Marijuana Use Predicts Cognitive Performance on Tasks of Executive Function.
Despite growing evidence that chronic marijuana use is associated with cognitive impairment, particularly when use is initiated at an early age, national trends demonstrate significant decreases in the perceived risk of marijuana corresponding with increased use, especially among youth. The current study assessed the impact of marijuana use on executive function and whether patterns of marijuana use, including earlier age at onset, higher frequency, and increased magnitude of use, predict impairment. Forty-four chronic, heavy marijuana smokers (37 male, 7 female) and 32 healthy, nonsmoking control participants (20 male, 12 female) recruited from the Greater Boston area completed two assessments of executive function: the Stroop Color Word Test and Wisconsin Card Sorting Test (WCST). Marijuana smokers had poorer executive function relative to control participants, a between-group difference that was primarily driven by individuals with early onset of marijuana use (before age 16; n = 21); significance remained even when controlling for frequency and magnitude of use. Further, earlier age at marijuana onset and increased marijuana use predicted poorer neurocognitive performance, and perseverative errors on the WCST significantly predicted marijuana group membership. These findings underscore the impact of early onset of marijuana use on executive function impairment independent of increased frequency and magnitude of use. In addition, poorer performance on the WCST may serve as a neuropsychological marker for heavy marijuana users. These results highlight the need for additional research to identify predictors associated with early marijuana use, as exposure to marijuana during a period of developmental vulnerability may result in negative cognitive consequences.


Cognitive Insight in First-Episode Psychosis: Changes during Metacognitive Training.
Metacognitive training (MCT) has demonstrated its efficacy in psychosis. However, the effect of each MCT session has not been studied. The aim of the study was to assess changes in cognitive insight after MCT: (a) between baseline, post-treatment, and follow-up; (b) after each session of the MCT controlled for intellectual quotient (IQ) and educational level. A total of 65 patients with first-episode psychosis were included in the MCT group from nine centers of Spain. Patients were assessed at baseline, post-treatment, and 6 months follow-up, as well as after each session of MCT with the Beck Cognitive Insight Scale (BCIS). The BCIS contains two subscales: self-reflectiveness and self-certainty, and the Composite Index. Statistical analysis was performed using linear mixed models with repeated measures at different time points. Self-certainty decreased significantly (p = 0.03) over time and the effect of IQ was negative and significant (p = 0.02). From session 4 to session 8, all sessions improved cognitive insight by significantly reducing self-certainty and the Composite Index. MCT intervention appears to have beneficial effects on cognitive insight by reducing self-certainty, especially after four sessions. Moreover, a minimum IQ is required to ensure benefits from MCT group intervention.


Characterization of Crystal Chirality in Amino Acids Using Low-Frequency Raman Spectroscopy.
We present a new method for differentiating racemic crystals from enantiopure crystals. Recently, developments in optical filters have enabled the facile use of Raman spectroscopy to detect low-frequency vibrational (LFV) modes. Here, for the first time, we use Raman spectroscopy to characterize the LFV modes for crystalline organic materials composed of chiral molecules. The LF-Raman spectra of racemic and enantiopure crystals exhibit a significant variation, which we attribute to different hydrogen-bond networks in the chiral crystal structures. Across a representative set of amino acids, we observed that when comparing racemic versus enantiopure crystals, the available LFV modes and their relative scattering intensity are strong functions of side chain polarity. Thus, LF-Raman can be used as a method that is complementary to the currently used methods for characterizing crystal chirality due to simpler, faster, and more sensitive measurements, along with the small sample size required, which is limited by the laser-beam diameter in the focus.


Expanded clinical presentation of community-acquired methicillin-resistant Staphylococcus aureus pneumonia.
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has been documented to cause community-acquired pneumonias (CAP), notable for necrotizing features. The frequency of occurrence, risk factors, and optimal treatment of CA-MRSA CAP are unclear. This was a retrospective analysis of patients admitted to Northwestern Memorial Hospital from January 2005 to April 2007 with initial clinical presentation of pneumonia and respiratory or blood culture positive for CA-MRSA. Definition of CA-MRSA was based on sensitivity to trimethoprim/sulfamethoxazole and clindamycin. Fifteen patients with CA-MRSA CAP were identified during the 28-month period. Only one of the 14 patients tested had evidence of preceding influenza, and no seasonal pattern was seen. Seven patients were never admitted to the ICU. Eight of 14 with chest CT scans had evidence of lung necrosis. Nine of 15 had evidence of pleural effusions early in their hospital course, and five of nine required at least one pleural drainage procedure. Seven of 15 were immunocompromised (three HIV, one acute lymphocytic leukemia [ALL], one high-dose steroids, and two immunoglobulin deficiency) with an additional three patients with diabetes. Mortality was only 13% (two of 15); both deaths occurred in patients with severe immunocompromise (ALL post chemotherapy and AIDS). Fourteen of 15 patients were treated with antimicrobials that inhibit exotoxin production (clindamycin or linezolid). CA-MRSA pneumonia is not necessarily a post-influenza infection. Despite necrotizing features in many, the mortality of CA-MRSA pneumonia in our series is lower than previously reported, and patients do not routinely require ICU care. Treatment with antibiotics that inhibit exotoxin production and/or nontoxigenic strains may explain this improved outcome.


Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein.
Pyrotinib is a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor that is used to treat HER2-positive breast cancer. In this study we investigated the metabolism and disposition of pyrotinib in six healthy Chinese men after a single oral dose of 402 mg of [14C]pyrotinib. At 240 h postdose, the mean cumulative excretion of the dose radioactivity was 92.6%, including 1.7% in urine and 90.9% in feces. In feces, oxidative metabolites were detected as major drug-related materials and the primary metabolic pathways were O-depicoline (M1), oxidation of pyrrolidine (M5), and oxidation of pyridine (M6-1, M6-2, M6-3, and M6-4). In plasma, the major circulating entities identified were pyrotinib, SHR150980 (M1), SHR151468 (M2), and SHR151136 (M5), accounting for 10.9%, 1.9%, 1.0%, and 3.0%, respectively, of the total plasma radioactivity based on the AUC0-∞ ratios. Approximately 58.3% of the total plasma radioactivity AUC0-∞ was attributed to covalently bound materials. After incubation of human plasma with [14C]pyrotinib at 37 °C for 2, 5, 8, and 24 h, the recovery of radioactivity by extraction was 97.4%, 91.8%, 69.6%, and 46.7%, respectively, revealing covalent binding occurred independently of enzymes. A group of pyrotinib adducts, including pyrotinib-lysine and pyrotinib adducts of the peptides Gly-Lys, Lys-Ala, Gly-Lys-Ala, and Lys-Ala-Ser, was identified after HCl hydrolysis of the incubated plasma. Therefore, the amino acid residue Lys190 of human serum albumin was proposed to covalently bind to pyrotinib via Michael addition. Finally, the covalently bound pyrotinib could dissociate from the human plasma protein and be metabolized by oxidation and excreted via feces.


Risk of hematologic toxicities with programmed cell death-1 inhibitors in cancer patients: a meta-analysis of current studies.
Programmed cell death-1 (PD-1) inhibitor-related hematologic toxicities are a category of rare but clinically serious and potentially life-threatening adverse events; however, little is known about their risks across different treatment regimens and tumor types. The objective of this study was to compare the incidences of PD-1 inhibitor-related hematologic toxicities among different therapeutic regimens and tumor types. Twenty-six original articles on PD-1 inhibitor trials were identified based on a PubMed search completed on September 26, 2017. The incidences of hematologic toxicities were collected. A total of 26 studies containing 5,088 patients were included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%-6%), particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%-12%), compared with all-grade thrombocytopenia (2%, 95% CI 1%-5%), leukopenia (2%, 95% CI 1%-3%), and neutropenia (1%, 95% CI 0-1%). However, low incidences of high-grade hematologic toxicities were observed in cancer patients treated with PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%-31%), thrombocytopenia (6%, 95% CI 2%-18%), leukopenia (5%, 95% CI 1%-35%), neutropenia (4%, 95% CI 1%-26%), and only high-grade thrombocytopenia (4%, 95% CI 1%-15%). In addition, all-grade and high-grade hematologic toxicities in chemotherapy and everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy arms. The risks of PD-1 inhibitor-related hematologic toxicities were higher in RCC than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.


Patterns of nutritional deficiency in head and neck cancer.
A nutritional assessment battery consisting of anthropometric measurements, skin tests, laboratory assessment of visceral and somatic proteins, and a questionnaire was used to characterize the nutritional status of 50 consecutive new head and neck tumor patients. Forty percent of our patients had good nutrition, 20% fair, and 40% poor, with elements of both protein-calorie and protein malnutrition. There was, as expected, a positive relationship between tumor stage and nutritional impairment, but this fell short of statistical significance. There was a just significant tendency for patients with pharyngeal tumors to exhibit poorer scores than did those with oral or laryngeal tumors. Age, sex, smoking history, admitted alcohol consumption, and type of hospital (university, private multispecialty, or Veterans Administration) were not correlated with nutritional status. The best predictor of impaired nutritional status was the patient's description of his recent diet: a normal diet predicted a good score (0-2), and a soft or liquid diet predicted a fair or poor score (3-5), with an overall accuracy of 72%.


