Relation between nasal/voice accelerometric values and interval estimates of hypernasality.
Nasal/throat accelerometric ratios were obtained from 12 hypernasal and three normal children. The accelerometric voltages comprising the ratio were analogs of nasal and anterior-neck tissue vibrations. Audio recordings, which were obtained simultaneously with the accelerometric voltages, were later judged for hypernasality using an equal-appearing-interval (EAI) scale. High correlations were evident between accelerometric and EAI values when a stimulus sentence contained obstruents, semivowels, and vowels. No correlation existed between accelerometric measures and hypernasality judgments when a sentence contained primarily nasal phonemes and vowels.


Antitumor effects of a monoclonal antibody to human CCR9 in leukemia cell xenografts.
Tumor expression of certain chemokine receptors is associated with resistance to apoptosis, migration, invasiveness and metastasis. Because CCR9 chemokine receptor expression is very restricted in healthy tissue, whereas it is present in tumors of distinct origins including leukemias, melanomas, prostate and ovary carcinomas, it can be considered a suitable candidate for target-directed therapy. Here, we report the generation and characterization of 91R, a mouse anti-human CCR9 IgG2b monoclonal antibody that recognizes an epitope within the CCR9 N-terminal domain. This antibody inhibits the growth of subcutaneous xenografts from human acute T lymphoblastic leukemia MOLT-4 cells in immunodeficient Rag2(-/-) mice. Tumor size in 91R-treated mice was reduced by 85% compared with isotype-matched antibody-treated controls. Tumor reduction in 91R-treated mice was concomitant with an increase in the apoptotic cell fraction and tumor necrotic areas, as well as a decrease in the fraction of proliferating cells and in tumor vascularization. In the presence of complement or murine natural killer cells, 91R promoted in vitro lysis of MOLT-4 leukemia cells, indicating that this antibody might eliminate tumor cells via complement- and cell-dependent cytotoxicity. The results show the potential of the 91R monoclonal antibody as a therapeutic agent for treatment of CCR9-expressing tumors.


The association between working alliance and clinical and functional outcome in a cohort of 400 patients with first-episode psychosis: a cross-sectional study.
Working alliance between patients with a first-episode psychosis and their case manager is regarded as a key element in specialized early intervention services. The impact of this patient-case manager dyad on functional and clinical outcome is unknown. We aimed to investigate if a strong working alliance was associated with fewer clinical symptoms and better social functioning. In a cross-sectional design, patients with first-episode schizophrenia spectrum disorders (ICD-10, F20-29) were included after 18 months of treatment (N = 400). Baseline data were collected between June 2009 and December 2011. Symptoms were assessed using Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment of Functioning (GAF), Brief Assessment of Cognition in Schizophrenia (BACS), Working Alliance Inventory (WAI), and General Self-Efficacy (GSE). Linear regression analyses were adjusted for age, sex, cognition, and self-efficacy. Results revealed significant associations between working alliance and fewer negative (β = -0.12; 95% CI, -0.19 to -0.04) and disorganized symptoms (β = -0.06; 95% CI, -0.11 to -0.01), and between working alliance and better social functioning (β = 1.45; 95% CI, 0.55 to 2.36). General self-efficacy mediated the effect of working alliance, explaining 14%-18% of the variance in associated outcomes. Global level of cognitive functioning, compliance, and self-efficacy influenced clinical and functional outcome more strongly than working alliance. Better working alliance was weakly associated with fewer negative and disorganized symptoms and better social functioning. A strong working alliance may be a prerequisite for adherence to the specialized early intervention services treatment, providing the basis for positive treatment outcome. ClinicalTrials.gov identifier: NCT00914238.


[Interferon-inducing activity of liposome-incorporated double-stranded polynucleotides and the means for its enhancement].
Natural double-stranded RNA (dsRNA) incorporated into liposomes upon parenteral inoculation induces 4 times as much amounts of interferon as inoculation of the equal amount of dsRNA without liposomes. Oral administration of liposome-incorporated dsRNA induces in animals serum interferon in amounts similar to those induced by parenteral inoculation of dsRNA without liposomes (320-640 units/ml). When liposome-incorporated dsRNA is used, interferon induction is prolonged to 24 hours. The prolongation period increases to 5 days after preliminary treatment of animals with "empty" liposomes. In M-19 cell culture, 2-hour treatment with liposome-incorporated dsRNA in a dose of 5-10 micrograms/ml induces a yield of 640-1280 units/ml interferon and 100% antiviral effect. The L-929 culture is more sensitive to dsRNA in liposomes. Even its minimal amounts (0.1-1 microgram/ml) after 2-3-hour contact produce a 100% antiviral effect in the presence of low amounts of interferon in the culture fluid (20-40 units/ml) or in its complete absence.


Transplantation of monoclonal antibody-purged autologous bone marrow for treatment of poor risk common acute lymphoblastic leukemia.
Two murine monoclonal antibodies, FMC-8 and WM-21, reactive with the human leucocyte differentiation antigens CD-9 (p-24) and CD-10 (CALLA), respectively, have been used for purging leukemic cells from remission bone marrow. Nine patients with the common variant of acute lymphoblastic leukemia (c-ALL) in second or subsequent remission underwent bone marrow harvesting. Bone marrow mononuclear cells underwent lytic incubation in vitro with antibodies FMC-8 and WM-21, and rabbit serum as a source of complement, and were then cryopreserved. A mean of 0.90 +/- 0.50 x 10(8) nucleated cells per kilogram of recipient body weight remained after treatment, with 0.38 +/- 0.24 x 10(8) nucleated cells and 8.3 +/- 10.3 x 10(4) CFUGM per kg being recovered on thawing. Seven patients subsequently received marrow-ablative treatment with high dose cyclophosphamide (120 mg/kg) and fractionated total body irradiation (12 Gy), followed by infusion of antibody-purged autologous bone marrow. Three deaths due to sepsis occurred within the first 35 days, compounded in one patient by poor marrow engraftment. All other patients engrafted promptly, and four remain in continuous complete remission at 2, 6, 9, and 28 months after transplantation. The procedure carries a substantial risk of early toxicity, but offers a significant chance of prolonged unmaintained remission to selected patients with poor prognosis acute lymphoblastic leukemia.


Fas ligand expression in colon cancer: a possible mechanism of tumor immune privilege.
To detect the expression of Fas ligand (FasL) in colon cancer tissues and cell lines and analyze the function of FasL-expressing colon cancer cells in inducing Fas-sensitive T lymphocyte apoptosis. Ninety surgically resected colon cancer tissues and 15 hepatic metastasis specimens were investigated by immunohistochemical method with normal colon mucosa and colon adenoma as control. The relationship between FasL expression and pathologic features was also analyzed. FasL expression of 4 colon cancer cell lines, SW620, Lovo, LS-174T and SW1116, were detected by Western blotting assay. The function of FasL expressed on colon cancer cells was determined by coculture assay with Jurkat T lymphocytes, the apoptotic rate of which was detected by flow cytometry assay. Fifty-six (62.22%) cases of all the 90 colon cancer tissues and all (100%) the liver metastasis specimens expressed FasL, significantly higher than normal colon mucosa and colonic adenoma. Higher expression of FasL was found in more advanced stage of colon cancer and in cancer tissues with lymphatic or hepatic metastasis. All the colon cancer cell lines were found to express FasL. After coculture with the SW1116 cells for 24 h with an effector: target ratio 10:1, the rate of apoptosis of Jurkat cells rose from 1.9% to 21.0%. The expression of FasL is upregulated in colon cancer and the functionally expressed FasL can induce apoptosis of Fas-expressing T lymphocytes.


Successful laparoscopic living donor nephrectomy: first experience in Lithuania.
The aim of this paper is to share the initial results of LLDN in high-volume university centre that is performing laparoscopic nephrectomies for other indications. During 2017, four LLDNs were performed. The transperitoneal approach was used in all cases and the kidney was removed using a suprapubic incision. All donors and recipients were prospectively analysed within six-month follow-up. The patients' clinical, laboratory, and operation-related data were collected from direct interviews with them and from medical records. All patients signed written informed consent. One male and three females donated their left kidneys by using the LLDN technique. The mean age was 58 ± 9 years; two of them with a history of previous cholecystectomy. All donated kidneys had a single renal artery and renal vein. Pre-operative average eGFR was 94.2 ± 7.1 ml/min/1.73 m2, immediately after LLDN 57.5 ± 10.3 ml/min/1.73 m2, after one month 56.0 ± 9.1 ml/min/1.73 m2. There were no intraoperative complications; surgery duration was 223.75 ± 21.74 min, the cold ischemia time was 77.5 ± 28.77 min, and the warm ischemia time 6.37 ± 3.14 min. There was one postoperative donor complication, one case of acute kidney injury, and one case of prolonged postoperative abdominal pain. The only recipient complication was one case of acute kidney rejection; there were no cases of delayed graft function. Our initial experience confirms that LLDN is an approach that is easy to learn, especially in a high-volume university hospital with expertise in performing laparoscopic nephrectomies for other indications.


Interstitial Lung Disease after Pleurodesis for Malignant Pleural Effusion.
Objective Pleurodesis is an effective therapy for malignant pleural effusion (MPE). While interstitial lung disease (ILD) has been regarded as a serious complication of pleurodesis, its clinicopathological characteristics have not been fully understood. This study was conducted to elucidate the incidence of ILD and the risk factors for ILD in patients who underwent pleurodesis to control MPE. Methods The medical records of patients who underwent pleurodesis in Aichi Medical University between March 2008 and February 2013, the period before the approval of talc in Japan, were retrospectively analyzed. Results A total of 84 patients underwent pleurodesis, all using OK-432. ILD occurred in 13 patients (15.5%). The development of ILD after pleurodesis was significantly associated with old age (odds ratio [OR]: 4.82, 95% confidence interval [CI]: 1.22-19.08) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment (OR: 5.97, CI: 1.7-20.9). A multivariate analysis revealed that >67 years of age (p=0.01) and EGFR-TKI treatment (p=0.02) were significantly associated with the development of pleurodesis-related ILD. Among the patients who received both pleurodesis and EGFR-TKIs (n=23), 8 patients developed ILD. All of these patients were receiving EGFR-TKI therapy at the time of pleurodesis or within 30 days after pleurodesis. In contrast, no cases of ILD were observed among the patients who stopped EGFR-TKIs before pleurodesis or started EGFR-TKIs at more than 30 days after pleurodesis. Conclusion ILD seemed to be a frequent complication of pleurodesis in patients using OK-432, especially elderly patients and those who underwent pleurodesis while receiving EGFR-TKI therapy or who started EGFR-TKI therapy within 30 days after pleurodesis.


