Nonadherence to anti-tuberculosis treatment, reasons and associated factors among pulmonary tuberculosis patients in the communities in Indonesia.

BACKGROUND: Tuberculosis (TB) is the world's major public health problem. We assessed the proportion, reasons, and associated factors for anti-TB treatment nonadherence in the communities in Indonesia. METHODS: This national coverage cross-sectional survey was conducted from 2013 to 2014 with stratified multi-stage cluster sampling. Based on the region and rural-urban location. The 156 clusters were distributed in 136 districts/cities throughout 33 provinces, divided into three areas. An eligible population of age ≥15 was interviewed to find TB symptoms and screened with a thorax x-ray. Those whose filtered result detected positive followed an assessment of Sputum microscopy, LJ culture, and Xpert MTB/RIF. Census officers asked all participants about their history of TB and their treatment-defined Nonadherence as discontinuation of anti-tuberculosis treatment for <6 months. Data were analyzed using STATA 14.0 (College Station, TX, USA). RESULTS: Nonadherence to anti-TB treatment proportion was 27.24%. Multivariate analysis identified behavioral factors significantly associated with anti-TB treatment nonadherence, such as smoking (OR = 1.78, 95% CI (1.47-2.16)); place of first treatment received: government hospital (OR = 1.45, 95% CI:1.06-1.99); private hospital (OR = 1.93, 95% CI: 1.38-2.72); private practitioner (OR = 2.24, 95% CI: 1.56-3.23); socio-demographic and TB status included region: Sumatera (OR = 1.44, 95% CI: 1.05-1.98); other areas (OR = 1.84, 95% CI: 1.30-2.61); low level of education (OR = 1.60, 95% CI: 1.27-2.03); and current TB positive status (OR = 2.17, 95% CI: 1.26-3.73). CONCLUSIONS: Nonadherence to anti-TB drugs was highly related to the personal perception of the respondents, despite smoking, current TB status, a place for the first treatment, education, and region. The position of the first TB treatment at the private practitioner was significantly associated with the risk of Nonadherence to treatment.

Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Tackling the Challenge of Extracting Microplastics from Soils: A Protocol to Purify Soil Samples for Spectroscopic Analysis.

Microplastic pollution in soils is an emerging topic in the scientific community, with researchers striving to determine the occurrence and the impact of microplastics on soil health, ecology, and functionality. However, information on the microplastic contamination of soils is limited because of a lack of suitable analytical methods. Because micro-Fourier-transform infrared spectroscopy (µ-FTIR), next to Raman spectroscopy, is one of the few methods that allows the determination of the number, polymer type, shape, and size of microplastic particles, the present study addresses the challenge of purifying soil samples sufficiently to allow a subsequent µ-FTIR analysis. A combination of freeze-drying, sieving, density separation, and a sequential enzymatic-oxidative digestion protocol enables removal of the mineral mass (>99.9% dry wt) and an average reduction of 77% dry weight of the remaining organic fraction. In addition to visual integrity, attenuated total reflectance FTIR, gel permeation chromatography, and differential scanning calorimetry showed that polyamide, polyethylene, polyethylene terephthalate, and polyvinyl chloride in the size range of 100 to 400 µm were not affected by the approach. However, biodegradable polylactic acid showed visible signs of degradation and reduced molecular weight distribution after protease treatment. Nevertheless, the presented purification protocol is a reliable and robust method to purify relatively large soil samples of approximately 250 g dry weight for spectroscopic analysis in microplastic research and has been shown to recover various microplastic fibers and fragments down to a size of 10 µm from natural soil samples. Environ Toxicol Chem 2022;41:844-857. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Phylogeny of the order Phyllachorales (Ascomycota, Sordariomycetes): among and within order relationships based on five molecular loci.