Human Papillomaviruses and genital co-infections in gynaecological outpatients.
High grade HPV infections and persistence are the strongest risk factors for cervical cancer. Nevertheless other genital microorganisms may be involved in the progression of HPV associated lesions. Cervical samples were collected to search for human Papillomavirus (HPV), bacteria and yeast infections in gynaecologic outpatients. HPV typing was carried out by PCR and sequencing on cervical brush specimens. Chlamydia trachomatis was identified by strand displacement amplification (SDA) and the other microorganisms were detected by conventional methods. In this cross-sectional study on 857 enrolled outpatients, statistical analyses revealed a significant association of HPV with C. trachomatis and Ureaplasma urealyticum (at high density) detection, whereas no correlation was found between HPV infection and bacterial vaginosis, Streptococcus agalactiae, yeasts, Trichomonas vaginalis and U. urealyticum. Mycoplasma hominis was isolated only in a few cases both in HPV positive and negative women and no patient was infected with Neisseria gonorrhoeae. Although bacterial vaginosis was not significantly associated with HPV, it was more common among the HPV positive women. A significant association between HPV and C. trachomatis was found and interestingly also with U. urealyticum but only at a high colonization rate. These data suggest that it may be important to screen for the simultaneous presence of different microorganisms which may have synergistic pathological effects.


Using Fidelity Measurement to Assess Quality of Early Psychosis Intervention Services in Ontario.
The First Episode Psychosis Services Fidelity Scale (FEPS-FS) is a validated measure of program delivery in relation to international standards. This study assessed fidelity in Ontario programs and the utility of the FEPS-FS for program improvement. Assessments were conducted in a volunteer sample of nine early psychosis intervention (EPI) programs. Thirty components of care were each rated on a 5-point scale; a rating of 4 indicates satisfactory performance. Trained assessor teams conducted site visits, and ratings were made by consensus. Program mean fidelity ratings ranged from 3.1 to 4.4 and exceeded 4 in five programs. Across the programs, item mean fidelity ratings ranged from 2.1 to 5 and exceeded 4 for 14 of 30 items. The FEPS-FS captured variation in program implementation and provided a baseline for measuring change. Additions to the scale are planned to address components of the Ontario EPI standards not covered by the FEPS-FS.


Morphological and functional changes in the enterocyte induced by fructose.
In the presence of 10-50 mM-fructose, enterocytes of organ-cultured pig intestinal-mucosal explants fail to glycosylate correctly their newly synthesized microvillar enzymes, and instead degrade them [Danielsen (1989) J. Biol. Chem. 264, 13726-13729]. In the present work, this degradation was shown to occur extremely rapidly as the microvillar enzyme aminopeptidase N (EC 18.104.22.168) was hardly detectable after a 10 min pulse with [35S]methionine. The abnormal biosynthesis of membrane glycoproteins affected both the morphology and the function of the Golgi complex as well as the microvillar membrane. Thus the stack of Golgi cisternae was condensed and devoid of dilated rims, and the secretion of a non-glycosylated protein, apolipoprotein A-1, was almost completely blocked in the presence of fructose, showing that transport through the secretory pathway is disturbed even for proteins unaffected by the defective glycosylation. The microvilli of the brush-border membrane were markedly shortened (by about 40%) in the presence of fructose, and incorporation of newly made actin into the microvillar cytoskeleton was similarly decreased. By affecting membrane glycoprotein synthesis, the common dietary sugar fructose thus profoundly perturbs the exocytic membrane traffic in the enterocyte.


Assessing the effectiveness of 3, 4-dimethylpyrazole phosphate (DMPP) inhibitor in mitigating N2O emissions from contrasting Cd-contaminated soils.
Improving nitrogen use efficiency of chemical fertilizers is essential to mitigate the negative environmental impacts of nitrogen. Nitrification, the conversion of ammonium to nitrate via nitrite by soil microbes, is a prominent source of nitrogen loss in soil systems. The effectiveness of nitrification inhibitors in reducing nitrogen loss through inhibition of nitrification is well-documented, however, their efficacy in heavy metals-contaminated soils needs thorough investigations. The current study assessed the efficacy of nitrification inhibitor 3, 4-dimethylpyrazole phosphate (DMPP) in reducing nitrous oxide (N2O) emissions in cadmium (Cd) contaminated paddy and red soils under lab-controlled environment. Obtained results indicated the substantial reduction in N2O emissions with DMPP in paddy and red soil by 48 and 35 %, respectively. However, Cd contamination resulted in reduced efficacy of DMPP, thus decreased the N2O emissions by 36 and 25 % in paddy and red soil, respectively. It was found that addition of DMPP had a significant effect on the abundance of ammonia oxidizing bacteria (AOB) and archaea (AOA). Notably, the reduction in N2O emissions by DMPP varied with the abundance of AOB. Moreover, Cd pollution resulted in a significant (P < 0.05) reduction in the abundance of archaeal and bacterial amoA genes, as well as bacterial nirK, nirS, and nosZ genes. The combined treatment of Cd and DMPP had a detrimental impact on denitrifiers, thereby influencing the overall efficiency of DMPP. These findings provide novel insights into the application of DMPP to mitigate nitrification and its potential role in reducing N2O emissions in contaminated soils.


Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer.
Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRAS(G12D) during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRAS(G12D) expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system. Outcrossing the inducible oncogenic KRAS(G12D) line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFβ, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRAS(G12D) showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFβ and Notch pathways. Increase in TGFβ, following KRAS(G12D) activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.


Runner's knee injuries.
In our series of running injuries 40% of all injuries have been related to the knee area. Over 20 million people in the United States run on a regular basis. Figures from large running sources show that 60% to 70% of individuals running regularly are injured severely enough to temporarily stop running. The figures are significant, not in the seriousness of the knee injury, but in the fact that seeking treatment for their knee problems. Orthopaedic surgeons, because of their ability to evaluate the entire lower extremity, become the central component for treatment of this large group of injured runners. As has been noted, the underlying biomechanical abnormality must be sought and dealt with or the symptoms return. By identification of the injured structure(s) integrated with biomechanical understanding, treatment can be developed on a rational basis, dealing with acute problems and prevention of future ones.


Emergency surgery for complicated acute diverticulitis.
Antecedent attacks of diverticulitis are thought to increase the risk of complicated diverticulitis, and unless elective surgery is performed, a high proportion of patients with recurrent symptoms will require emergency operations for complicated diverticulitis with its associated morbidity. In this multicentre study, we aim to assess impact of previous attacks of diverticulitis on patients requiring an emergency surgical intervention. All patients operated on as an emergency for complicated diverticulitis were retrospectively analysed. Patients were separated into two groups: group A included patients without previous history of diverticular disease, and group B those with previous attacks of diverticulitis. A total of 96 patients were included in the study. Group A included 68 (70.8%) patients, and group B 28 (29.2%) patients. Generalized peritonitis was the reason for operation in 50 (73.5%) patients in-group A and only four (14%) patients in group B. Perforated diverticulitis occurred more often in group A, whereas pericolonic abscess and phlegmon formation occurred more commonly in group B. Resection was performed in all patients in group B; 50% had a Hartmann's procedure, and the other 50% patients had primary anastomosis. Hartmann's procedure was performed in 52 patients (76.5%) in group A, and 8 patients (11.7%) had resection and primary anastomosis. No difference in postoperative complications was identified between the groups. Multiple attacks of diverticulitis are not associated with an increased risk of complicated diverticulitis. Recurrent episodes of diverticulitis are not associated with a less favourable outcome or an increased risk of fatality if complications ensue.


Imatinib mesylate alters the expression of genes related to disease progression in an animal model of uveal melanoma.
Imatinib mesylate (IM) is a compound that inhibits both BCR-ABL tyrosine kinase and c-kit receptors. Tyrosine kinases are important in cellular signaling and mediate major cellular processes such as proliferation, differentiation, apoptosis, attachment, and migration. Twenty-six albino rabbits were injected with 1 × 10(6) human uveal melanoma (UM) cells (92.1) into the suprachoroidal space. Animals were immunosuppressed (cyclosporin A) over the course of the 12-week experiment and divided into two groups (n = 13). The experimental group received IM once daily by gavage while the control group received a placebo. One animal per group was sacrificed every week after the 2nd week. Upon necropsy, organs were harvested for histopathological examination. Cells from the primary tumors were recultured and tested in proliferation and invasion assays. A PCR array was used to investigate the differences in expression of 84 genes related to tumor metastasis. In the treated group, 4 rabbits developed intraocular tumors, with an average largest tumor dimension (LTD) of 2.5 mm and 5 animals reported metastatic disease. Whereas 6 rabbits in the control group developed intraocular tumors, with an average LTD of 5.8 mm and 6 animals reported metastatic disease. The recultured cells from the treated group demonstrated lower proliferation rates and were less invasive (p < 0.001). The PCR array showed differences in expression of genes related to metastasis. Notably, there was 290-fold increase in SERPINB5, a tumor suppressor gene, and a 10-fold higher expression of KISS1, a metastasis suppressor gene, in the treated group. Proangiogenic genes such as VEGFA, PDGFA and PDGFB were downregulated in the treated group. To the best of our knowledge, this is the first report detailing the altered expression of specific genes in UM cells after treatment with IM.