Morphological behavior of carcinoma of the pancreas. 1. Histological classification and electron microscopical observation.
A total of 84 autopsied and 10 operative pancreatic carcinoma cases were studied to investigate their morphological behavior, by light and electron microscopies. The autopsied materials were classified into 70 duct cell carcinomas, 11 undifferentiated carcinomas including 2 giant cell carcinomas simulating giant cell tumor of bone, and 3 endocrine cell carcinomas which might be called carcinoid or oat cell carcinoma. No acinar cell carcinoma was found. Duct cell carcinomas were further subclassified into 37 large and 24 small duct-forming adenocarcinomas, 8 adenosquamous carcinomas, and 1 cystadenocarcinoma. The majority of undifferentiated carcinomas were considered to be of ductal or ductular cell origin. Rare tumors, such as cystadenocarcinoma, giant cell carcinoma, and endocrine cell carcinoma, were shown as case presentations. Electron microscopic features of duct cell carcinoma and its related findings were also presented. These studies should be pursued, because it may be important clinically and disclose, in the future, possible differences in etiology or effective therapeutic agents among the categories, although the classification, made from a viewpoint of histogenesis, did not reflect prognostic differences at the present.


Brain changes in schizophrenia. Volumetric MRI study of families multiply affected with schizophrenia--the Maudsley Family Study 5.
Structural brain abnormalities have been reported in schizophrenia. We tested the hypothesis that these abnormalities represented a marker for the genetic liability to schizophrenia in a sample of people with schizophrenia and their relatives from families multiply affected with the disorder. We compared 31 people with schizophrenia, 57 relatives and 39 unrelated control subjects. Volumetric measurement of brain structures was carried out using stereological principles from three-dimensional reconstructed magnetic resonance images. Subjects with schizophrenia had larger lateral ventricles than their relatives and the normal control subjects. Relatives who were 'presumed obligate carriers' had larger left lateral ventricles than other relatives and the control subjects. Subjects with schizophrenia showed smaller whole brain and cerebellar volumes and larger lateral ventricles than their age- and gender-matched unaffected siblings. In families multiply affected with schizophrenia lateral ventricular enlargement distinguishes people with schizophrenia and presumed obligate carriers from other relatives and unrelated control subjects. These changes may be a marker for a genetic liability to schizophrenia.


Efficient automated error detection in medical data using deep-learning and label-clustering.
Medical datasets inherently contain errors from subjective or inaccurate test results, or from confounding biological complexities. It is difficult for medical experts to detect these elusive errors manually, due to lack of contextual information, limiting data privacy regulations, and the sheer scale of data to be reviewed. Current methods for training robust artificial intelligence (AI) models on data containing mislabeled examples generally fall into one of several categories-attempting to improve the robustness of the model architecture, the regularization techniques used, the loss function used during training, or selecting a subset of data that contains cleaner labels. This last category requires the ability to efficiently detect errors either prior to or during training, either relabeling them or removing them completely. More recent progress in error detection has focused on using multi-network learning to minimize deleterious effects of errors on training, however, using many neural networks to reach a consensus on which data should be removed can be computationally intensive and inefficient. In this work, a deep-learning based algorithm was used in conjunction with a label-clustering approach to automate error detection. For dataset with synthetic label flips added, these errors were identified with an accuracy of up to 85%, while requiring up to 93% less computing resources to complete compared to a previous model consensus approach developed previously. The resulting trained AI models exhibited greater training stability and up to a 45% improvement in accuracy, from 69 to over 99% compared to the consensus approach, at least 10% improvement on using noise-robust loss functions in a binary classification problem, and a 51% improvement for multi-class classification. These results indicate that practical, automated a priori detection of errors in medical data is possible, without human oversight.


Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders. A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I-IV). The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies). Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.


Discordant expression of CD20 by flow cytometry and immunohistochemistry in a patient responding to rituximab: an unusual mechanism.
Immunohistochemistry using the L26 antibody recognizes an intracellular domain of CD20, whereas the L27 antibody used for surface CD20 staining by flow cytometry (FC) recognizes an extracellular domain and would be expected to be a better predictor of response to rituximab. We present a 75-year-old man who was initially treated for CD20- diffuse large B-cell lymphoma based on FC and, at relapse, still had CD20- disease by FC but CD20+ disease by immunohistochemistry. The patient responded to rituximab alone. On further study, it was shown that the malignant B cells, but not normal B cells, expressed the L27 surface binding site only within the intracellular domain. Therefore, it appears that the rituximab binding site is distinct from the surface binding site, and when there is a disparity between the methods to detect CD20 expression, consideration should be given to include rituximab in the treatment plan.


Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention.
Epidemiological evidence has demonstrated a reduced risk of prostate cancer associated with cruciferous vegetable intake. Follow-up studies have attributed this protective activity to the metabolic products of glucosinolates, a class of secondary metabolites produced by crucifers. The metabolic products of glucoraphanin and glucobrassicin, sulforaphane, and indole-3-carbinol respectively, have been the subject of intense investigation by cancer researchers. Sulforaphane and indole-3-carbinol inhibit prostate cancer by both blocking initiation and suppressing prostate cancer progression in vitro and in vivo. Research has largely focused on the anti-initiation and cytoprotective effects of sulforaphane and indole-3-carbinol through induction of phases I and II detoxification pathways. With regards to suppressive activity, research has focused on the ability of sulforaphane and indole-3-carbinol to antagonize cell signaling pathways known to be dysregulated in prostate cancer. Recent investigations have characterized the ability of sulforaphane and indole-3-carbinol derivatives to modulate the activity of enzymes controlling the epigenetic status of prostate cancer cells. In this review, we will summarize the well-established, "classic" non-epigenetic targets of sulforaphane and indole-3-carbinol, and highlight more recent evidence supporting these phytochemicals as epigenetic modulators for prostate cancer chemoprevention.


Identification of Specialists and Abundance-Occupancy Relationships among Intestinal Bacteria of Aves, Mammalia, and Actinopterygii.
The coalescence of next-generation DNA sequencing methods, ecological perspectives, and bioinformatics analysis tools is rapidly advancing our understanding of the evolution and function of vertebrate-associated bacterial communities. Delineation of host-microbe associations has applied benefits ranging from clinical treatments to protecting our natural waters. Microbial communities follow some broad-scale patterns observed for macroorganisms, but it remains unclear how the specialization of intestinal vertebrate-associated communities to a particular host environment influences broad-scale patterns in microbial abundance and distribution. We analyzed the V6 region of 16S rRNA genes amplified from 106 fecal samples spanning Aves, Mammalia, and Actinopterygii (ray-finned fish). We investigated the interspecific abundance-occupancy relationship, where widespread taxa tend to be more abundant than narrowly distributed taxa, among operational taxonomic units (OTUs) within and among host species. In a separate analysis, we identified specialist OTUs that were highly abundant in a single host and rare in all other hosts by using a multinomial model without excluding undersampled OTUs a priori. We show that intestinal microbes in humans and other vertebrates display abundance-occupancy relationships, but because intestinal host-associated communities have undergone intense specialization, this trend is violated by a disproportionately large number of specialist taxa. Although it is difficult to distinguish the effects of dispersal limitations, host selection, historical contingency, and stochastic processes on community assembly, results suggest that intestinal bacteria can be shared among diverse hosts in ways that resemble the distribution of "free-living" bacteria in the extraintestinal environment.


miR-4454 up-regulated by HPV16 E6/E7 promotes invasion and migration by targeting ABHD2/NUDT21 in cervical cancer.
The abnormal expression of HPV16 E6/E7 activates oncogenes and/or inactivates tumor suppressor genes, resulting in the selective growth and malignant transformation of cancer cells. miR-4454 was selected by sequencing due to its abnormal high expression in HPV16 E6/E7 positive CaSki cell compared with HPV16 E6/E7 negative C33A cell. Overexpression of miR-4454 enhances cervical cancer cell invasion and migration. ABHD2 and NUDT21 are identified as a target gene of miR-4454.The effects of ABHD2 and NUDT21 on migration and invasion of CaSki and C33A cells were determined. The dual luciferase and RT-qPCR assays confirmed that miR-4454 might regulate its targets ABHD2 and NUDT21 to promote the proliferation, invasion and migration, whereas, inhibit the apoptosis in CaSki and C33A cells.


Leisure time physical activity: a protective factor against metabolic syndrome development.
Physical activity (PA) is a modifiable factor in preventing/treating cardiometabolic disease. However, no studies have yet compared specific moderate-to-vigorous PA (MVPA) domains with the risk of metabolic syndrome (MetS) in detail. Here, the present study was conducted to examine the impact of different MVPA domains (leisure-time PA (LTPA) vs. occupational PA (OPA) vs. total MVPA) on the risk of MetS in Korean adults. Data from the 2014 to 2021 Korea National Health and Nutrition Examination Survey were analyzed (N = 31,558). MetS was defined according to the criteria by revised NCEP/ATP-III. The domain-specific MVPA was assessed using the K-GPAQ. The LTPA and OPA status were classified into four categories: (1) 0 min/week, (2) 1 to 149 min/week, (3) 150 to 299 min/week, and 4) ≥ 300 min/week. In addition, the present study calculated total MVPA as a sum of OPA and LTPA and further classified it into six groups; (1) 0 min/week, (2) 1 to 149 min/week, (3) 150 to 299 min/week, (4) 300 to 449 min/week, (5) 450 to 599 min/week, 6) ≥ 600 min/week. The ≥ 300 min/week and the 150 to 299 min/week of LTPA showed better outcomes in cardiometabolic disease risk factors and surrogate markers of insulin resistance compared with the 0 min/week of LTPA regardless of adiposity status. Risk of MetS in ≥ 300 min/week of LTPA was lower than in 0 min/week, 1 to 149 min/week, and 150 to 299. In addition, LTPA was significantly associated with a risk of the MetS in a curvilinear dose-response curve, however, no significant effects of a non-linear relationship between OPA and risk of the MetS. Our findings showed that LTPA was associated with a risk of MetS with a dose-response curve, whereas no significant non-linear effects were found between OPA and the risk of MetS. Therefore, the MVPA domain is an independent factor of the risk of MetS.