The order Phyllachorales (Pezizomycotina, Ascomycota) is a group of biotrophic, obligate plant parasitic fungi with a tropical distribution and high host specificity. Traditionally two families are recognised within this order: Phyllachoraceae and Phaeochoraceae, based mostly on morphological and host characteristics. Currently, the position of the order within the class Sordariomycetes is inconclusive, as well as the monophyly of the order, and its internal phylogenetic structure. Here we present a phylogeny of the order Phyllachorales based on sequence data of 29 species with a broad host range resulting from a wide geographical sampling. We inferred Maximum Likelihood and Bayesian phylogenies from data of five DNA regions: nrLSU rDNA, nrSSU rDNA, ITS rDNA, and the protein coding genes RPB2, and TEF1. We found that the order Phyllachorales is monophyletic and related to members of the subclass Sordariomycetidae within Sordariomycetes. Within the order, members of the family Phaeochoraceae form a monophyletic group, and the family Phyllachoraceae is split into two lineages. Maximum Likelihood ancestral state reconstructions indicate that the ancestor of Phyllachorales had a monocotyledonous host plant, immersed perithecia, and a black stroma. Alternative states of these characters evolved multiple times independently within the order. Based on our results we redefine the family Phyllachoraceae and propose the new family Telimenaceae with Telimena erythrinae as type species, resulting in three families in the order. Species of Telimena spp. occur in several monocotyledonous and eudicotyledonous host plants except Poaceae, and generally have enlarged black pseudostroma around the perithecia, a character not present in species of Phyllachoraceae.

Isolated progressive visual loss after coiling of paraclinoid aneurysms.

BACKGROUND AND PURPOSE: The proximity of the paraclinoid segment of the internal carotid artery to the visual pathways may result in visual deficits when patients present with aneurysms in this segment. Although surgical clip ligation of these aneurysms has been the standard of care for decades, the advent of coil embolization has permitted endovascular therapy in those aneurysms with favorable dome-to-neck ratios. Although immediate nonprogressive visual loss after coil embolization of paraclinoid aneurysms has been well described, isolated progressive visual loss immediately or shortly following coil embolization, to our knowledge, has not. We have identified 8 patients who experienced progressive loss of vision, unassociated with any other neurologic deficits, developing immediately or shortly after apparently uncomplicated coil embolization of a paraclinoid aneurysm. MATERIALS AND METHODS: This study is a retrospective case series of 8 patients seen at 4 separate academic institutions. Inpatient and outpatient records were examined to determine patient demographics, previous ocular and medical history, and ophthalmic status before endovascular embolization. In addition, details of the primary endovascular therapy and subsequent surgical and nonsurgical interventions were recorded. Follow-up data, including most recent best-corrected visual acuity, postoperative course, and duration of follow-up were documented. RESULTS: Eight patients developed progressive visual loss in 1 or both eyes immediately or shortly after apparently uncomplicated coiling of a paraclinoid aneurysm. MR imaging findings suggested that the visual loss was most likely caused by perianeurysmal inflammation related to the coils used to embolize the aneurysm, enlargement or persistence of the aneurysm despite coiling, or a combination of these mechanisms. Most patients experienced improvement in vision, 2 apparently related to treatment with systemic corticosteroids. CONCLUSION: Patients in whom endovascular treatment of a paraclinoid aneurysm is contemplated should be warned about the potential for both isolated nonprogressive and progressive visual loss in 1 or both eyes. Patients in whom progressive visual loss occurs may benefit from treatment with systemic corticosteroids.

Repression of the human immunodeficiency virus type-1 long terminal repeat by the c-Myc oncoprotein.

The effect of trans-acting factors on cis-acting DNA elements on the HIV-1 promoter are the principal determinant regulating transcriptional activation and repression. Host factors that limit viral replication can contribute to the emergence and maintenance of proviral reservoirs. The current paradigm is that this sub-population of latently infected cells confers a biological advantage to the virus by facilitating evasion of immunologic responses and therapeutic strategies resulting in life-long and persistent infection. In this report, we show that ectopic expression of the nuclear phosphoprotein, c-Myc can inhibit HIV-1 gene expression and virus production in CD4+ T-lymphocytes. The effect exerted does not appear to involve other known functions of c-Myc such as proliferation, or apoptosis. The mechanism does implicate c-Myc in a direct role. We have found evidence that c-Myc can specifically recognize the HIV-1 initiator element surrounding the start site of transcription and linker scanning mutagenesis experiments confirmed a loss of c-Myc-mediated repression in the absence of this region. Moreover, we show that c-Myc can interact with the initiator binding proteins YY-1 and LBP-1 and can cooperate with these factors to synergistically repress HIV-1 LTR transcription. Taken together, these results indicate that c-Myc is an important regulator of HIV-1 transcription that potentially contributes to the latent proviral state.

Ganglion cell axon pathfinding in the retina and optic nerve.