Evaluation of the effectiveness of Tai Chi for improving balance and preventing falls in the older population--a review.
One of the challenges faced by people with advancing age is decreased postural stability and increased risks for falls. There has been an increased interest over the last decade in using Tai Chi as an intervention exercise for improving postural balance and preventing falls in older people. Despite the increased number of studies in recent years relating Tai Chi to balance and fall prevention, results are scattered and inconsistent. There is wide variation in the use of balance measures, subject population, type and duration of Tai Chi exercise, and type of study. This paper provides a systematic review/analysis of currently available study reports. The goal of the review is to address the following concerns: how the effect of Tai Chi on balance or fall prevention has been evaluated to date, what level of evidence exists supporting Tai Chi as an effective exercise for improving balance or preventing falls, and what factors could possibly affect the benefit of Tai Chi on balance or falls. This review also helps identify directions for future research.


Leber's idiopathic stellate neuroretinitis: differential diagnosis and approach to management.
Leber's idiopathic stellate neuroretinitis (LISN) is a relatively uncommon clinical entity that is characterized by optic disc oedema and associated macular hard exudates. A broad range of causes can produce such a fundus appearance. The clinical experience of the authors is combined with a review of the pertinent literature to describe the features of LISN and its differential diagnosis. A knowledge of the potential causes of neuroretinitis is important in order to formulate an effective management strategy.


Hepatic adenoma and focal nodular hyperplasia.
Hepatic adenoma and focal nodular hyperplasia are benign lesions of the liver. The incidence of these conditions has been increasing since 1970. Hepatic adenoma primarily affects young women of childbearing age who have a long history of using oral contraceptives, while focal nodular hyperplasia has a wider age distribution and is not associated with the use of oral contraceptives. The most extensive complication of hepatic adenoma is intratumoral or intraperitoneal hemorrhage, which occurs in 50 to 60 per cent of patients. Patients with focal nodular hyperplasia are usually asymptomatic and rarely experience complications. Hepatic adenoma is distinct from focal nodular hyperplasia both in its clinical behavior and its pathologic features; the two can usually be differentiated radiographically using a combination of radionuclide scanning and angiography. There is a proved association between the use of oral contraceptives and the development of hepatic adenoma; the longer the duration of oral contraceptive use, the more the risk of having hepatic adenoma develop. In addition, users of oral contraceptives who have hepatic adenoma develop are likely to have larger tumors and higher rates of bleeding and rupture than nonusers who have hepatic adenoma develop. Although hepatic adenomas may regress after discontinuation of oral contraceptive use, this is not a consistent finding. In addition, it has now been demonstrated that hepatic adenomas do undergo malignant transformation and that this can be detected by measuring the alpha-fetoprotein level. Focal nodular hyperplasia may be a precursor for fibrolamellar hepatocellular carcinoma. Elective resection of hepatic adenoma has a mortality rate of less than 1 per cent, while the mortality rate with free rupture is 5 to 10 per cent. Because of the relative safety of elective versus emergency resection and the potential for malignant change, the treatment of choice for hepatic adenoma is surgical resection.


[Age-related characteristics of the effect of adrenomimetics and adrenoblockaders on the calcium and magnesium content of the rat myocardium].
The effects of noradrenaline (0.025 mg/kg), izadrin (0.1 mg/kg), adrenaline (0.025 mg/kg), ephedrine (5 mg/kg) phentolamine (5 mg/kg), dibenamine (5 mg/kg), anaprilin (1 mg/kg), alpheprol (1 mg/kg) on calcium and magnesium contents in the myocardium of growing rats (7 and 30 days, 3-5 months) were studied. During the animal development and growth the effects of adrenomimetics on calcium and magnesium metabolism decrease to a lesser degree than those of adrenoblockers. The data obtained indicate the enhancement of the regulatory factors and attenuation of the metabolic factors of the mechanism of adrenergic agents' action in the process of the postnatal development.


Looking Upstream to Understand Race/Ethnicity as a Moderator for Poststroke Neuroinflammation and a Social Determinant for Poststroke Aphasia Outcomes.
Over the past decade, the stroke literature has begun to acknowledge and explore explanations for longstanding racial/ethnic differences in stroke outcomes. Poststroke cognitive impairment (PSCI) and poststroke aphasia are two such negative poststroke outcomes where racial/ethnic differences exist. Physiological differences, such as stroke type and lesion size, have been used to partially explain the variation in PSCI and aphasia. However, there is some evidence, although limited, that suggests neuroinflammatory processes as part of allostatic load may be a key contributor to the observed disparities. In this tutorial, we explore the influence of race differences in inflammation on poststroke cognitive outcomes. We suggest lifetime stress and other external determinants of health such as neighborhood environment and discriminatory practices through "weathering" explain differences in inflammation. While using an allostatic load framework, we explore the literature focusing specifically on the role of neuroinflammation on poststroke outcomes. Examination of the immune response poststroke provides a foundation for understanding the mechanisms of PSCI and poststroke aphasia and the potential contributions of neuroinflammatory processes on poststroke cognitive outcomes. Furthermore, understanding of racial differences in those processes may contribute to a better understanding of racial disparities in general stroke outcomes as well as poststroke aphasia.


[High expression of long noncoding RNA UCA1 promotes invasion, migration and epithelial-mesenchymal transition of trophoblasts in vitro].
To investigate the role of urothelial carcinoma antigen 1 (UCA1) in regulation of invasion, migration and epithelial-mesenchymal transition (EMT) of trophoblast HTR-8/SVneo cells and its association with tubal pregnancy. Cultured HTR- 8/SVneo cells stimulated with interleukin-6 (IL-6) were examined for changes in UCA1 expression and cell migration ability using qRT-PCR and scratch assay, respectively. A HTR-8/SVneo cell model with UCA1 silencing was constructed by transient transfection, and the migration and invasion abilities of the cells were assessed using Scratch assay and Transwell assay; qRT-PCR and Western blotting were performed to detect the mRNA and protein expression levels of EMT markers. HTR-8/SVneo cells stimulated with IL-6 exhibited significantly increased migration ability and up-regulated expression of UCA1 (P < 0.01). UCA1 silencing obviously suppressed migration and invasion abilities of HTR-8/SVneo cells (P < 0.01), significantly up-regulated the mRNA and protein expressions of EMT epithelial marker E-cadherin (P < 0.01), and down-regulated the expressions of the mesenchymal markers integrin β3, vimentin and N-cadherin (P < 0.05). UCA1 may be a key gene that promotes the occurrence of tubal pregnancy and thus provides a new therapeutic target for tubal pregnancy.


Capacity of optical wireless communication channels.
Optical wireless communications are realized by modulating the intensity of a light source and detecting intensity fluctuations at the receiver. This mode of operation, known as intensity modulation and direct detection (IM/DD), is simple to implement in practice. However, computing the channel capacity of the underlying channel is not straightforward because of the amplitude constraints that arise due to IM/DD operation. In particular, the transmit signal must be non-negative, while the peak and average amplitudes are constrained due to practical and safety considerations. Though a closed form for the capacity of IM/DD channels is not known, much work has been done to find capacity bounds and asymptotic capacity expressions. In this paper, a description of the IM/DD channel and its physical constraints is presented, followed by a review of recent progress pertaining to the capacity of IM/DD channels. Additionally, capacity-achieving distributions are discussed along with simple constructions that approach capacity. This article is part of the theme issue 'Optical wireless communication'.


Health care quality assurance: tracer analysis in quality assessment of ambulatory care provided by two out patient teaching clinics.
Population-based assessment of medical care provides information on the quality of care generated by a health care facility over a range of services. Patient chart review was undertaken via "tracer analysis" at two ambulatory care teaching clinics to obtain a measure of the clinical services provided by chiropractic interns for a range of diagnoses. The assessment indicated that chiropractic interns perform best when rendering care for spinal conditions. However, a greater emphasis on development of clinical problem-solving skills versus the use of routine standardized examination procedures would improve the quality of care across a broader spectrum of conditions encountered within the patient base of the clinics. Improved documentation of concurrent medical care or medical referral is warranted in instances of systemic comorbidity.


Lifespan snapshot of physical activity assessed by accelerometry in Porto.
The purpose of the study is to evaluate age and gender differences in objectively measured levels of physical activity (PA) in a large and diverse sample of residents from an urban area in Porto, Portugal. Participants included 822 residents, 334 males (41%), and 488 females (59%), aged 6 to 90 years. GT1M accelerometer was used to assess daily PA over 7 consecutive days, and the measurement was from October (2007) to June (2008). Males were more active than females. This difference was attenuated in the 2 oldest age groups (40-59 and 60+ yrs). An accentuated declined in all PA variables occurred between the youngster group (6-11 yrs) and adolescents group (12-19 yrs). Surprisingly, young adults (20-39 yrs) engaged in more moderate-to-vigorous PA (MVPA) than adolescents. Further, females also had higher MVPA in the fourth group (40-59 yrs) compared with the second group (12-19 yrs). Males had higher compliance rates of PA guidelines than females regardless the age group considered. Adolescents had very low compliance rates (females = 18.18%; males = 33.50%). Porto metropolitan area residents had low rates of compliance with current PA guidelines. A low level of PA in Porto adolescents is a matter of concern and suggests that interventions are needed.


Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia.
CCR3 has been implicated as a co-receptor for human immunodeficiency virus type 1 (HIV-1), particularly in brain microglia cells. We sought to clarify the comparative roles of CCR3 and CCR5 in the central nervous system (CNS) HIV-1 infection and the potential utility of CCR3 as a target for manipulation via gene transfer. To target CCR3, we developed a single-chain antibody (SFv) and an interfering RNA (RNAi), R3-526. Coding sequences for both were cloned into Tag-deleted SV40-dervied vectors, as these vectors transduce brain microglia and monocyte-derived macrophages (MDM) highly efficiently. These anti-CCR3 transgenes were compared to SFv-CCR5, an SFv against CCR5, and RNAi-R5, an RNAi that targets CCR5, for the ability to protect primary human brain microglia and MDM from infection with peripheral and neurotropic strains of HIV-1. Downregulation of CCR3 and CCR5 by these transgenes was independent from one another. Confocal microscopy showed that CCR3 and CCR5 co-localized at the plasma membrane with each other and with CD4. Targeting either CCR5 or CCR3 largely protected both microglia and MDM from infection by many strains of HIV-1. That is, some HIV-1 strains, isolated from either the CNS or periphery, required both CCR3 and CCR5 for optimal productive infection of microglia and MDM. Some HIV-1 strains were relatively purely CCR5-tropic. None was purely CCR3-tropic. Thus, some CNS-tropic strains of HIV-1 utilize CCR5 as a co-receptor but do not need CCR3, while for other isolates both CCR3 and CCR5 may be required.


Grammaticality Judgments of Tense and Agreement by Children With and Without Developmental Language Disorder Across Dialects of English.
Within General American English (GAE), the grammar weaknesses of children with developmental language disorder (DLD) have been documented with many tasks, including grammaticality judgments. Recently, Vaughn et al. replicated this finding with a judgment task targeting tense and agreement (T/A) structures for children who spoke African American English (AAE), a dialect that contains a greater variety of T/A forms than GAE. In the current study, we further tested this finding for children who spoke Southern White English (SWE), another dialect that contains a greater variety of T/A forms than GAE but less variety than AAE. Then, combining the SWE and AAE data, we explored the effects of a child's dialect, clinical group, and production of T/A forms on the children's judgments. The data were from 88 SWE-speaking children (DLD, n = 18; typically developing [TD], n = 70) and 91 AAE-speaking children (DLD, n = 34; TD, n = 57) previously studied. As in the AAE study, the SWE judgment data were examined both with A' scores and percentages of acceptability, with comparisons between dialects made on percentages of acceptability. As in AAE, the SWE DLD group had significantly different A' scores and percentages of acceptability than the SWE TD group for all sentence types, including those with T/A structures. Additional analyses indicated that the judgments of the TD but not the DLD groups showed dialect effects. Except for verbal -s, overt production and grammaticality judgments were correlated for the TD but not for the DLD groups. Children with DLD across dialects of English present grammar difficulties that affect their ability to make judgments about sentences. More cross-dialectal research is needed to better understand the grammatical weaknesses of childhood DLD, especially for structures such as verbal -s that are expressed differently across dialects of English.


Physical inactivity and chronic kidney disease in Australian adults: the AusDiab study.
Physical inactivity is associated with cardiovascular risk however its relationship to chronic kidney disease is largely unknown. We examined the association between leisure-time physical activity and risk of chronic kidney disease in a prospective, population-based cohort of Australians aged ≥ 25 years (AusDiab). The baseline sample included 10,966 adults (4951 males and 6015 females). From this sample, 6318 participants with complete baseline and 5-year follow-up urinalysis and serum creatinine measurements formed the study population for longitudinal analysis. Self-reported leisure-time physical activity was measured using a validated, interviewer-administered questionnaire. Compared with sufficiently active individuals (≥ 150 min physical activity per week), those who were inactive (0 min/week) were more likely to have albuminuria at baseline (multivariate-adjusted OR=1.34, 95% CI 1.10-1.63). Inactivity (versus sufficient physical activity) was associated with increased age- and sex-adjusted odds of an estimated glomerular filtration rate <3rd percentile (OR=1.30, 95% CI 1.02-1.65), although this was not significant after multivariate adjustment (OR=1.17, 95% CI 0.91-1.50). Obese, inactive individuals were significantly more likely to have albuminuria at baseline (multivariate-adjusted OR=1.74, 95% CI 1.35-2.25), compared with sufficiently active, non-obese individuals. Baseline physical activity status was not significantly associated with longitudinal outcomes. Physical inactivity is cross-sectionally associated with albuminuria prevalence, particularly when combined with obesity. Future studies are needed to determine whether this association is causal and the importance of physical activity in CKD prevention.


Why are psychotic experiences associated with self-injurious thoughts and behaviours? A systematic review and critical appraisal of potential confounding and mediating factors.
Psychotic experiences (PEs), including hallucination- and delusion-like experiences, are robustly associated with self-injurious thoughts and behaviours (SITB) in the general population. However, it remains unclear as to why there is an association. The purpose of this systematic review was to elucidate the role of other factors that influence the association between PEs and SITB and, in doing so, highlight potential mechanisms underlying the relationship. A search of electronic international databases was undertaken, including PubMed, PsycINFO and EMBASE, and eligible studies were grouped according to seven confounder categories: sociodemographics, mental disorders, alcohol and substance use, environmental, psychological, intervention and family history/genetic factors. The systematic search strategy identified 41 publications reporting on 1 39 427 participants from 16 different countries. In the majority of studies, where adjustment for other variables occurred, the association between PEs and SITB persisted, suggesting PEs have an independent role. Common mental disorders, psychological distress and negative environmental exposures explained a substantial amount of the variance and therefore need to be considered as potential underlying mechanisms. There was high variability in the variables adjusted for in these studies, and so the question still remains as to whether the association between PEs and self-harm/suicidality can be attributed (fully or in part) to confounding and mediating factors or directly causal mechanisms. Regardless of causality, the now extensive literature reporting an association between these two clinical phenomena supports the broad usefulness of PEs as an indicator of risk for SITB.


Esophagogastric fistula. A complication of combined operations for esophageal disease.
Esophagogastric fistula developed in two patients following operations combining fundoplication and other operative procedures on the esophagus. To our knowledge, this complication has not been previously reported or described. Accurate endoscopy and appropriate barium roentgenographic studies provided the definitive diagnosis. A second reconstruction was successful in one patient; conservative treatment was sufficient in the other.


Modelling and Development of a Mechanical Eye for the Evaluation of Robotic Systems for Surgery.
Ophthalmic surgery, which addresses critical eye diseases such as retinal disorders, remains a formidable and arduous surgical pursuit. Nevertheless, with the advent of cutting-edge robotics and automation technology, significant advancement has been made in recent years to enhance the safety and efficacy of these procedures through meticulous research and development efforts. Ensuring the safe and effective execution of micro-surgical procedures requires stringent quality control measures, notably concerning evaluating and testing the devices utilized. During the development phase, these instruments must undergo extensive and continual evaluation by clinical practitioners to guarantee their safety and efficacy. Ideally, the test conditions should be identical to those of an actual operation. When testing robotic systems for ophthalmology, essential variables of the human eye, such as tissue properties and movement mechanisms, should be addressed. To minimize the discrepancy of tests and actual eye surgery conditions, in this paper, we propose a developed mechanical eye model to enable the realistic evaluation of ophthalmic surgical systems. After developing a virtual and physical model, the model was tested by an eye surgeon. The eye surgeon rated the model with four out of five possible points.Clinical relevance- This method ensures minimal discrepancy in verification of ophthalmic surgical devices by allowing the mechanical eye model to behave similar to the human eye, thus providing a realistic surgical procedure.


In vivo confocal microscopic analysis of normal human anterior limbal stroma.
To characterize the microarchitecture of anterior limbal stroma in healthy individuals using in vivo confocal microscopy (IVCM) and to correlate it with mesenchymal stem cells (MSCs), a component of the limbal niche. The corneal side of the superior limbus was scanned in 30 eyes of 17 normal subjects beyond the basal epithelium, deep into the stroma using an HRT III laser scanning microscope. The IVCM findings were correlated with the immunohistochemical features of MSCs in the anterior limbal stroma. Clusters of hyperreflective structures were observed in the anterior limbal stroma, subjacent to the basal epithelium (depth, 50.2 ± 8.7 μm to 98 ± 12.8 μm), but not in the corneal stroma. The structures showed unique morphology compared with epithelial cells, keratocytes, neurons, and dendritic cells. In parallel, confocal analysis of immunostained sections showed clusters of cells, double positive for MSC-specific markers (CD90 and CD105) in the anterior limbal stroma at a depth of 55.3 ± 12.7 μm to 72 ± 37.6 μm. The organization and distribution of the MSC clusters locates them within the hyperreflective region in the anterior limbal stroma. The hyperreflective structures, demonstrated for the first time in the human anterior limbal stroma, probably represent an important component of the limbal niche. Our approach of in vivo imaging may pave the way for assessing the limbal stromal health.


Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes.
Sitagliptin, a novel orally-active dipeptidyl-peptidase (DPP-4) inhibitor has been introduced into type 2 diabetes therapy. Sitagliptin inhibits the degradation of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), as well as that of other regulatory peptides important for glucose homeostasis. It reduces haemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose- dependent stimulation of insulin secretion and inhibition of glucagon secretion. Sitagliptin is weight neutral. Indirect measures show a possible improvement of beta-cell function. Sitagliptin does not cause hypoglycemia when compared to metformin or placebo. Metformin, which has a different unique mechanism, has been used in type 2 diabetes for approximately 50 years. Metformin improves insulin resistance and is the first-line antidiabetic drug in use today. The combination of a DPP-4 inhibitor with metformin allows a broad and complementary spectrum of antidiabetic actions. This combination does not increase the risk of hypoglycaemia nor does it promote weight gain, an adverse effect of various other oral antidiabetic combinations. This article gives an overview of the data available on the combined antidiabetic effects of metformin and sitagliptin.


A healthy dietary pattern may be associated with primary insomnia among Iranian adults: A case-control study.
Objective: While it has been reported that both foods and nutrients for individuals are connected with sleep, there is no evidence regarding the association of dietary patterns, identified by factor analysis, with primary insomnia. The present study sought to evaluate the association between major dietary patterns and the chance of having primary insomnia. Methods: The present case-control study was performed using 444 people (111 cases and 333 control), aged 18 to 60 years, referred to Isfahan health centers. Dietary intake was assessed via a food frequency questionnaire in a case-control study in Isfahan, Iran. Principal component analysis was used to determine major dietary patterns. The presence of primary insomnia was measured via the insomnia severity index questionnaire, and the subjects were grouped as healthy or insomniac. Results: Three major dietary patterns were recognized, and named; Western, Iranian Traditional and Healthy, respectively. The cumulative percentage of variance explained by three dietary patterns was 48.2%. Those in second (OR = 0.30; 95%CI: 0.2-0.46) and third (OR = 0.22; 95%CI: 0.15-0.35) tertiles of healthy dietary pattern were less likely suffer with insomnia. This association remained significant only in the highest tertile after adjusting potential confounders (OR = 0.45; 95%CI: 0.32-0.95). We found no significant association between greater adherence to Western or Iranian traditional dietary patterns and primary insomnia. Conclusions: The findings showed that although no statistically significant association was observed between both Western and Iranian traditional dietary patterns with primary insomnia, people with greater adherence to the healthy dietary pattern are less likely to have primary insomnia.


The role of the thalamic reticular neurons in alpha- and gamma-oscillations in neocortex: a mechanism for selective perception and stimulus binding.
The long-term objective is to understand how large masses of neurons in the brain process information during various learning and memory paradigms. Both time- and space-dependent processes have been identified in animals through computer-based analytic quantifications of event-related extracellular potentials. New nonlinear analyses have been introduced that presume that the fine-grain variation in the signal is determined and patterned in phase-space. Some neurons in the primary visual cortex manifest gamma-band oscillations. These cells show both a nonspecific phase-alignment (response synchrony) and a specific tuning (orientation tuning) when stimuli are presented to their receptive fields. This dual regulation of the sensory cells is proposed to underlie stimulus binding, a theoretical mechanism for "object" perception. Nonlinear analytic results from gamma-activities in a simple model neuropil (olfactory bulb) suggest that neuroplasticity may arise through self-organization, a process in which a nonlinear change in the dynamics of the oscillatory field potentials is the hallmark. This self-organization may follow simple dynamical laws in which global cooperativity among the neurons is transiently brought about that, over trials, results in enduring changes in the nonlinear dynamics of some neurons. In conclusion, the sculpturing of the synaptic throughput in the sensory cortex (stimulus binding) may be associated with the irregular phases of the gamma-activities and may result from both specific and nonspecific systems operating together in a nonlinear self-organizing manner.


Ore metals through geologic history.
The ores of chromite, nickel, copper, and zinc show a wide distribution over geologic time, but those of iron, titanium, lead, uranium, gold, silver, molybdenum, tungsten, and tin are more restricted. Many of the limitations to specific time intervals are probably imposed by the evolving tectonic history of Earth interacting with the effects of the biomass on the evolution of the earth's s surface chemistry. Photosynthetic generation of free oxygen and "carbon" contributes significantlly to the diversity of redox potentials in both sedimentary and igneous-related processes of ore formation, influencing the selection of metals at the source, during transport, and at the site of ore deposition.


Impact of fortified biscuits on micronutrient deficiencies among primary school children in Bangladesh.
Micronutrient deficiencies can compromise the development potential of school-aged children, and their later health and productivity as adults. School feeding and school-based fortification approaches have been utilized globally to redress nutritional deficiencies in this age group. We explored the acceptability and micronutrient impact of a Bangladesh Government supported school-based micronutrient fortification program for children attending rural primary schools in 10 disadvantaged sub-districts. We applied a mixed methods approach. The quantitative component assessed the impact of micronutrient fortification on 351 children aged 6-11 years using a cohort pre-post research design with a control group. The qualitative component explored the acceptability of the intervention using focus group discussions, body mapping and semi-structured interviews with teachers, school-going children and school authorities. Daily consumption of fortified biscuits by primary school children had a significant positive impact on mean levels of iron, folic acid, vitamin B12, retinol and vitamin D controlling for sex, baseline deficiency status, CRP, and H. pylori. Levels of anemia and vitamin D deficiency were also significantly reduced. Qualitative findings indicated the widespread acceptability of the daily biscuit. Teachers perceived students to be more attentive in class, less tired, and some attributed better school performance to biscuit consumption. Children reported similar improvements in concentration and energy levels. This study is among the first in Bangladesh to comprehensively assess a school-based fortification program in terms of its acceptability and impact on micronutrient status of children aged 6-11 years of age. While results strongly support this modality of school feeding, research on the cognitive impacts of micronutrient fortified biscuits will help clarify the case for scaled-up investments in school- based feeding program in Bangladesh and other low and middle income countries.


Sequential intracellular release of water-soluble cargos from Shell-crosslinked polymersomes.
Polymer vesicles, i.e. polymersomes (PS), present unique nanostructures with an interior aqueous core that can encapsulate multiple independent cargos concurrently. However, the sequential release of such co-loaded actives remains a challenge. Here, we report the rational design and synthesis of oxidation-responsive shell-crosslinked PS with capability for the controlled, sequential release of encapsulated hydrophilic molecules and hydrogels. Amphiphilic brush block copolymers poly(oligo(ethylene glycol) methyl ether methacrylate)-b-poly(oligo(propylene sulfide) methacrylate) (POEGMA-POPSMA) were prepared to fabricate PS via self-assembly in aqueous solution. As a type of unique drug delivery vehicle, the interior of the PS was co-loaded with hydrophilic molecules and water-soluble poly(N-isopropylacrylamide) (PNIPAM) conjugates. Due to the thermosensitivity of PNIPAM, PNIPAM conjugates within the PS aqueous interior underwent a phase transition to form hydrogels in situ when the temperature was raised above the lower critical solution temperature (LCST) of PNIPAM. Via control of the overall shell permeability by oxidation, we realized the sequential release of two water-soluble payloads based on the assumption that hydrogels have much smaller membrane permeability than that of molecular cargos. The ability to control the timing of release of molecular dyes and PNIPAM-based hydrogels was also observed within live cells. Furthermore, leakage of hydrogels from the PS was effectively alleviated in comparison to molecular cargos, which would facilitate intracellular accumulation and prolonged retention of hydrogels within the cell cytoplasm. Thus, we demonstrate that the integration of responsive hydrogels into PS with crosslinkable membranes provides a facile and versatile technique to control the stability and release of water-soluble cargos for drug delivery purposes.


Whole-genome analysis to describe a human adenovirus D8 conjunctivitis outbreak in a tertiary hospital.
Conjunctivitis is a frequent ocular disorder caused by human adenoviruses (HAdVs). Only a few of the 45 HAdV-D species are associated with epidemic keratoconjunctivitis, including HAdV-D8. Nosocomial outbreaks due to HAdV-D8 have been rarely described, because keratoconjunctivitis cases are clinically diagnosed and treated without having to characterize the causative agent. Moreover, molecular typing is tedious when using classical techniques. In this study, a hospital outbreak of conjunctivitis caused by HAdV-D8 was characterized using the recently developed whole-genome sequencing (WGS) method. Of the 363 patients attending the Ophthalmology Department between July 13 and August 13, 2018, 36 may have acquired intrahospital conjunctivitis. Also, 11 of 22 samples sent to the Virology section were selected for WGS analysis. The WGS results revealed that 10 out of 11 HAdV-D8 strains were closely related. The remaining strain (Case 28) was more similar to a strain from an outbreak in Germany obtained from a public sequence database. WGS results showed that outbreak HAdV-D8 strains had a minimum percentage of identity of 94.3%. WGS is useful in a clinical setting, because it avoids carrying out viral culture or specific polymerase chain reaction sequencing. The public availability of sequence reads makes it easier to compare clusters in circulation. In conclusion, WGS can play an important role in standard routines to describe viral outbreaks.