Lkb1 regulates granule cell migration and cortical folding of the cerebellar cortex.
Cerebellar growth and foliation require the Hedgehog-driven proliferation of granule cell precursors (GCPs) in the external granule layer (EGL). However, that increased or extended GCP proliferation generally does not elicit ectopic folds suggests that additional determinants control cortical expansion and foliation during cerebellar development. Here, we find that genetic loss of the serine-threonine kinase Liver Kinase B1 (Lkb1) in GCPs increased cerebellar cortical size and foliation independent of changes in proliferation or Hedgehog signaling. This finding is unexpected given that Lkb1 has previously shown to be critical for Hedgehog pathway activation in cultured cells. Consistent with unchanged proliferation rate of GCPs, the cortical expansion of Lkb1 mutants is accompanied by thinning of the EGL. The plane of cell division, which has been implicated in diverse processes from epithelial surface expansions to gyrification of the human cortex, remains unchanged in the mutants when compared to wild-type controls. However, we find that Lkb1 mutants display delayed radial migration of post-mitotic GCPs that coincides with increased cortical size, suggesting that aberrant cell migration may contribute to the cortical expansion and increase foliation. Taken together, our results reveal an important role for Lkb1 in regulating cerebellar cortical size and foliation in a Hedgehog-independent manner.


A randomized trial comparing perioperative pelvic FLOor physical therapy to current standard of care in transgender Women undergoing vaginoplasty for gendER affirmation: the FLOWER Trial.
There are sparse data on the use of postoperative pelvic floor physical therapy (PFPT) in patients undergoing vaginoplasty. The primary objective of this study was to compare the impact of PFPT on the ease of vaginal dilation after vaginoplasty in transgender women. We hypothesized that patients undergoing PFPT would report better ease of vaginal dilation following surgery. This was a randomized trial of transgender women undergoing vaginoplasty. Patients were randomized to either no PFPT or PFPT 3 and 6 weeks following surgery. Subjects completed the Pelvic Floor Disorders Inventory and the Pelvic Floor Impact Questionnaire at baseline and at 12 weeks. At 12 weeks, subjects underwent vaginal length measurement and completed the Patient Global Impression of Improvement and a visual analogue scale (0-10) for ease of vaginal dilation and pain with dilation. A total of 17 subjects in each arm were needed to detect a significant difference in ease of dilation between the two groups. Forty-one subjects were enrolled and 12-week data were available for 37 subjects (20 PFPT, 17 no PFPT). Mean age and BMI were 31 ± 13 years and 24.9 (± 4.0) kg/m2. Subjects were on hormone therapy for a median of 39 (20-240) months and 5 (13.5%) patients had undergone previous orchiectomy. At 12 weeks, the median vaginal length was 12.5 (10-16) cm, reported mean ease of dilation was 7.3 (± 1.6), and pain with dilation was 2.4 (± 1.7). There were no differences in these outcomes or in pelvic floor symptoms between the groups. In this study, routine postoperative PFPT did not improve outcomes in patients undergoing vaginoplasty.


[The nursing team and the myth of group work].
This paper has two objectives: the first one is analyzing the individual behaviors indicated by non-verbal communication during shift exchanges; the second one is analyzing group behavior during shift exchanges based on the observation the videotaped scenes of a nursing staff during a shift exchange. A list of non-verbal communication signs was used to analyze individual behaviors. The concepts group were used to analyze group behaviors. The results showed that ineffective non-verbal signs prevailed over effective ones and inadequate non-verbal signs were more visible than the adequate ones. One may conclude that shift exchange was not a group activity.


[Possible influence of ramets on the population structure and distribution of the giant tree Warszewiczia uxpanapensis, Tilarán Mountain Range, Costa Rica].
The distribution and population structure of Warszewiczia (=Elaeagia) uxpanapensis, a tree that reaches a height of 45 m, a DBH of 1.40 m and 8 m tall buttresses, was studied on two 1-ha plots of premontane pluvial forest. It had a frequency of 49 % and a mean dominance of 6.5 %. The adult distribution was random (mean distance to the nearest neighboring tree in plot 1, it was 14.26 m, n = 15; Clark-Evans Index (IC-E) = 1.07; in plot 2, it was 15.33 m, n = 18, IC-E = 1.34,). The seedlings represented 60.3 % of the sampled population (plot 1, n = 94; plot 2, n = 85). This species has a very high capability of propagating itself vegetatively through clones ("ramets"), which influence its distribution and population structure. With a ramet density in plot 1 of 0.8 and in plot 2 of 0.3/100 m2, its propagation could be from fallen trees or branches (which also create clearings in the forest) or from standing trees and even live branches that produce adventitious roots.


Predictive role of gene polymorphisms affecting thrombin-generation pathway in variable efficacy of photodynamic therapy for neovascular age-related macular degeneration.
Age-related macular degeneration (AMD) represents the leading cause of central blindness in developed countries. The majority of severe vision loss occurs in the neovascular form of AMD, generally characterized by the presence of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) and drugs acting against vascular endothelial growth factor are the most commonly employed treatments for AMD-related subfoveal CNV. The combined use of both these strategies is the most promising therapeutic approach towards this harmful disease. The therapeutic action of PDT-V depends to a photochemical perturbation of thrombo-coagulative processes within CNV. Predictive correlations between peculiar coagulation-balance gene polymorphisms and different levels of post-PDT-V benefit have been recently documented in Caucasian patients with neovascular AMD. Particularly, heterozygous A-allele carriers of factor V Leiden 1691 or prothrombin 20210 gene are characterized by a greater possibility to exhibit clinical benefit after PDT-V. Both mutations induce thrombophilia increasing the thrombin generation in plasma and, thus, they can consistently intensify the photothrombotic phase of the therapeutic CNV occlusion. In prospect, considering the different individual susceptibility to PDT-V, a preoperative assessment of the genotypic thrombophilic background could optimize the eligibility criteria of this intriguing treatment. This review summarizes some of the recent published patents on treatment of neovascular AMD, with a particular attention to PDT-V application in combined therapeutic modalities.


Susceptibility to Fosfomycin and Nitrofurantoin of ESBL-Positive Escherichia coli and Klebsiella pneumoniae Isolated From Urine of Pediatric Patients.
Pediatric urinary tract infection (UTI) caused by extended-spectrum β-lactamase (ESBL)-positive gram-negative bacilli (GNB) has limited options for oral antibiotic treatment. The purpose of this study was to investigate the susceptibility of ESBL-positive Escherichia coli and Klebsiella pneumoniae isolates from pediatric urine samples to two oral antibiotics (fosfomycin and nitrofurantoin). From November 2020 to April 2022, ESBL-positive E. coli and K. pneumoniae isolates from urine samples were collected at Samsung Medical Center, Seoul, Korea. Patients over 18 years of age or with malignancy were excluded. For repeated isolates from the same patient, only the first isolate was tested. Minimum inhibitory concentrations (MICs) were measured using agar (fosfomycin) or broth (nitrofurantoin) dilution methods. MIC50 and MIC90 were measured for fosfomycin and nitrofurantoin in both E. coli and K. pneumoniae. There were 117 isolates from 117 patients, with a median age of 7 months (range, 0.0-18.5 years). Among 117 isolates, 92.3% (108/117) were E. coli and 7.7% (9/117) were K. pneumoniae. Isolates from the pediatric intensive care unit (PICU) and general ward (GW) was 11.1% (13/117) and 88.9% (104/117), respectively. Among 108 E. coli isolates, MIC50 and MIC90 for fosfomycin were 0.5 μg/mL and 2 μg/mL, respectively. Fosfomycin susceptibility rate was 97.2% (105/108) with a breakpoint of 128 μg/mL. Fosfomycin susceptibility rate was significantly lower in PICU isolates than in GW isolates (81.8% vs. 99.0%, P = 0.027). For nitrofurantoin, both the MIC50 and MIC90 were 16 μg/mL. Nitrofurantoin susceptibility rate was 96.3% (104/108) with a breakpoint of 64 μg/mL based on Clinical and Laboratory Standards Institute guidelines. Among the nine K. pneumoniae isolates, the MIC50 and MIC90 for fosfomycin was 2 μg/mL and 32 μg/mL, respectively. MIC50 and MIC90 for nitrofurantoin were 64 μg/mL and 128 μg/mL, respectively. For uncomplicated UTI caused by ESBL-positive GNB in Korean children, treatment with fosfomycin and nitrofurantoin for E. coli infections can be considered as an effective oral therapy option.


The patch as method: The arts' contribution towards understandings of conflict.
This article asks: how do art practice and research give form to changing dynamics of conflict? Its argument is two-fold: art's contribution can be developed from empirical considerations (what art finds out), and from methodological ones (how art finds something out). Bringing in art practice and the research methods it informs into political science helps understand conflict and its changes: by engaging simultaneously with the interaction between the collective and the personal, art practice and research elucidates those complex and layered narratives used by various actors in conflict that often resist approaches rooted in social and political sciences. By paying attention to everyday interactions and emphasizing dynamism, art provides a different way to chart changes in armed conflict. Art documents discourses that are difficult to communicate otherwise and allows us to detect and engage with the grey areas, transformations, processes and ambivalences of conflicts that escape neat categorizations.