The eye is a highly specialized structure that gathers and converts light information into neuronal signals. These signals are relayed along axons of retinal ganglion cells (RGCs) to visual centers in the brain for processing. In this review, we discuss the pathfinding tasks RGC axons face during development and the molecular mechanisms known to be involved. The data at hand support the presence of multiple axon guidance mechanisms concentrically organized around the optic nerve head, each of which appears to involve both growth-promoting and growth-inhibitory guidance molecules. Together, these strategies ensure proper optic nerve formation and establish the anatomical pathway for faithful transmission of information between the retina and the brain.

No evidence for loss of hippocampal neurons in non-Alzheimer dementia patients.

OBJECTIVE: To use stereological methods for estimating the total number of neurons in hippocampi of non-Alzheimer demented patients. MATERIAL AND METHODS: Hippocampi from six women with severely impaired memory but without Alzheimer pathology were compared with six mentally intact age-matched female controls. The total number of neurons was estimated in the granule cell layer of the dentate gyrus, the hilus of the dentate gyrus, the pyramidal cell layer of CA3 and CA2, the pyramidal cell layer of CA1 and the cellular layer of subiculum using the optical fractionator. RESULTS: The total neuron number was the same in the dementia cases, 22.4 x 106, compared with 22.7 x 106 in the controls (P = 0.85). No region-specific group differences or side difference were found. Two cases without clinical signs of dementia but with abundant plaques and tangles in hippocampus and neocortex had total neuron numbers within normal limits. CONCLUSION: Our results indicate that severely impaired memory can occur in the presence of intact numbers of hippocampal neurons in non-Alzheimer dementia and that nerve cell loss in the hippocampus might be characteristic for Alzheimer's disease, and perhaps other forms of primary cortical dementia.

Connecting the eye to the brain: the molecular basis of ganglion cell axon guidance.

In the past several years, a great deal has been learnt about the molecular basis through which specific neural pathways in the visual system are established during embryonic development. This review provides a framework for understanding the principles of retinal ganglion cell axon guidance, and introduces some of the families of axon guidance molecules involved. In addition, the potential relevance of retinal axon guidance to human visual developmental disorders, and to retinal axon regeneration, is discussed.

Retinal axon growth cones respond to EphB extracellular domains as inhibitory axon guidance cues.

Axon pathfinding relies on cellular signaling mediated by growth cone receptor proteins responding to ligands, or guidance cues, in the environment. Eph proteins are a family of receptor tyrosine kinases that govern axon pathway development, including retinal axon projections to CNS targets. Recent examination of EphB mutant mice, however, has shown that axon pathfinding within the retina to the optic disc is dependent on EphB receptors, but independent of their kinase activity. Here we show a function for EphB1, B2 and B3 receptor extracellular domains (ECDs) in inhibiting mouse retinal axons when presented either as substratum-bound proteins or as soluble proteins directly applied to growth cones via micropipettes. In substratum choice assays, retinal axons tended to avoid EphB-ECDs, while time-lapse microscopy showed that exposure to soluble EphB-ECD led to growth cone collapse or other inhibitory responses. These results demonstrate that, in addition to the conventional role of Eph proteins signaling as receptors, EphB receptor ECDs can also function in the opposite role as guidance cues to alter axon behavior. Furthermore, the data support a model in which dorsal retinal ganglion cell axons heading to the optic disc encounter a gradient of inhibitory EphB proteins which helps maintain tight axon fasciculation and prevents aberrant axon growth into ventral retina. In conclusion, development of neuronal connectivity may involve the combined activity of Eph proteins serving as guidance receptors and as axon guidance cues.

Myc is an essential negative regulator of platelet-derived growth factor beta receptor expression.

Platelet-derived growth factor BB (PDGF BB) is a potent mitogen for fibroblasts as well as many other cell types. Interaction of PDGF BB with the PDGF beta receptor (PDGF-betaR) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-betaR downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-betar mRNA expression. Our studies show that pdgf-betar mRNA suppression is regulated by the c-myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-betar mRNA and protein. Suppression of pdgf-betar mRNA in response to Myc is specific, since expression of the related receptor pdgf-alphar is not affected. We further show that Myc suppresses pdgf-betar mRNA expression by a mechanism which is distinguishable from Myc autosuppression. Analysis of c-Myc-null fibroblasts demonstrates that Myc is required for the repression of pdgf-betar mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-betar mRNA levels plays an important role in the regulation of basal pdgf-betar expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-betaR.