Palladium-based catalytic systems for the synthesis of conjugated enynes by sonogashira reactions and related alkynylations.
Conjugated alkynes are recurring building blocks in natural products, a wide range of industrial intermediates, pharmaceuticals and agrochemicals, and molecular materials for optics and electronics. The palladium-catalyzed cross-coupling between sp(2)-hybridized carbon atoms of aryl, heteroaryl, and vinyl halides with sp-hybridized carbon atoms of terminal acetylenes is one of the most important developments in the field of alkyne chemistry over the past 50 years. The seminal work of the 1970s has initiated an intense search for more general and reliable reaction conditions. The interest in the catalytic activation of demanding substrates, the need to minimize the consumption of depletive resources, and the search for easy access to an increased variety of functionalized enynes has led to the current generations of high-turnover catalysts. This Review gives an overview of the highly efficient palladium catalyst systems for the direct alkynylation of C(sp(2)) halides with terminal alkynes, both in homogeneous and heterogeneous phases.


Comparing Real-Time Self-Tracking and Device-Recorded Exercise Data in Subjects with Type 1 Diabetes.
Insulin therapy, medical nutrition therapy, and physical activity are required for the treatment of type 1 diabetes (T1D). There is a lack of studies in real-life environments that characterize patient-reported data from logs, activity trackers, and medical devices (e.g., glucose sensors) in the context of exercise. The objective of this study was to compare data from continuous glucose monitor (CGM), wristband heart rate monitor (WHRM), and self-tracking with a smartphone application (app), iDECIDE, with regards to exercise behaviors and rate of change in glucose levels. Participants with T1D on insulin pump therapy tracked exercise for 1 month with the smartphone app while WHRM and CGM recorded data in real time. Exercise behaviors tracked with the app were compared against WHRM. The rate of change in glucose levels, as recorded by CGM, resulting from exercise was compared between exercise events documented with the app and recorded by the WHRM. Twelve participants generated 277 exercise events. Tracking with the app aligned well with WHRM with respect to frequency, 3.0 (2.1) and 2.5 (1.8) days per week, respectively (p = 0.60). Duration had very high agreement, the mean duration from the app was 65.6 (55.2) and 64.8 (54.9) minutes from WHRM (p = 0.45). Intensity had a low concordance between the data sources (Cohen's kappa = 0.2). The mean rate of change of glucose during exercise was -0.27 mg/(dL*min) and was not significantly different between data sources or intensity (p = 0.21). We collated and analyzed data from three heterogeneous sources from free-living participants. Patients' perceived intensity of exercise can serve as a surrogate for exercise tracked by a WHRM when considering the glycemic impact of exercise on self-care regimens.


Inguinal neuralgia: a review of 50 patients.
Inguinal neuralgia, an uncommon condition, can readily be diagnosed if the anatomy of the sensory nerves of the lumbar plexus is understood. The authors review 50 patients with this condition, pointing out the importance of injury to these nerves, not only on the anterior abdominal wall but also in the retroperitoneal space on the posterior abdominal wall. Successful treatment is achieved by surgical section of the nerves. First the inguinal region is explored; if this does not result in cure the authors recommend retroperitoneal section of the nerve.


Body Composition Predicts Growth in Infants and Toddlers With Chronic Liver Disease.
This cross-sectional study was conducted on 15 infants and toddlers with chronic liver disease to validate arm anthropometry as an accurate measure of body composition (BC) compared to dual-energy x-ray absorptiometry and to predict growth from BC. The z score means of the anthropometric indicators were <-2 standard deviation, except for body fat index and subscapular skinfold, which were between -2 and +2 standard deviation. Fat mass was predicted by arm adiposity indicators and fat-free mass by arm muscle area. Bone mineral content explained 87% of variation in length. Two multiple regression models predicted length: 1 with fat mass plus fat-free mass; and the second with fat mass and bone mineral content. These observations suggest that arm anthropometry is a useful tool to estimate BC and the nutritional status in infants and toddlers with chronic liver disease. Length and head circumference can be predicted by fat mass, fat-free mass, and bone mineral content.


A federalist strategy for nuclear waste management.
The federal government plans to rely on a policy of "consultation and concurrence" with state governments in developing nuclear waste repositories. The weaknesses of the concurrence approach are analyzed, and an alternative institutional framework for locating a waste repository is proposed: a siting jury that provides representation for state and local interests, while maintaining a high level of technical review. The proposal could be tested in the siting of away-from-reactor storage facilities for spent nuclear fuel.


Complete two-loop QCD contributions to the lightest Higgs-boson mass in the MSSM with complex parameters.
Higher-order corrections to the MSSM Higgs-boson masses are desirable for accurate predictions currently testable at the LHC. By comparing the prediction with the measured value of the discovered Higgs signal, viable parameter regions can be inferred. For an improved theory accuracy, we compute all two-loop corrections involving the strong coupling for the Higgs-boson mass spectrum of the MSSM with complex parameters. Apart from the dependence on the strong coupling, these contributions depend on the weak coupling and Yukawa couplings, leading to terms of O α α s and O α q 1 α q 2 α s , ( q 1 , 2 = t , b , c , s , u , d ). The full dependence on the external momentum and all relevant mass scales is taken into account. The calculation is performed in the Feynman-diagrammatic approach which is flexible in the choice of the employed renormalization scheme. For the phenomenological results presented here, a renormalization scheme consistent with higher-order corrections included in the code FeynHiggs is adopted. For the evaluation of the results, a total of 513 two-loop two-point integrals with up to five different mass scales are computed fully numerically using the program SecDec. A comparison with existing results in the limit of real parameters and/or vanishing external momentum is carried out, and the impact on the lightest Higgs-boson mass is discussed, including the dependence on complex phases. The new results will be included in the public code FeynHiggs.


Near-Field Infrared Pump-Probe Imaging of Surface Phonon Coupling in Boron Nitride Nanotubes.
Surface phonon modes are lattice vibrational modes of a solid surface. Two common surface modes, called longitudinal and transverse optical modes, exhibit lattice vibration along or perpendicular to the direction of the wave. We report a two-color, infrared pump-infrared probe technique based on scattering type near-field optical microscopy (s-SNOM) to spatially resolve coupling between surface phonon modes. Spatially varying couplings between the longitudinal optical and surface phonon polariton modes of boron nitride nanotubes are observed, and a simple model is proposed.


Midwives' Perception of Using a Knowledge Base on Fetal Impact of Drugs.
A non-commercial knowledge base providing assessments of fetal risks of medicinal drugs is a useful tool in the everyday work of midwives. The information is freely available on the internet, and according to a questionnaire study, nearly 95% of the midwives are familiar with the database, 30% use the information weekly, and 80% express that it affects their medical decisions. A vast majority of the midwives also state that it is time-saving.


An Exploration of Sex Trading for Compensation and LGBTQ+ Inclusive Screening Practices: Perspectives of Young People who have Experienced Sex Trading and/or Homelessness.
Young people's perspectives on social and healthcare providers' assessments of sex trading for financial compensation are lacking. This is particularly important for LGBTQ+ youth who experience substantial barriers in navigating health and social services. Further, increased internet access (because of COVID-19 and other factors) has changed the landscape of the sex trades in ways that are not fully understood. Our study aimed to understand (1) how young people trade sex, and (2) provider strategies that increase youths' comfort in disclosing sex trading and related risks. This community-based participatory research study surveyed currently or formerly homeless youth (ages 16-29). We co-created a cross sectional survey that explored youths' perceptions of: (1) sex trading type, compensation, and meaning; and (2) practices to increase youths' comfort in disclosing sex trading. Participants (N = 103; Mage = 22.9 [SD = 3.5]; 34% white, 55% ciswomen/21% trans; 51% queer) reported that "sex trading" signified multiple meanings, ranging from sex work/occupation to exploitation/trafficking, and included diverse in-person and virtual forms for varied compensation types. Youth reported being more comfortable disclosing when the provider indicated they would advocate for them if they are victims of discrimination. Compared to cisgender youth, trans youth reported feeling significantly more comfortable disclosing sexual activity when a service provider used gender/sexuality inclusive practices (e.g., pronoun pins). Findings suggest important implications for gender-inclusive practice strategies to ultimately reduce potential harms of sex trading and multi-item measures to assess the complexity of sex trading.