Next-Generation Human Immunodeficiency Virus Sequencing for Patient Management and Drug Resistance Surveillance.
High-quality, simplified, and low-cost human immunodeficiency virus (HIV) drug resistance tests that are able to provide timely actionable HIV resistance data at individual, population, and programmatic levels are needed to confront the emerging drug-resistant HIV epidemic. Next-generation sequencing technologies embedded in automated cloud-computing analysis environments are ideally suited for such endeavor. Whereas NGS can reduce costs over Sanger sequencing, automated analysis pipelines make NGS accessible to molecular laboratories regardless of the available bioinformatic skills. They can also produce highly structured, high-quality data that could be examined by healthcare officials and program managers on a real-time basis to allow timely public health action. Here we discuss the opportunities and challenges of such an approach.


Two new chlorinated amides from Nicotiana glauca R. Graham.
Two new chlorinated amides, N-(2',6'-diethyl phenyl)-2-chloroacetamide (1) and N-(butyloxymethyl)-N-(2',6'-diethyl phenyl)-2-chloroacetamide (2) were isolated for the first time from the ethanolic extract of the leaves of Nicotiana glauca R. Graham in addition to triacontanol (3), scopoletin (4) and stigmasterol-3-beta-O-D-gluco-pyranoside (5). The structures of the isolated compounds were elucidated by spectroscopic analysis (1D, 2D NMR, EIMS, HR-EIMS, IR and UV).


Management of neoplastic pericardial effusions.
Malignant pericardial effusion and cardiac tamponade are known complications of many advanced malignancies such as breast cancer, lung cancer, lymphomas and leukemias. Overall survival is low, due to other metastatic localizations. The present study evaluated the clinical outcome and prognosis in patients with advanced cancer with pericardial effusion. We studied 7 patients, 4 men and 3 women, with malignant pericardial effusion, affected by breast cancer (2 patients), lung cancer (adenocarcinoma in 3 patients, microcytoma in 1 patient), and B-cell non-Hodgkin lymphoma (1 patient). All patients underwent pericardiocentesis; 3 patients underwent an instillation of thiotepa. One terminal patient treated with pericardiocentesis died after only a few hours. All the remaining patients experienced immediate symptomatic improvement and no operative complications. At the end of the study period, 2 patients were alive at 59 and 33 months, respectively, and 4 died of disease progression at 1 to 32 months (mean, 10.5). Pericardiocentesis is an active necessary approach, and intrapericardial treatment with thiotepa was able to reduce pericardial effusion and to prevent its reaccumulation. The standard treatment of malignant effusion and cardiac tamponade has not yet been defined. Physicians should consider the status and the prognosis of each case.


Severe cutaneous adverse drug reactions manifesting as Stevens-Johnson syndrome and toxic epidermal necrolysis reported to the national pharmacovigilance center in Nigeria: a database review from 2004 to 2017.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions (SCARs). There is scant literature on the characteristics and causes of these conditions among the Nigerian population. Here, we describe the epidemiology, associated morbidity and mortality, and culpable drugs in SJS and TEN cases using the National Pharmacovigilance (NPC) database in Nigeria. A retrospective review of the NPC database was done to analyze SJS and TEN cases reported over a period of 14 years. Annual reports, age and sex of patients, type of reporter, suspects and concomitant drugs, time to onset (TTO) of the reactions, and outcome of SJS and TEN were evaluated. The NPC received a total of 24,015 adverse drug reaction (ADR) reports. SJS and TEN accounted for 284 (0.1%) of the total reports, of which 254 (89.4%) were SJS and the remainder were TEN. Females (n = 184, 64.8%) and individuals aged 19-40 years (n = 181, 63.7%) were the most affected by SJS and TEN. Antiretrovirals, followed by antibiotics, were the most common drug classes reported to cause SJS and TEN, with nevirapine (n = 174, 40.7%) and co-trimoxazole (n = 143, 33.5%) being the most widely implicated drugs. Among patients with reported outcomes, 73 (28.7%) SJS and 3 (10.0%) TEN cases recovered without sequelae, at the time of reporting. Severity of the SCAR was reported for only 171 (69.0%) cases, of which 12 (4.7%) and 8 (26.7%) resulted in death (Grade 5) among SJS and TEN cases, respectively. Antiretroviral and antibiotics were the commonly reported offending group of drugs for SJS and TEN cases. Nevirapine and co-trimoxazole were the commonly reported suspect drugs. SJS and TEN were reported most frequently in females and in patients aged 19-40 years, indicating that drug surveillance and counseling in these groups of patients may be beneficial.


Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity.
The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of IKur blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of IKur that describes KV1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the IKur formulation to account for state-specificity and kinetics of KV1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC50 value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (kon) and reverse (koff) binding rates to the closed, open, and inactivated states of the KV1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti-AF options.


Results of a phase II study of high-dose thoracic radiation therapy with concurrent cisplatin and etoposide in limited-stage small-cell lung cancer (NCCTG 95-20-53).
To evaluate the outcome of patients with limited-stage small-cell lung cancer (L-SCLC) treated with cisplatin and etoposide (PE), early prophylactic cranial irradiation (PCI), and high-dose twice-daily thoracic radiotherapy (bid RT). A total of 76 assessable patients were treated on this phase II trial, which included six cycles of PE. PCI (25 Gy/10 fractions) was delivered during cycle 3 to responding patients. Cycles 4 and 5 included concurrent chemotherapy and thoracic RT (30 Gy/20 bid fractions, a 2-week break, and another 30 Gy/20 bid fractions). Of the 76 assessable patients, 74 patients (97%) suffered grade 3 or greater (3+) toxicity and 61 patients (80%) had grade 4 or greater (4+) toxicity. Of these adverse events, grade 3+ hematologic toxicity occurred in 72 patients (95%), and grade 3+ nonhematologic toxicity occurred in 55 patients (72%). Only one (2%) of the 61 patients who received PCI experienced treatment failure in the brain. The 5-year survival rate of the 76 assessable patients was 24% (median, 20 months). The 5-year survival rate of the 64 patients who received thoracic RT was 29% (median, 22 months). The 5-year cumulative incidence of in-field treatment failure was 34%. This regimen included a high total dose of bid TRT, which resulted in a favorable 5-year survival rate. Local failure remains a problem that will require additional investigation. Newer technology should allow the safe administration of greater doses of RT, which should improve patient outcome. Data from eight trials were combined to demonstrate a relationship between RT dose fractionation and 5-year survival.


A patent perspective of antiangiogenic agents.
Angiogenesis plays a crucial role in the development of numerous vascular structures and is involved in a variety of physiologic and pathologic processes, including psoriasis, diabetic retinopathy, and especially cancer. By obstructing the process of angiogenesis, these therapies effectively inhibit the progression of the disease. Consequently, anti-angiogenic agents were subsequently developed. This review provides a comprehensive summary of the anti-angiogenic inhibitors developed in the past five years in terms of chemical structure, biochemical/pharmacological activity and potential clinical applications. A literature search was conducted using utilizing the databases Web of Science, Scifinder and Pubmed with the key word 'anti-angiogenic agents' and 'angiogenesis inhibitor.' This is despite the fact that the concept of antiangiogenesis has been proposed for more than fifty years and angiogenesis inhibitors are extensively employed in clinical practice. However, significant challenges continue to confront them. In recent years, there has been a significant increase in the number of patents focusing on angiogenesis inhibitors. These patents aim to enhance the selectivity of drugs against VEGF/VEGFR, explore new targets to overcome drug resistance, and explore potential drug combinations, thereby expanding the therapeutic possibilities in this field.


Submilisievert ultralow-dose CT colonography using iterative reconstruction technique: a feasibility study.
Computed tomography (CT) colonography is a well established modality for the examination of symptomatic patients as well as in screening. Recent technical advances in improving image quality by iterative reconstruction contribute to the reduction of the radiation dose which is a major concern in CT imaging. To evaluate image quality of ultralow-dose submilisievert CT colonography using hybrid iterative reconstruction technique. Sixteen patients underwent contrast-enhanced CT colonography with standard protocol in supine position and ultralow-dose protocol in prone position. Ultralow-dose datasets were reconstructed with filtered back projection and an advanced hybrid iterative reconstruction technique. Two radiologists independently evaluated 96 colonic segments for image quality in the endoluminal view and axial thin sections. Colonic distension, smoothness of colonic wall and distortion of folds in the endoluminal view, sharpness of colonic wall delineation, perceived image noise, and presence of photon starvation artifact were rated on a five-point scale. Intraluminal noise expressed as standard deviation of Hounsfield density was measured in all segments. The mean radiation dose was 0.42 mSv and 5.48 mSv in prone and supine scans, respectively. All distended segments were rated evaluable in standard dose and ultralow-dose series reconstructed with the iterative reconstruction technique, whereas in 61% segments image quality was rated poor or unacceptable in ultralow-dose series where filtered back projection was used with worst ratings in the rectum and the sigmoid colon. This pilot study shows that iterative reconstruction technique is a feasible method to decrease the radiation dose from CT colonography for both positions below 1mSv. Further investigations of larger scale need to be done to clarify, whether such a low radiation dose would influence the detection of polyps.


Angiogenesis inhibition by a lichen compound olivetoric acid.
Lichens have been used in folk medicine for centuries and are symbiotic organisms of fungi and algae that produce unique secondary metabolites. Olivetoric acid is one of these secondary metabolites. In the present study, the effect of olivetoric acid isolated from acetone extract of the lichen Pseudevernia furfuracea (var. ceratea) on angiogenesis was evaluated. It displayed potent anti-angiogenic activities in vitro: inhibited proliferation of rat adipose tissue endothelial cells (RATECs) and disrupted endothelial tube formation in a dose-dependent manner. Furthermore, dose-dependent depolymerization effects of olivetoric acid on F-actin stress fibers were observed. Decrease in the tube formation of RATECs by olivetoric acid might be explained by a disorganization of the actin cytoskeleton. These findings suggest that olivetoric acid is a new anti-angiogenic agent and can be developed as a new therapeutic agent for angiogenesis-related diseases.