Promotion of growth and apoptosis in c-myc nullizygous fibroblasts by other members of the myc oncoprotein family.

c-myc nullizygous fibroblasts (KO cells) were used to compare the abilities of c-myc, N-myc and L-myc oncoproteins to accelerate growth, promote apoptosis, revert morphology, and regulate the expression of previously described c-myc target genes. All three myc oncoproteins were expressed following retroviral transduction of KO cells. The proteins all enhanced the growth rate of KO cells and significantly shortened the cell cycle transition time. They also accelerated apoptosis following serum deprivation, reverted the abnormal KO cell morphology, and modulated the expression of previously described c-myc target genes. In most cases, L-myc was equivalent to c-myc and N-myc in restoring all of the c-myc-dependent activities. These findings contrast with the previously reported weak transforming and transactivating properties of L-myc. Myc oncoproteins may thus impart both highly similar as well as dissimilar signals to the cells in which they are expressed.

Tiaprofenic acid-induced cystitis--three cases and a literature review.

Tiaprofenic acid is a non-steroidal anti-inflammatory drug that may cause severe non-bacterial cystitis. Three cases are described and the literature is reviewed.

[Toxoplasma encephalitis with atypical manifestation and normal CT]. / Toxoplasma-encephalitis med atypisk manifestation og normal CT.

A case of cerebral toxoplasmosis in a HIV-positive man with unusual clinical manifestations and a normal computed tomographic (CT) scanning is presented. Even though most patients with cerebral toxoplasmosis have focal neurological deficits on physical examination, the patients can also present with more diffuse symptoms. Neither the lack of antitoxoplasma antibodies nor normal findings at CT scanning exclude the diagnosis of toxoplasma encephalitis. The sensitivity is higher with magnetic resonance than with CT scanning. We present a case story that demonstrate how delusive cerebral toxoplasmosis can be in HIV positive patients. It is recommended that the possibility of cerebral toxoplasmosis be considered in every HIV-positive patient with neurological symptoms and empirical therapy be instituted on wide indications.

Uncoupled expression of p33 and p92 permits amplification of tomato bushy stunt virus RNAs.

Tomato bushy stunt virus (TBSV) is a plus-sense RNA virus which encodes a 33-kDa protein in its 5'-most open reading frame (ORF). Readthrough of the amber stop codon of the p33 ORF results in the production of a 92-kDa fusion protein. Both of these products are expressed directly from the viral genome and are suspected to be involved in viral RNA replication. We have investigated further the roles of these proteins in the amplification of viral RNAs by using a complementation system in which p33 and p92 are expressed from different viral RNAs. Our results indicate that (i) both of these proteins are necessary for viral RNA amplification; (ii) translation of these proteins can be uncoupled while maintaining amplification of viral RNAs; (iii) if compatibility requirements exist between p33 and p92, they are not exceptionally strict; and (iv) the C-terminal approximately 6% of p33 is necessary for its functional activity. Interestingly, no complementation was observed when a p33-encoding replicon containing a deletion of a 3'-located segment, region 3.5, was tested. However, when 5'-capped transcripts of the same replicon were analyzed, complementation allowing for RNA amplification was observed. This ability to compensate functionally for the absence of region 3.5 by the addition of a 5' cap suggests that this RNA segment may act as a translational enhancer for the expression of virally encoded products.

Six billion neurons lost in AIDS. A stereological study of the neocortex.

Human immunodeficiency virus type 1 (HIV1) is neurotropic. One of the morphological changes that is seen in patients with acquired immunodeficiency syndrome (AIDS) is cerebral atrophy affecting various structures including the neocortex. The cause of atrophy is not known. The total number of neocortical neurons was estimated in formalin fixed brains of 12 males with AIDS and 12 male controls matched for age and height. The mean number of neocortical neurons was 16.0 x 10(9) (coefficient of variation = 0.11) in the AIDS patients compared with 21.9 x 10(9) (coefficient of variation = 0.22) in the controls, a difference of approximately six billion (p < 0.005, 2-tailed). The global neuronal loss was 37%, and affected all four neocortical lobes. Ten patients did not have a history of central nervous system symptoms; two patients had a history of dementia. The number of neurons in the AIDS cases was not associated with dementia. AIDS is the first disease in which a global loss of neocortical neurons has been demonstrated using unbiased stereological methods. The loss of more than one third of the neurons may partly explain the cortical atrophy. Focal neuron loss has been reported by several authors, but none have been based on unbiased methods. In this group of AIDS patients the severe loss of neurons did not correspond to neurological deficits.