Phenotype-Specific Response of Circulating miRNAs Provides New Biomarkers of Slow or Fast Muscle Damage.
Skeletal muscle is a heterogeneous tissue composed of a continuum of contracting fibers ranging from slow-type to fast-type fibers. Muscle damage is a frequent event and a susceptibility of fast-fibers to exercise-induced damage (EIMD) or statins toxicity has been reported. Biological markers of muscle damage such as creatine kinase (CK) are not fiber-type specific and new biomarkers are needed. Some microRNAs (miRNAs) are specific to the muscle tissue, can be found in the extracellular compartment and can rise in the plasma following muscle damage. Our aim was to identify whether a set of circulating miRNAs can be used as fiber-type specific biomarkers of muscle damage in a model of traumatic (crush) injuries induced either in the slow soleus (SOL) or in the fast extensor digitorum longus (EDL) muscles of rats. A subset of miRNAs composed of miR-1-3p, -133a-3p, -133b-3p, 206-3p, -208b-3p, 378a-3p, -434-3p, and -499-5p were measured by RT-PCR in non-injured SOL or EDL muscle and in the plasma of rats 12 h after damage induced to SOL or EDL. MiR-133b-3p, -378a-3p, and -434-3p were equally expressed both in SOL and EDL muscles. MiR-1-3-p and -133a-3p levels were higher in EDL compared to SOL (1.3- and 1.1-fold, respectively). Conversely, miR-206-3p, -208b-3p, and -499-5p were mainly expressed in SOL compared to EDL (7.4-, 35.4-, and 10.7-fold, respectively). In the plasma, miR-1-3p and -133a-3p were elevated following muscle damage compared to a control group, with no difference between SOL and EDL. MiR-133b-3p and -434-3p plasma levels were significantly higher in EDL compared to SOL (1.8- and 2.4-fold, respectively), while miR-378a-3p rose only in the EDL group. MiR-206-3p levels were elevated in SOL only (fourfold compared to EDL). Our results show that plasma miR-133b-3p and -434 are fast-fiber specific biomarkers, while miR-206-3p is a robust indicator of slow-fiber damage, opening new perspectives to monitor fiber-type selective muscle damage in research and clinic.


What activities might facilitate personal recovery for adults who continue to self-harm? A meta-synthesis employing the connectedness/hope and optimism/identity/meaning/empowerment framework.
Self-harm is an international concern. While treatment in health care focusses on methods to reduce the act, there is less exploration in how to assist adults who are unable to minimize their self-harm. In order to aid these people, in the present systematic review, we employed a qualitative meta-synthesis to explore the lived experience of what activities might facilitate personal recovery for adults who continue to self-harm. Findings were interpreted by drawing on the CHIME framework; a taxonomy of personal recovery comprising of connectedness, hope and optimism, identity, meaning and purpose, and empowerment. The located activities in the review converged on different support groups, and although face-to-face groups were discovered, the majority highlighted the benefits of Internet forums where mutuality and reciprocity were key to promoting personal recovery. Adults desired time to share accounts of themselves, to develop connection and identity. Furthermore, hope was established by group members accepting that self-harm has a role, while congregating with others who did not judge the act. Helping relationships also promoted hope by having a balance between goals and protection against disappointment. The nature of writing online seemingly had cathartic properties fostering meaning, alongside empowerment being facilitated by adults controlling the narrative of their self-harm. It is hoped that these insights might guide self-harm research to develop beyond the confines of minimizing self-injury in health care.


Quantitative analysis of nuclear localization signal (NLS)-importin alpha interaction through fluorescence depolarization. Evidence for auto-inhibitory regulation of NLS binding.
We have developed a quantitative in vitro steady-state fluorescence depolarization assay to measure the interaction of a nuclear localization signal (NLS) substrate with its receptors. This assay relies on the change in fluorescence depolarization of an NLS fused to the green fluorescent protein upon binding to receptor. No binding is observed in the absence of a functional NLS, and binding affinities measured correlate with previous in vivo studies of NLS function. We have used this assay to test an auto-inhibitory model for the interaction of an NLS with the NLS receptor complex. This model suggests that NLS binding to importin alpha is modulated by an auto-inhibitory sequence within the N terminus of importin alpha, which is displaced by importin beta binding. Consistent with this model, NLS substrates bind tightly to an N-terminally truncated importin alpha lacking the auto-inhibitory domain (K(d) approximately 10 nm), but measurable binding to full-length importin alpha is only observed upon addition of importin beta. Our quantitative results support the auto-inhibitory model and suggest a mechanism for a switch between a cytoplasmic, high affinity and a nuclear, low affinity NLS receptor. This predicted mode of interaction would facilitate binding of substrate in the cytoplasm and its subsequent release into the nucleus.


14CO2-in-air sampling with passive diffusion samplers.
Passive diffusion samplers designed for measuring HTO-in-air have been evaluated for measuring 14CO2-in-air. Controlled exposures to HTO-in-air, 14CO2-in-air, and a combination of the two gases were carried out. The sampling rate of the 14CO2-in-air was found to be approximately 0.7 that of HTO-in-air. This value is consistent with the calculated relative sampling rates based on the diffusion coefficients of the gases. Passive diffusion samplers currently used for sampling HTO-in-air at CANDU facilities have been shown to be suitable for also measuring 14CO2-in-air and HTO-in-air simultaneously when prepared with the appropriate sampling solution.


Postfire biodiversity database for eastern Iberia.
In the summer of 2012, two fires affected Mediterranean ecosystems in the eastern Iberian Peninsula. The size of these fires was at the extreme of the historical variability (megafires). Animals are traditionally assumed to recolonize from source populations outside of the burned area (exogenous regeneration) while plants recover from endogenous regeneration (resprouting and seeding). However, there is increasing evidence of in situ fire survival in animals. To evaluate the effect of large-scale fires on biodiversity and the mechanism of recovery, in 2013, we set up 12 plots per fire, covering burned vegetation at different distances from the fire perimeter and unburned vegetation. In each plot, we followed the postfire recovery of arthropods, reptiles (including some of their parasites), and plants for 2 to 5 years. Here we present the resulting database (POSTDIV) of taxon abundance. POSTDIV totals 19,906 records for 457 arthropod taxa (113,681 individuals), 12 reptile taxa (503 individuals), 4 reptile parasites (234 individuals), and 518 plant taxa (cover-abundance). We provide examples in the R language to query the database.


Increased expression of the pro-apoptotic Bcl2 family member PUMA and apoptosis by the muscle regulatory transcription factor MyoD in response to a variety of stimuli.
We have previously reported that the level of MyoD expression correlates with the level of apoptosis that occurs in a subpopulation of skeletal myoblasts induced to differentiate by serum withdrawal. Herein we document that MyoD expression contributes to the level of apoptosis in myoblasts and fibroblasts in response to a variety of apoptotic stimuli. Specifically, re-expression of MyoD in skeletal myoblasts rendered defective for both differentiation and apoptosis by the expression of oncogenic Ras restores their ability to undergo both differentiation and apoptosis in response to serum withdrawal. Further, using a fibroblast cell line expressing an estrogen receptor:MyoD fusion protein, we have determined that addition of estrogen sensitizes these fibroblasts to apoptosis induced by serum withdrawal, or by treatment with etoposide or thapsigargin. RNAi mediated silencing of MyoD in either 23A2 or C2C12 myoblasts renders these cells resistant to apoptosis induced by serum withdrawal, or by treatment with etoposide or thapsigargin. Finally, MyoD mediated regulation of the apoptotic response to these various stimuli, in both myoblasts and fibroblasts, correlates with the level of induction of the pro-apoptotic Bcl2 family member PUMA.


[The interhemispheric asymmetry of the spatial-temporal organization of cortical potentials in the rabbit].
In experiments on freely moving rabbits the existence of interhemispheric asymmetry of spatial-temporal organization of the cortical potentials in the state of calm alertness was shown. Episodes were revealed of interhemispheric discordance of spatial reconstructions of momentary reliefs of the cortical potentials topograms 1/64-1/3-1/5 s in duration, i.e. periods of the theta- or delta-rhythms. Total duration of time of interhemispheric asymmetry (according to significant divergences in dynamics of resemblance coefficients of consequent reliefs of the cortical potentials topograms) in most cases was not less than 10% and not more than 30% of time of analysis epoch and consisted of discordance episodes both of different global reconstructions of spatial correlations of the left and right hemisphere potentials and of interhemispheric local shifts in spatial organization of the cortex potentials.


Gillick, bone marrow and teenagers.
The Human Tissue Authority can authorise a bone marrow harvest on a child of any age if a person with parental responsibility consents to the procedure. Older children have the legal capacity to consent to medical procedures under Gillick, but it is unclear if Gillick can be applied to non-therapeutic medical procedures. The relevant donation guidelines state that the High Court shall be consulted in the event of a disagreement, but what is in the best interests of the teenage donor under s.1 of the Children Act 1989? There are no legal authorities on child bone marrow harvests in the United Kingdom. This article considers the best interests of the older saviour sibling and questions whether, for the purposes of welfare, the speculative benefits could outweigh the physical burdens.