Type 2 diabetes as a risk factor for cognitive impairment: current insights.
Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive dysfunction and dementia in the elderly. T2DM has been thought to be associated with vascular diseases, eventually leading to vascular dementia, but recent studies have established that T2DM is also associated with Alzheimer's disease (AD). With the increase in the number of elderly individuals with T2DM, the number of diabetic patients with cognitive dysfunction has been increasing. T2DM may accelerate AD-associated pathologies through insulin resistance. Vascular pathologies may also be associated with cognitive dysfunction and dementia in T2DM subjects. Several other mechanisms also seem to be involved in T2DM-related cognitive dysfunction. More investigations to clarify the association of T2DM with cognitive impairment are warranted. These investigations may help to increase our understanding of AD and open a new door to the development of therapeutics. Recent pharmaceutical advancement in T2DM treatment has resulted in the availability of a wide range of antidiabetics. Some evidence has suggested that antidiabetic therapies help to prevent cognitive dysfunction. At present, however, the optimal level of blood glucose control and the best combination of medications to achieve it in terms of cognitive preservation have not been established. More investigation is warranted. Cognitive dysfunction is an emerging new complication of T2DM that requires further study.


Materials for microfluidic chip fabrication.
Through manipulating fluids using microfabricated channel and chamber structures, microfluidics is a powerful tool to realize high sensitive, high speed, high throughput, and low cost analysis. In addition, the method can establish a well-controlled microenivroment for manipulating fluids and particles. It also has rapid growing implementations in both sophisticated chemical/biological analysis and low-cost point-of-care assays. Some unique phenomena emerge at the micrometer scale. For example, reactions are completed in a shorter amount of time as the travel distances of mass and heat are relatively small; the flows are usually laminar; and the capillary effect becomes dominant owing to large surface-to-volume ratios. In the meantime, the surface properties of the device material are greatly amplified, which can lead to either unique functions or problems that we would not encounter at the macroscale. Also, each material inherently corresponds with specific microfabrication strategies and certain native properties of the device. Therefore, the material for making the device plays a dominating role in microfluidic technologies. In this Account, we address the evolution of materials used for fabricating microfluidic chips, and discuss the application-oriented pros and cons of different materials. This Account generally follows the order of the materials introduced to microfluidics. Glass and silicon, the first generation microfluidic device materials, are perfect for capillary electrophoresis and solvent-involved applications but expensive for microfabriaction. Elastomers enable low-cost rapid prototyping and high density integration of valves on chip, allowing complicated and parallel fluid manipulation and in-channel cell culture. Plastics, as competitive alternatives to elastomers, are also rapid and inexpensive to microfabricate. Their broad variety provides flexible choices for different needs. For example, some thermosets support in-situ fabrication of arbitrary 3D structures, while some perfluoropolymers are extremely inert and antifouling. Chemists can use hydrogels as highly permeable structural material, which allows diffusion of molecules without bulk fluid flows. They are used to support 3D cell culture, to form diffusion gradient, and to serve as actuators. Researchers have recently introduced paper-based devices, which are extremely low-cost to prepare and easy to use, thereby promising in commercial point-of-care assays. In general, the evolution of chip materials reflects the two major trends of microfluidic technology: powerful microscale research platforms and low-cost portable analyses. For laboratory research, chemists choosing materials generally need to compromise the ease in prototyping and the performance of the device. However, in commercialization, the major concerns are the cost of production and the ease and reliability in use. There may be new growth in the combination of surface engineering, functional materials, and microfluidics, which is possibly accomplished by the utilization of composite materials or hybrids for advanced device functions. Also, significant expanding of commercial applications can be predicted.


Occupational resettlement in aphasia.
An account is given of the occupational resettlement and progress of four patients with severe dysphasia, due to cerebrovascular accidents. The dysphasia was predominantly expressive in two cases and predominantly receptive in the other two. Three of the patients were resettled in gainful employment and the fourth in a sheltered occupation. In all four cases, the patients attained a very adequate level of working efficiency, distinctly above what had been anticipated on clinical and psychometric grounds. While these results are encouraging, it is stressed that fuller and more extensive long-term follow-up studies of occupational resettlement in aphasia are necessary before firm conclusions can be drawn.


Unravelling Ipsilateral Interactions Between Left Dorsal Premotor and Primary Motor Cortex: A Proof of Concept Study.
Few studies have identified the intrahemispheric functional connectivity between the ipsilateral dorsal premotor cortex (PMd) and the primary motor hand area (M1hand) due to technical limitations. In this proof-of-concept study, a novel neuronavigated dsTMS set-up was employed, combining stimulation over left PMd and left M1hand using the edge of a butterfly coil and a small cooled-coil. This arrangement was warranted because coil (over)heating and inter coil distance are limiting factors when investigating connectivity between stimulation targets in close proximity and over a longer duration. The proposed set-up was designed to deal with these limitations. Specifically, the effect of four dual-site transcranial magnetic stimulation (dsTMS) protocols on twenty-eight right-handed participants (12 males) was evaluated. These protocols differed in stimulus order, interstimulus interval and current direction induced in PMd. A structural scan with electric (E-)field modeling was obtained from seven participants prior to dsTMS, demonstrating that PMd and M1hand were effectively stimulated. Results indicate that one protocol, in which a latero-medial current was induced in PMd 2.8 ms prior to stimulation over M1hand, induced a sex-mediated effect. In males, significant inhibition of motor-evoked potentials was identified, whereas females demonstrated a facilitatory effect that did not survive correction for multiple comparisons. E-field simulations revealed that the E-field induced by the coil targeting PMd was maximal in PMd, with weaker E-field strengths extending to regions beyond PMd. Summarizing, the current dsTMS set-up enabled stimulating at an inter-target distance of 35 mm without any indications of coil-overheating.


Bacterial clonal diagnostics as a tool for evidence-based empiric antibiotic selection.
Despite the known clonal distribution of antibiotic resistance in many bacteria, empiric (pre-culture) antibiotic selection still relies heavily on species-level cumulative antibiograms, resulting in overuse of broad-spectrum agents and excessive antibiotic/pathogen mismatch. Urinary tract infections (UTIs), which account for a large share of antibiotic use, are caused predominantly by Escherichia coli, a highly clonal pathogen. In an observational clinical cohort study of urgent care patients with suspected UTI, we assessed the potential for E. coli clonal-level antibiograms to improve empiric antibiotic selection. A novel PCR-based clonotyping assay was applied to fresh urine samples to rapidly detect E. coli and the urine strain's clonotype. Based on a database of clonotype-specific antibiograms, the acceptability of various antibiotics for empiric therapy was inferred using a 20%, 10%, and 30% allowed resistance threshold. The test's performance characteristics and possible effects on prescribing were assessed. The rapid test identified E. coli clonotypes directly in patients' urine within 25-35 minutes, with high specificity and sensitivity compared to culture. Antibiotic selection based on a clonotype-specific antibiogram could reduce the relative likelihood of antibiotic/pathogen mismatch by ≥ 60%. Compared to observed prescribing patterns, clonal diagnostics-guided antibiotic selection could safely double the use of trimethoprim/sulfamethoxazole and minimize fluoroquinolone use. In summary, a rapid clonotyping test showed promise for improving empiric antibiotic prescribing for E. coli UTI, including reversing preferential use of fluoroquinolones over trimethoprim/sulfamethoxazole. The clonal diagnostics approach merges epidemiologic surveillance, antimicrobial stewardship, and molecular diagnostics to bring evidence-based medicine directly to the point of care.


C-H...pi-interactions in proteins.
A non-redundant set of 1154 protein structures from the Protein Data Bank was examined with respect to close interactions between C-H-donor and pi-acceptor groups. A total of 31,087 interactions were found to satisfy our selection criteria. Their geometric parameters suggest that these interactions can be classified as weak hydrogen bonds.A set of 12 interaction classes were defined based on the division of the donors into three groups and the acceptors into four groups. These classes were examined separately, and the respective interactions described in detail in each class. Most prominent were interactions between aliphatic C-H donors and aromatic pi-acceptors and interactions between aromatic C-H donors and aromatic pi-acceptors. About three-quarters of the Trp-rings, half of all Phe and Tyr-rings and a quarter of all His-rings were found to be involved as acceptors in C-H...pi-interactions. On the donor side, a preference for aromatic C-H groups was observed, but also for the aliphatic side-chains of the long, extended amino acid residues Lys, Arg and Met, and the Pro ring. The average distance between the C-donor and the center-of-mass of the pi-acceptor was observed to be significantly longer in the 174 protein structures determined at >2.5 A resolution. Also, the distribution is significantly wider. This resolution dependence suggests that the force fields commonly used for the refinement of protein structures may not be adequate. C-H...pi-interactions involving aromatic groups either as donor or as acceptor groups are found mostly in the interior of the protein. The more hydrophilic the participating groups are, the closer to the surface are the interactions located. About 40 % of all C-H...pi-interactions occur between amino acid residue side-chains that are separated by nine or less residues in sequence. Dependent on the interaction class, different preferences for secondary structure, residue type and side-chain conformation were observed. It is likely that the C-H...pi-interactions contribute significantly to the overall stability of a protein.


