susceptibility to TB challenge. Immunologic analysis revealed an altered CD4+ T-cell selection and maintenance in B6.I-103 mice, as well as seriously impaired expression of the H2-Aαb/Aβj molecule on the surface of antigen presenting cells. Unlike previously reported cases of Class II malfunctioning, the defective phenotype arose not from strong structural mutations, but from regular recombination events within the MHC-II recombination hot spot region.DiscussionOur findings provide evidence that Class II α/β-chain cis-allelic mismatches created by regular genetic recombination may severely affect immune system functioning. This issue is discussed in the context of the MHC evolution.

Electrification with heat pumps is often cited as a preferred pathway to decarbonize US space heating in the transition to a net-zero energy system. However, fully electrifying building heat may significantly increase peak electric system loads during cold weather, thus challenging extensive adoption. A hybrid home heating system uses both heat pumps and conventional natural gas furnaces, where the gas appliance operates during peak heating periods. Here, we assess the marginal abatement costs of fully electrifying peak heating demands as opposed to allowing hybrid heating in current gas connected and ducted homes. We use a least-cost energy system optimization model that considers household, electric, and gas system costs, including electric distribution system expansion and gas system cost recovery. To ensure the cost of sufficient low-carbon dispatchable electric capacity is captured, the model includes historical days with peak heating demands and low wind and solar availability. We find hybrid heat pumps can achieve substantial decarbonization, with US natural gas residential heating consumption decreasing 70% to 95% from 2020 levels at marginal abatement costs below $200 per tonne CO _2 e. The cost of fully electrifying heating in cold regions is very high, with the marginal abatement cost of eliminating the last 1% of natural gas consumption exceeding $1000 per tonne CO _2 e even in scenarios designed to be favorable to electrification. The robust value of hybrid heat pumps in northern cold climates indicates the importance of flexible building heat decarbonization policies such as clean heat standards.

The objective of this study was to compare, by qPCR, the circulating blood parasite load of Trypanosoma cruzi in the buffy coat, and in whole blood mixed with boiled and unboiled guanidine hydrochloride-EDTA buffer, of individuals with chronic ChD. The concentration and purity of DNA were evaluated in a Nanodrop Denovix DS-11FX Series Spectrophotometer (DeNovix Inc., Wilmington, NC, USA). The parasite load was determined with the Taqman® qPCR system using a Stratagene Mx3000P thermocycler (Agilent Technologies, Santa Clara, CA, USA) with Cruzi 1 and Cruzi 2 satellite primers. Student’s t-test with Bonferroni correction, Chi-squared (χ2) tests and Spearman’s correlation coefficient were applied. The concentration and purity of DNA were higher in the buffy coat. Parasite DNA was detected and quantifiable in the three types of samples in seven patients, without statistically significant differences in the parasite load obtained. Higher correlations were found between the total DNA concentrations and the parasite loads obtained in the samples of the buffy coat.