Randomized comparison trial of teicoplanin i.v., teicoplanin i.m., and cefazolin therapy for skin and soft tissue infections caused by gram-positive bacteria.

Teicoplanin, a glycopeptide antibiotic chemically related to the vancomycin-ristocetin group of antibiotics, has potent activity against aerobic and anaerobic gram-positive bacteria. In this study, we examined the efficacy and safety of teicoplanin for parenteral treatment of skin and soft tissue infections caused by gram-positive bacteria. Ninety-six hospitalized adults with moderate to severe skin and soft tissue infections were randomized to receive either teicoplanin intravenously (i.v.) once a day, teicoplanin intramuscularly (i.m.) once a day, or cefazolin i.v. every 8 hours. We evaluated patients' clinical and microbiologic status and assessed clinical and laboratory adverse events. Of 76 clinically assessable patients, 26 of 26 (100%) given teicoplanin i.v., 21 of 22 (95%) given teicoplanin i.m., and 26 of 28 (93%) given cefazolin showed improvement or cure. Of 60 microbiologically assessable patients, 22 of 22 (100%) given teicoplanin i.v., 16 of 18 (89%) given teicoplanin i.m, and 18 of 20 (90%) given cefazolin were cured. Of 96 patients assessable for adverse events, 7 of 34 (21%) given teicoplanin i.v., 4 of 31 (13%) give teicoplanin i.m., and 1 of 31 (3%) given cefazolin had adverse events. In this study, once daily teicoplanin appeared to be safe and effective therapy for skin and soft tissue infections.

Cerebral atrophy in AIDS: a stereological study.

Stereological estimates of mean volumes, surface areas, and cortical thicknesses were obtained on formalin-fixed brains from 19 men with AIDS and 19 controls. Volumes of neocortex, white matter, central brain nuclei, ventricles and archicortex were estimated using point counting and Cavalieri's unbiased principle for volume estimation. In AIDS, the mean volume of neocortex was reduced by 11%, and that of the central brain nuclei by 18%. Mean ventricular volume was increased by 55%. Mean neocortical thickness was reduced by 12%. The mean volume of white matter was reduced by 13%. The findings in 6 clinically demented AIDS patients were not statistically different from the rest of the group.

Nosocomial acquisition of beta-lactamase--negative, ampicillin-resistant enterococcus.

BACKGROUND: A recent prospective study at the Department of Veterans Affairs Medical Center, Martinez, Calif, revealed that 9% of enterococcal clinical isolates were ampicillin resistant. We prospectively studied 100 patients hospitalized in one general medicine ward and in the medical intensive care unit to study determinants of acquisition of ampicillin-resistant enterococcus. METHODS: Rectal swabs and urine cultures were obtained from patients within 72 hours of admission to the study ward and twice weekly until discharge from the ward or the intensive care unit. Cultures were obtained from the hands of personnel and from environmental surfaces in the general medical ward and the intensive care unit. Ampicillin-resistant enterococcal isolates were examined for molecular relatedness by plasmid DNA analysis. RESULTS: The cultures from 23 patients yielded ampicillin-resistant enterococci. The rectal swabs yielded ampicillin-resistant enterococci before the urine cultures did except in one patient whose urine and rectal cultures were both positive on the same day. Acquisition of ampicillin-resistant enterococci was significantly associated with previous antimicrobial agents, Foley catheterization, and being bedridden. Resistant enterococci were not isolated from hospital personnel or environmental surfaces. Plasmid analysis by gel electrophoresis demonstrated nine strains, two of which predominated. Rectal and urine isolates from the same patient had identical plasmid electrophoresis patterns. CONCLUSIONS: We conclude that ampicillin-resistant enterococci are common in the rectal flora, can spread to the urinary system, are associated with patient characteristics that predipose to nosocomial infection, and may become an emerging clinical problem.

Endovascular infections caused by enterococci highly resistant to ampicillin.

Enterococci frequently cause endocarditis and are the most common gram-positive isolates in polymicrobial bacteremia. We report three cases of polymicrobial endovascular infections at a single institution during a 12-month period; the enterococcal isolates were highly resistant to penicillins. These cases comprised 18% of all enterococcal endovascular isolates during the same 12-month period. Previous use of antibiotics, presence of endovascular catheters, and nosocomial acquisition of the organism occurred in all three cases. Clinicians should be aware of enterococcal resistance to penicillins and should exercise care in designing appropriate regimens for serious enterococcal infections.