Formation of DNA adducts in HL-60 cells treated with the toluene metabolite p-cresol: a potential biomarker for toluene exposure.
We have examined DNA adduct formation in myeloperoxidase containing HL-60 cells treated with the toluene metabolite p-cresol. Treatment of HL-60 cells with the combination of p-cresol and H(2)O(2) produced four DNA adducts 1: (75.0%), 2: (9.1%), 3: (7.0%) and 4: (8.8%) and adduct levels ranging from 0.3 to 33.6 x 10(-7). The levels of DNA adducts formed by p-cresol were dependent on concentrations of p-cresol, H(2)O(2) and treatment time. In vitro incubation of p-cresol with myeloperoxidase and H(2)O(2) produced three DNA adducts 1: (40.5%), 2: (28.4%) and 3: (29.7%) with a relative adduct level of 0.7x10(-7). The quinone methide derivative of p-cresol (PCQM) was prepared by Ag(I)O oxidation. Reaction of calf thymus DNA with PCQM produced four adducts 1: (18.5%), 2: (36.4%), 3: (29.0%) and 5: (16.0%) with a relative adduct level 1.6x10(-7). Rechromatography analyses indicates that DNA adducts 1-3 formed in HL-60 cells treated with p-cresol and after myeloperoxidase activation of p-cresol were similar to those formed by reaction of DNA with PCQM. This observation suggests that p-cresol is activated to a quinone methide intermediate in each of these activation systems. Taken together, these results suggest PCQM is the reactive intermediate leading to the formation of DNA adducts in HL-60 cells treated with p-cresol. Furthermore, the DNA adducts formed by PCQM may provide a biomarker to assess occupational exposure to toluene.


Enzymatically cross-linked alginic-hyaluronic acid composite hydrogels as cell delivery vehicles.
An injectable composite gel was developed from alginic and hyaluronic acid. The enzymatically cross-linked injectable gels were prepared via the oxidative coupling of tyramine modified sodium algiante and sodium hyaluronate in the presence of horse radish peroxidase (HRP) and hydrogen peroxide (H2O2). The composite gels were prepared by mixing equal parts of the two tyraminated polymer solutions in 10U HRP and treating with 1.0% H2O2. The properties of the alginate gels were significantly affected by the addition of hyaluronic acid. The percentage water absorption and storage modulus of the composite gels were found to be lower than the alginate gels. The alginate and composite gels showed lower protein release compared to hyaluronate gels in the absence of hyaluronidase. Even hyaluronate gels showed only approximately 10% protein release after 14 days incubation in phosphate buffer solution. ATDC-5 cells encapsulated in the injectable gels showed high cell viability. The composite gels showed the presence of enlarged spherical cells with significantly higher metabolic activity compared to cells in hyaluronic and alginic acid gels. The results suggest the potential of the composite approach to develop covalently cross-linked hydrogels with tuneable physical, mechanical, and biological properties.


miRNA expression profiling in a human stem cell-based model as a tool for developmental neurotoxicity testing.
The main aim of this study was to evaluate whether microRNA (miRNA) profiling could be a useful tool for in vitro developmental neurotoxicity (DNT) testing. Therefore, to identify the possible DNT biomarkers among miRNAs, we have studied the changes in miRNA expressions in a mixed neuronal/glial culture derived from carcinoma pluripotent stem cells (NT2 cell line) after exposure to methyl mercury chloride (MeHgCl) during the process of neuronal differentiation (2-36 days in vitro (DIV1)). The neuronal differentiation triggered by exposure to retinoic acid (RA) was characterized in the control culture by mRNA expression analysis of neuronal specific markers such as MAP2, NF-200, Tubulin βIII, MAPT-tau, synaptophysin as well as excitatory (NMDA, AMPA) and inhibitory (GABA) receptors. The results obtained from the miRNA expression analysis have identified the presence of a miRNA signature which is specific for neural differentiation in the control culture and another for the response to MeHgCl-induced toxicity. In differentiated neuronal control cultures, we observed the downregulation of the stemness phenotype-linked miR-302 cluster and the overexpression of several miRNAs specific for neuronal differentiation (e.g. let-7, miR-125b and miR-132). In the cultures exposed to MeHgCl (400 nM), we observed an overexpression of a signature composed of five miRNAs (miR-302b, miR-367, miR-372, miR-196b and miR-141) that are known to be involved in the regulation of developmental processes and cellular stress response mechanisms. Using gene ontology term and pathway enrichment analysis of the validated targets of the miRNAs deregulated by the toxic treatment, the possible effect of MeHgCl exposure on signalling pathways involved in axon guidance and learning and memory processes was revealed. The obtained data suggest that miRNA profiling could provide simplified functional evaluation of the toxicity pathways involved in developmental neurotoxicity in comparison with the transcriptomics studies.


Molecular dynamics simulations of layer-by-layer assembly of polyelectrolytes at charged surfaces: effects of chain degree of polymerization and fraction of charged monomers.
We performed molecular dynamics simulations of the electrostatic assembly of multilayers of flexible polyelectrolytes at a charged surface. The multilayer build-up was achieved through sequential adsorption of oppositely charged polymers in a layer-by-layer fashion from dilute polyelectrolyte solutions. The steady-state multilayer growth proceeds through a charge reversal of the adsorbed polymeric film which leads to a linear increase in the polymer surface coverage after completion of the first few deposition steps. Moreover, substantial intermixing between chains adsorbed during different deposition steps is observed. This intermixing is consistent with the observed requirement for several deposition steps to transpire for completion of a single layer. However, despite chain intermixing, there are almost perfect periodic oscillations of the density difference between monomers belonging to positively and negatively charged macromolecules in the adsorbed film. Weakly charged chains show higher polymer surface coverage than strongly charged ones.


Antiangiogenic activity of sophorolipids extracted from refined bleached deodorized palm olein.
Sophorolipids (SLs) are a group of surface-active glycolipids produced by a type of nonpathogenic yeast Candida bombicola in the presence of vegetable oil through fermentation technology. SLs have shown antitumor activity; however, the mechanism of action underlying the anticancer activity of SLs is poorly understood. This work evaluated the anticancer activity of SLs fermented from palm oil by exploring its antiangiogenic activity. The SLs that were fermented and further characterized for their biochemical activities. Cytotoxicity study was performed to assess cytostatic properties. A series of in vitro and ex vivo angiogenesis assay was also carried out. The relative fold change in the expression of p53 mRNA by SLs was also studied. Altogether, the data show that SLs derived from palm oil fermentation process inhibited neovascularization in the ex vivo tissue segments and also the endothelial cell proliferation between 50% and 65% inhibition as a whole. The palm oil derived SLs also caused downregulation of the suppression level of vascular endothelial growth factor and also upregulate the p53 mRNA level. The analytical studies revealed the presence of high amount of phenolic compounds but with relatively weak antioxidant activity. The gas chromatography-mass spectrometry studies revealed abundant amount of palmitic and oleic acid, the latter an established antiangiogenic agent, and the former being proangiogenic. Therefore, it can be concluded from this study that SLs derived from fermented palm oil have potent antiangiogenic activity which may be attributed by its oleic acid component.


Immune cellular components and signaling pathways in the tumor microenvironment.
During the past decade there has been a revolution in cancer therapeutics by the emergence of antibody-based and cell-based immunotherapies that modulate immune responses against tumors. These new therapies have extended and improved the therapeutic efficacy of chemo-radiotherapy and have offered treatment options to patients who are no longer responding to these classic anti-cancer treatments. Unfortunately, tumor eradication and long-lasting responses are observed in a small fraction of patients, whereas the majority of patients respond only transiently. These outcomes indicate that the maximum potential of immunotherapy has not been reached due to incomplete knowledge of the cellular and molecular mechanisms that guide the development of successful anti-tumor immunity and its failure. In this review, we discuss recent discoveries about the immune cellular composition of the tumor microenvironment (TME) and the role of key signaling mechanisms that compromise the function of immune cells leading to cancer immune escape.


Position-Specific Isotope Analysis of Xanthines: A (13)C Nuclear Magnetic Resonance Method to Determine the (13)C Intramolecular Composition at Natural Abundance.
The natural xanthines caffeine, theobromine, and theophylline are of major commercial importance as flavor constituents in coffee, cocoa, tea, and a number of other beverages. However, their exploitation for authenticity, a requirement in these commodities that have a large origin-based price-range, by the standard method of isotope ratio monitoring by mass spectrometry (irm-MS) is limited. We have now developed a methodology that overcomes this deficit that exploits the power of isotopic quantitative (13)C nuclear magnetic resonance (NMR) spectrometry combined with chemical modification of the xanthines to enable the determination of positional intramolecular (13)C/(12)C ratios (δ(13)Ci) with high precision. However, only caffeine is amenable to analysis: theobromine and theophylline present substantial difficulties due to their poor solubility. However, their N-methylation to caffeine makes spectral acquisition feasible. The method is confirmed as robust, with good repeatability of the δ(13)Ci values in caffeine appropriate for isotope fractionation measurements at natural abundance. It is shown that there is negligible isotope fractionation during the chemical N-methylation procedure. Thus, the method preserves the original positional δ(13)Ci values. The method has been applied to measure the position-specific variation of the (13)C/(12)C distribution in caffeine. Not only is a clear difference between caffeine isolated from different sources observed, but theobromine from cocoa is found to show a (13)C pattern distinct from that of caffeine.


Complex II from a structural perspective.
The super-macromolecular complex, succinate:quinone oxidoreductase (SQR, Complex II, succinate dehydrogenase) couples the oxidation of succinate in the matrix / cytoplasm to the reduction of quinone in the membrane. This function directly connects the Krebs cycle and the aerobic respiratory chain. Until the recent first report of the structure of SQR from Escherichia coli (E. coli) the structure-function relationships in SQR have been inferred from the structures of the homologous QFR, which catalyses the same reaction in the opposite direction. The structure of SQR from E. coli, analogous to the mitochondrial respiratory Complex II, has provided new insight into SQR's molecular design and mechanism, revealing the electron transport pathway through the enzyme. Comparison of the structures of SQR, QFR and other related flavoproteins shows how common amino acid residues at the interface of two domains facilitate the inter-conversion of succinate and fumarate. Additionally, the structure has provided a possible explanation as to why certain organisms utilise both SQR and QFR despite the fact that both can catalyse the inter-conversion of succinate and fumarate, in vitro and in vivo. Here we review how this structure has advanced our knowledge of this important enzyme and compare the structural information to other members of the Complex II superfamily and related flavoproteins.


Synergy-Driven Musculoskeletal Modeling to Estimate Muscle Excitations and Joint Moments at Different Walking Speeds in Individuals with Transtibial Amputation.
The main requirement for an amputee is to regain the function of the lost limb. In order to fully benefit from powered prosthetic legs, the user must rely on the dynamic control of the device. Progress in high-level control for powered prosthetic legs is currently challenged by the inability of current control schemes to generalize to large repertoires of movements as well as adapting to external mechanical demands. This ultimately leads the user to adopt compensatory movements, lack of comfort, higher energy requirements during walking and standing. This study uses a feedforward model of muscle activation and force generation that applies mathematical formulations of muscle synergies to generate synthetic activation profiles underlying walking across different speeds. Estimated activation profiles are used to drive forward subject-specific numerical models of the lower extremity musculoskeletal system. The model was validated on one individual with uni-lateral transtibial amputation and its predictions were compared to experimental torques from inverse dynamic calculations. Results showed that a generic muscle synergy driven personalized musculoskeletal model can fit the ankle torques of the intact limb of a person with transtibial amputation (RMSD = 0.1329±0.02). The estimated moments might be suitable as the control signal to drive powered prostheses to ultimately improve physical interaction between the user and a powered prostheses during dynamic motor tasks.


Role of the renin angiotensin system in diabetic nephropathy.
Diabetic nephropathy has been the cause of lot of morbidity and mortality in the diabetic population. The renin angiotensin system (RAS) is considered to be involved in most of the pathological processes that result in diabetic nephropathy. This system has various subsystems which contribute to the disease pathology. One of these involves angiotensin II (Ang II) which shows increased activity during diabetic nephropathy. This causes hypertrophy of various renal cells and has a pressor effect on arteriolar smooth muscle resulting in increased vascular pressure. Ang II also induces inflammation, apoptosis, cell growth, migration and differentiation. Monocyte chemoattractant protein-1 production responsible for renal fibrosis is also regulated by RAS. Polymorphism of angiotensin converting enzyme (ACE) and Angiotensinogen has been shown to have effects on RAS. Available treatment modalities have proven effective in controlling the progression of nephropathy. Various drugs (based on antagonism of RAS) are currently in the market and others are still under trial. Amongst the approved drugs, ACE inhibitors and angiotensin receptor blockers (ARBs) are widely used in clinical practice. ARBs are shown to be superior to ACE inhibitors in terms of reducing proteinuria but the combined role of ARBs with ACE inhibitors in diabetic nephropathy is under debate.


Effects of Environmental Factors on Severity and Mortality of COVID-19.
Background: Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. Methods: We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. Findings: Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973-0.988, p < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773-0.944, p = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Interpretation: Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.


Lithuania: health system review.
This analysis of the Lithuanian health system reviews the developments in organization and governance, health financing, health-care provision, health reforms and health system performance since 2000.The Lithuanian health system is a mixed system, predominantly funded from the National Health Insurance Fund through a compulsory health insurance scheme, supplemented by substantial state contributions on behalf of the economically inactive population amounting to about half of its budget. Public financing of the health sector has gradually increased since 2004 to 5.2 per cent of GDP in 2010.Although the Lithuanian health system was tested by the recent economic crisis, Lithuanias counter-cyclical state health insurance contribution policies (ensuring coverage for the economically inactive population) helped the health system to weather the crisis, and Lithuania successfully used the crisis as a lever to reduce the prices of medicines.Yet the future impact of cuts in public health spending is a cause for concern. In addition, out-of-pocket payments remain high (in particular for pharmaceuticals) and could threaten health access for vulnerable groups.A number of challenges remain. The primary care system needs strengthening so that more patients are treated instead of being referred to a specialist, which will also require a change in attitude by patients. Transparency and accountability need to be increased in resource allocation, including financing of capital investment and in the payer provider relationship. Finally, population health,albeit improving, remains a concern, and major progress can be achieved by reducing the burden of amenable and preventable mortality.


Novel Taxa Associated with Human Fungal Black-Grain Mycetomas: Emarellia grisea gen. nov., sp. nov., and Emarellia paragrisea sp. nov.
Eumycetoma is a debilitating, chronic, fungal infection that is endemic in India, Indonesia, and parts of Africa and South and Central America. It remains a neglected tropical disease in need of international recognition. Infections follow traumatic implantation of saprophytic fungi and frequently require radical surgery or amputation in the absence of appropriate treatment. Several fungal species can cause black-grain mycetomas, including Madurella spp. (Sordariales), Falciformispora spp., Trematosphaeria grisea, Biatriospora mackinnonii, Pseudochaetosphaeronema larense, and Medicopsis romeroi (all Pleosporales). We performed phylogenetic analyses based on five loci on 31 isolates from two international culture collections to establish the taxonomic affiliations of fungi that had been isolated from cases of black-grain mycetoma and historically classified as Madurella grisea Although most strains were well resolved to species level and corresponded to known agents of eumycetoma, six independent isolates, which failed to produce conidia under any conditions tested, were only distantly related to existing members of the Pleosporales Five of the six isolates shared >99% identity with each other and are described as Emarellia grisea gen. nov. and sp. nov; the sixth isolate represents a sister species in this novel genus and is described as Emarellia paragrisea. Several E. grisea isolates were present in both United Kingdom and French culture collections and had been isolated independently over 6 decades from cases of imported eumycetoma. Four of the six isolates involved patients that had originated on the Indian subcontinent. All isolates were all susceptible in vitro to the azole antifungals, but had elevated MICs with caspofungin.


The effect of highly variable topography on the spatial distribution of Aniba perutilis (Lauraceae) in the Colombian Andes.
Topography is a factor that can significantly affect the diversity and the distribution of trees species in tropical forests. Aniba perutilis, a timber species listed as vulnerable to extinction, is widely distributed in Andean forest fragments, especially in those with highly variable topography. Based on field surveys and logistic regression analyses, we studied the population structure and the effect of highly variable topography on the spatial distribution of this tree in three protected forest fragments in the central Andes of Colombia. Individuals of A. perutilis were mainly found on mountain ridges and hills with gentle slopes; no individuals were found in valleys. Using a species distribution model with presence/absence data, we showed that the available habitat for A. perutilis is significantly smaller than the extension of the fragments and much smaller than the extension of the currently protected areas. Our results have important implications for the conservation ofA. perutilis and likely for other threatened Andean tree species, which can also have locally restricted distributions due to highly variable local topography.


The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. Tyrosine kinase inhibitors (TKIs) are commonly used to treat CML; however, drug resistance of CML cells to TKIs has limited their clinical application. Shikonin, a traditional Chinese herb, has long been used to treat leukemia in China, but the roles and related molecular mechanisms of shikonin treatment in CML remain unclear. Here, we aimed to evaluate the effects of shikonin on the proliferation, apoptosis, and migration of K562 cells, a CML cell line. Firstly, K562 cell proliferation and apoptosis were tested by CCK8 assay and flow cytometry with Annexin V-FITC/PI staining. Cell migration was measured by Transwell migration assay. In addition, western blot was performed to determine the proteins (PI3K, Bax, Bcl-2, cleaved caspase-3, PTEN, p-AKT, AKT, CXCR4, SDF-1, CD44) involved in the mechanism of action of shikonin. Finally, neutrophils from peripheral blood of CML patients were obtained, and cell proliferation and apoptosis were tested by CCK8 assay and flow cytometry. Shikonin reduced the proliferation of K562 cells in a time- and dose-dependent manner and promoted the apoptosis of K562 cells. Moreover, shikonin increased the PTEN level and inactivated the PI3K/AKT signaling pathway, subsequently upregulating BAX in K562 cells. In addition, shikonin could block K562 cell migration via the CXCR4/SDF-1 axis. Finally, shikonin significantly inhibited the proliferation and promoted the apoptosis of neutrophils from CML patients. These results demonstrated that shikonin inhibits CML proliferation and migration and induces apoptosis by the PTEN/PI3K/AKT pathway, revealing the effects of shikonin therapy on CML.


Methane oxidation in slurry storage surface crusts.
Livestock manure is a significant source of atmospheric methane (CH4), especially during liquid storage. In liquid manure (slurry) storages a surface crust may form naturally, or an artificial surface crust can be established. We investigated whether there is a potential for CH4 oxidation in this environment. Surface crust materials were sampled from experimental storages with cattle slurry (with natural crust) or anaerobically digested cattle slurry (with straw layer) that had been stored with or without a wooden cover. Extracts of surface crust material were incubated with 5.6% CH4 in the headspace, and methanotrophic activity was demonstrated in all four treatments following a 4- to 10-d lag phase. Subsequent incubation of field-moist surface crust material with 350 microL L(-1) CH4 also showed CH4 oxidation, indicating a potential for CH4 removal under practical storage conditions. There was no CH4 oxidation activity during incubation of autoclaved samples. Methane oxidation rates were 0.1 to 0.5 mg kg(-1) organic matter (OM) h(-1), which is comparable with the activity in wetlands and rice paddies. Partial drying increased CH4 oxidation to 0.2 to 1.4 mg kg(-1) OM h(-1), probably as a result of improved diffusivity within the surface crust. Rewetting reversed the stimulation of methanotrophic activity in some treatments, but not in others, possibly due to a decline in CH4 production in anaerobic volumes, or to growth of methanotrophs during incubation. This study presents direct evidence for methanotrophic activity in slurry storages. Measures to ensure crust formation with or without a solid cover appear to be a cost-effective greenhouse gas mitigation option.


Prevalence and distribution pattern of malaria and soil-transmitted helminth co-endemicity in sub-Saharan Africa, 2000-2018: A geospatial analysis.
Limited understanding exists about the interactions between malaria and soil-transmitted helminths (STH), their potential geographical overlap and the factors driving it. This study characterised the geographical and co-clustered distribution patterns of malaria and STH infections among vulnerable populations in sub-Saharan Africa (SSA). We obtained continuous estimates of malaria prevalence from the Malaria Atlas Project (MAP) and STH prevalence surveys from the WHO-driven Expanded Special Project for the Elimination of NTDs (ESPEN) from Jan 1, 2000, to Dec 31, 2018. Although, MAP provides datasets on the estimated prevalence of Plasmodium falciparum at 5km x 5km fine-scale resolution, we calculated the population-weighted prevalence of malaria for each implementation unit to ensure that both malaria and STH datasets were on the same spatial resolution. We incorporated survey data from 5,935 implementation units for STH prevalence and conducted the prevalence point estimates before and after 2003. We used the bivariate local indicator of spatial association (LISA analysis) to explore potential co-clustering of both diseases at the implementation unit levels among children aged 2-10 years for P. falciparum and 5-14 years for STH, living in SSA. Our analysis shows that prior to 2003, a greater number of SSA countries had a high prevalence of co-endemicity with P.falciparium and any STH species than during the period from 2003-2018. Similar prevalence and distribution patterns were observed for the co-endemicity involving P.falciparum-hookworm, P.falciparum-Ascaris lumbricoides and P.falciparum-Trichuris trichiura, before and after 2003. We also observed spatial variations in the estimates of the prevalence of P. falciparum-STH co-endemicity and identified hotspots across many countries in SSA with inter-and intra-country variations. High P. falciparum and high hookworm co-endemicity was more prevalent in West and Central Africa, whereas high P. falciparum with high A. lumbricoides and high P. falciparum with high T. trichiura co-endemicity were more predominant in Central Africa, compared to other sub-regions in SSA. Wide spatial heterogeneity exists in the prevalence of malaria and STH co-endemicity within the regions and within countries in SSA. The geographical overlap and spatial co-existence of malaria and STH could be exploited to achieve effective control and elimination agendas through the integration of the vertical control programmes designed for malaria and STH into a more comprehensive and sustainable community-based paradigm.


Modeling studies on phospholipase A2-inhibitor complexes.
Phospholipase A2 (PLA2) is a ubiquitous enzyme that specifically catalyzes hydrolysis of membrane phospholipids to produce lysophospholipids and free fatty acid, namely arachidonic acid, which provides substrate for eicosanoids biosynthesis. Thus, the compounds inhibiting PLA2 have been implicated as potential therapeutic agents in treatment of inflammation related diseases. Plant and marine organisms serve as sources of compounds that act as potential therapeutic agents for treatment of various diseases. The present study reveals the relationship between the structure and function of the medicinally important herbal compounds (acalyphin, chlorogenic acid, stigmasterol, curcumin and tectoridin) and marine compounds (gracilin A and aplysulphurin A). To understand the binding mechanisms of these compounds, molecular modeling studies has been performed with Russell's viper and bovine pancreatic PLA2 as target molecules using molecular operating environment (MOE) software. These compounds show favorable interactions with the amino acid residues at the active site of Russell's viper and bovine pancreatic PLA2, thereby substantiating their proven efficacy as anti-inflammatory compounds and antidotes.


A method to qualitatively assess arm use in stroke survivors in the home environment.
Wearable sensor technology has enabled unobtrusive monitoring of arm movements of stroke survivors in the home environment. However, the most widely established method, based on activity counts, provides quantitative rather than qualitative information on arm without functional insights, and is sensitive to passive arm movements during ambulatory activities. We propose a method to quantify functionally relevant arm use in stroke survivors relying on a single wrist-worn inertial measurement unit. Orientation of the forearm during movements is measured in order identify gross arm movements. The method is validated in 10 subacute/chronic stroke survivors wearing inertial sensors at 5 anatomical locations for 48 h. Measurements are compared to conventional activity counts and to a test for gross manual dexterity. Duration of gross arm movements of the paretic arm correlated significantly better with the Box and Block Test ([Formula: see text]) than conventional activity counts when walking phases were included ([Formula: see text]), and similar results were found when comparing ratios of paretic and non-paretic arms for gross movements and activity counts. The proposed gross arm movement metric is robust against passive arm movements during ambulatory activities and requires only a single-sensor module placed at the paretic wrist for the assessment of functionally relevant arm use.


Controlling arbitrary humidity without convection.
In this paper we show a way that allows for the first time to induce arbitrary humidity of desired value for systems without convective flow. To enable this novelty we utilize a semi-closed environment in which evaporation is not completely suppressed. In this case, the evaporation rate is determined both by the outer (open) humidity and by the inner (semi-closed) geometry including the size/shape of the evaporating medium and the size/shape of the semi-closure. We show how such systems can be used to induce desired humidity conditions. We consider water droplet placed on a solid surface and study its evaporation when it is surrounded by other drops, hereon "satellite" drops and covered by a semi-closed hemisphere. The main drop's evaporation rate is proportional to its height, in agreement with theory. Surprisingly, however, the influence of the satellite drops on the main drop's evaporation suppression is not proportional to the sum of heights of the satellite drops. Instead, it shows proportionality close to the satellite drops' total surface area. The resultant humidity conditions in the semi-closed system can be effectively and accurately induced using different satellite drops combinations.


Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalization - Five Veterans Affairs Medical Centers, United States, February 1-August 6, 2021.
COVID-19 mRNA vaccines (Pfizer-BioNTech and Moderna) have been shown to be highly protective against COVID-19-associated hospitalizations (1-3). Data are limited on the level of protection against hospitalization among disproportionately affected populations in the United States, particularly during periods in which the B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19, predominates (2). U.S. veterans are older, more racially diverse, and have higher prevalences of underlying medical conditions than persons in the general U.S. population (2,4). CDC assessed the effectiveness of mRNA vaccines against COVID-19-associated hospitalization among 1,175 U.S. veterans aged ≥18 years hospitalized at five Veterans Affairs Medical Centers (VAMCs) during February 1-August 6, 2021. Among these hospitalized persons, 1,093 (93.0%) were men, the median age was 68 years, 574 (48.9%) were non-Hispanic Black (Black), 475 were non-Hispanic White (White), and 522 (44.4%) had a Charlson comorbidity index score of ≥3 (5). Overall adjusted vaccine effectiveness against COVID-19-associated hospitalization was 86.8% (95% confidence interval [CI] = 80.4%-91.1%) and was similar before (February 1-June 30) and during (July 1-August 6) SARS-CoV-2 Delta variant predominance (84.1% versus 89.3%, respectively). Vaccine effectiveness was 79.8% (95% CI = 67.7%-87.4%) among adults aged ≥65 years and 95.1% (95% CI = 89.1%-97.8%) among those aged 18-64 years. COVID-19 mRNA vaccines are highly effective in preventing COVID-19-associated hospitalization in this older, racially diverse population of predominately male U.S. veterans. Additional evaluations of vaccine effectiveness among various age groups are warranted. To prevent COVID-19-related hospitalizations, all eligible persons should receive COVID-19 vaccination.


Axisymmetric fundamental solutions for a finite layer with impeded boundaries.
Axisymmetric fundamental solutions that are applied in the consolidation calculations of a finite clay layer with impeded boundaries were derived. Laplace and Hankel integral transforms were utilized with respect to time and radial coordinates, respectively in the analysis. The derivation of fundamental solutions considers two-boundary value problems involving unit point loading and ring loading in the vertical. The solutions are extended to circular distributed and strip distributed normal load. The computation and analysis of settlements, vertical total stress and excess pore pressure in the consolidation layer subject to circular loading are presented.


The TRF1-binding protein TERB1 promotes chromosome movement and telomere rigidity in meiosis.
During meiotic prophase, telomere-mediated chromosomal movement along the nuclear envelope is crucial for homologue pairing and synapsis. However, how telomeres are modified to mediate chromosome movement is largely elusive. Here we show that mammalian meiotic telomeres are fundamentally modified by a meiosis-specific Myb-domain protein, TERB1, that localizes at telomeres in mouse germ cells. TERB1 forms a heterocomplex with the canonical telomeric protein TRF1 and binds telomere repeat DNA. Disruption of Terb1 in mice abolishes meiotic chromosomal movement and impairs homologous pairing and synapsis, causing infertility in both sexes. TERB1 promotes telomere association with the nuclear envelope and deposition of the SUN-KASH complex, which recruits cytoplasmic motor complexes. TERB1 also binds and recruits cohesin to telomeres to develop structural rigidity, strikingly reminiscent of centromeres. Our study suggests that TERB1 acts as a central hub for the assembly of a conserved meiotic telomere complex required for chromosome movements.


Psychobiological dysregulation in violence-exposed mothers: salivary cortisol of mothers with very young children pre- and post-separation stress.
To understand the determinants of frightening/frightened and other atypical maternal behavior, the authors studied a sample of 41 inner-city mothers of very young children (ages 8-50 months), the mothers of whom had lifetime histories of interpersonal violent trauma (i.e., physical or sexual abuse, and domestic violence) and related posttraumatic stress. The authors measured (1) maternal salivary cortisol levels before and 30 minutes after a videotaped play paradigm with their children, involving two separations and reunions; and (2) cortisol reactivity 30 minutes after separation stress. Data were analyzed using Pearson bivariate correlations, ANOVA, and multiple linear regressions. Salivary cortisol "baseline" values were significantly negatively correlated with childhood interpersonal violent trauma severity (i.e., trauma severity prior to age 16). However, cortisol reactivity was not significantly correlated with interpersonal violent trauma severity at this level of analysis. Although baseline salivary cortisol values were not significantly correlated with current overall psychiatric or depressive symptoms, they were negatively correlated with severity of current posttraumatic stress symptoms (PTSS) and with dissociative symptoms. Neither dimensions of negativity nor distortion of maternal attributions showed any significant association with prestress or poststress salivary cortisol levels. Salivary cortisol baseline was negatively correlated with atypical maternal behavior via measurement of the level of disrupted communication, at a trend-level of significance. Violent trauma-associated dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may be a marker for increased risk for intergenerational transmission via parenting behavior with young children. Low salivary cortisol prior to separation stress and blunted cortisol reactivity to separation may also be markers for posttraumatic stress.