Membranes as a possible pacemaker of metabolism in cypriniform fish: does phylogeny matter?
The 'membrane pacemaker theory of metabolism' proposes that membranes set metabolic rate by modulating protein activity, and thus purports to explain membrane fatty acid allometry. This relationship has never been tested across species in ectotherms. After accounting for phylogeny, recent analyses have failed to support this theory based on correlations between muscle membrane composition and body mass across mammals. Therefore, the goal of this study was to seek phylogenetically corrected correlations between membrane composition, body mass and calcium-ATPase activity, using 12 species of closely related cypriniform fish (4-5500 g) covering a much narrower genetic scale than in previous tests. The results show that fish membrane unsaturation decreases with mass, but through different mechanisms from those in endotherms: 16:0 replacing 22:6 in muscle and 18:0 replacing 16:1, 18:1 and 18:2 in liver. This shows that allometric patterns differ between endotherms and ectotherms as well as between tissues. After accounting for phylogeny, however, almost all these relationships lose significance except for overall unsaturation. No relationship between calcium-ATPase activity and mass or phospholipid composition was detected. This study shows that membrane unsaturation of cypriniforms decreases with mass, but that genetic cues unrelated to size account for differences in the relative abundance of individual fatty acids. The membrane pacemaker concept accurately predicts general membrane properties such as unsaturation, but fails to explain finer scale allometric patterns. Future examinations of the membrane pacemaker hypothesis will have to take into account that allometric patterns vary between endotherms and ectotherms and between tissues of the same animal class.


Bimodal dynamics of mechanically constrained hydrogen bonds revealed by vibrational photon echoes.
We have investigated the dynamics of the hydrogen bonds that connect the components of a [2]rotaxane in solution. In this rotaxane, the amide groups in the benzylic-amide macrocycle and the succinamide thread are connected by four equivalent N-H⋅⋅⋅O=C hydrogen bonds. The fluctuations of these hydrogen bonds are mirrored by the frequency fluctuations of the NH-stretch modes, which are probed by means of three-pulse photon-echo peak shift spectroscopy. The hydrogen-bond fluctuations occur on three different time scales, with time constants of 0.1, 0.6, and ≥200 ps. Comparing these three time scales to the ones found in liquid formamide, which contains the same hydrogen-bonded amide motif but without mechanical constraints, we find that the faster two components, which are associated with small-amplitude fluctuations in the strength of the N-H⋅⋅⋅O=C hydrogen bonds, are very similar in the liquid and the rotaxane. However, the third component, which is associated with the breaking and subsequent reformation of hydrogen bonds, is found to be much slower in the rotaxane than in the liquid. It can be concluded that the mechanical bonding in a rotaxane does not influence the amplitude and time scale of the small-amplitude fluctuations of the hydrogen bonds, but strongly slows down the complete dissociation of these hydrogen bonds. This is probably because in a rotaxane breaking of the macrocycle-axle contacts is severely hindered by the mechanical constraints. The hydrogen-bond dynamics in rotaxane-based molecular machines can therefore be regarded as liquidlike on a time scale 1 ps and less, but structurally frozen on longer (up to at least 200 ps) time scales.


[Reintervention after valve replacement surgery. Study of 358 cases].
There is still a place for conservative surgery in valvular disease of the heart to the extent that artificial prostheses have not yet been perfected sufficiently for them to be regarded as the method of choice. While these conservative operations are rarely applicable to the aortic valve, techniques such as Carpentier's ring occupy an important place in the treatment armamentarium for disorders of the mitral valve, and even more so of the tricuspid valve.


Desensitization versus intraturbinal injection of corticosteroid for nasal allergy: indications, effectiveness, and patient acceptance.
Severe allergic nasal symptoms often require corticosteroids for control. Although I most often utilize intraturbinal injection, they may also be administered systemically (oral or intramuscular) or as nasal aerosols. I advise allergy testing and desensitization for refractory cases unresponsive to conservative management, or instances of recurrent severe symptoms requiring repeated intranasal steroid injections (eg, six or more in one year, five or more per year for two years). A survey of patients who had been treated by both allergy desensitization and intranasal steroid injection revealed a much greater patient acceptance of the latter treatment. Desensitization was judged by most patients as good to fair in providing relief, while all patients questioned in a random sampling rated intranasal steroid injection excellent to good. About half the patients had discontinued their allergy injections, generally because of lack of results or growing tired of repeated injections. Intranasal steroid injection affords good symptomatic relief for the patient with severe allergic rhinitis, while allergy desensitization offers the only "cure" possible. Both measures have a place in the management of nasal allergy. However, patients must be advised of the goals and limitations of each measure.


A shape-from-shading method of polyhedral objects using prior information.
We propose a new method for recovering the 3D shape of a polyhedral object from its single 2D image using the shading information contained in the image and the prior information on the object. In a strict sense, we cannot recover the shape of a polyhedron from an incorrect line drawing, even if it is practically almost correct. In order to overcome this problem, we propose a flexible face positioning method that can permit inconsistencies in the recovered shape that arise from vertex-position errors contained in incorrect line drawings. Also, we propose to use prior information about the horizontality and verticality of special faces and the convex and concave properties of the edges in order to attain good solutions and present a method of formulating such prior information as physical constraints. The shape-from-shading method is formulated as a minimization problem of a nonlinear cost function with the nonlinear constraints and its solution is searched by a global optimization algorithm. In the experiments with a synthetic image and three kinds of real images, shapes that are similar to those of the actual objects were recovered in all cases. As a result, the proposed method has proven to be effective in the shape recovery of simple-shape polyhedral objects.


Substance P diminishes lipopolysaccharide and interferon-gamma-induced TGF-beta 1 production by cultured murine macrophages.
Recent evidence has demonstrated the importance of substance P and its receptor in macrophage-mediated inflammatory responses. While previous studies have shown that substance P can augment proinflammatory monokine production, little is known about the effects of this neuropeptide on the production of monokines that might limit inflammation. In the present study we have investigated the effect of substance P treatment on the production of transforming growth factor-beta 1 (TGF-beta 1) in cultured murine macrophages. We report that, while substance P agonist alone elicited increases in TGF-beta 1 mRNA expression and modest increases in TGF-beta 1 secretion, substance P dramatically diminished LPS- or IFN-gamma-induced TGF-beta 1 production. These results suggest a previously unrecognized mechanism where substance P may act as a proinflammatory mediator by limiting the production of excessive levels of TGF-beta 1 by LPS- or IFN-gamma-activated macrophages.


Real-time observation of carbonic acid formation in aqueous solution.
Despite the widespread importance of aqueous bicarbonate chemistry, its conjugate acid, carbonic acid, has remained uncharacterized in solution. Here we report the generation of deuterated carbonic acid in deuterium oxide solution by ultrafast protonation of bicarbonate and its persistence for nanoseconds. We follow the reaction dynamics upon photoexcitation of a photoacid by monitoring infrared-active marker modes with femtosecond time resolution. By fitting a kinetic model to the experimental data, we directly obtain the on-contact proton-transfer rate to bicarbonate, previously inaccessible with the use of indirect methods. A Marcus free-energy correlation supports an associated pKa (Ka is the acid dissociation constant) of 3.45 +/- 0.15, which is substantially lower than the value of 6.35 that is commonly assumed on the basis of the overall carbon dioxide-to-bicarbonate equilibrium. This result should spur further exploration of acid-base reactivity in carbon dioxide-rich aqueous environments such as those anticipated under sequestration schemes.


Optimizing a real-time PCR assay for rapid detection of Candida auris in nasal and axillary/groin samples.
Introduction. Candida auris is an emerging fungal pathogen. The organism can cause invasive infections associated with high mortality, has been implicated in outbreaks in healthcare settings and is frequently resistant to multiple antifungal agents, making it a significant challenge to infection prevention and patient treatment.Aim. To implement a real-time PCR assay for detection of C. auris in patient surveillance samples collected with the Copan Liquid Amies elution swab (ESwab) collection and transport system.Methodology. We optimized a real-time PCR testing procedure based on the sample collection device used in our institution.Results . ESwab transport medium was strongly inhibitory to the real-time PCR. Removing the medium with centrifugation, followed by suspending the pellet in PBS-BSA buffer (concentration 1 %), sufficiently eliminated the inhibition. The manual sample preparation method, freeze-thaw followed by mechanical disruption, allowed the detection of C. auris at the lowest cell concentration.Conclusion . The optimized procedure was used to test 1414 patient surveillance samples. The real-time PCR detected all culture-positive samples with 100 % sensitivity and 100 % specificity.


Development of major depressive disorder during smoking-cessation treatment.
Several studies have shown an association between smoking and major depressive disorder (MDD), but few have prospectively examined subjects who develop MDD after quitting smoking. This descriptive study evaluated the development of MDD after smoking cessation, as assessed by a structured clinical interview at both baseline and the end of treatment. Nondepressed participants (N = 114) in a trial investigating the effect of fluoxetine on smoking cessation were administered the Structured Clinical Interview for DSM-III-R at baseline and posttreatment to evaluate the impact of quitting smoking on the development of MDD. Depressive symptoms were additionally assessed with the Beck Depression Inventory and the Hamilton Rating Scale for Depression. At baseline, 32% of the subjects reported a history of MDD. Sixty-nine subjects completed the SCID at baseline and posttreatment. At posttreatment, 5 subjects (7%) met threshold criteria for MDD; none were taking the highest dose of fluoxetine (60 mg), 4 were taking 30 mg, and 1 was taking placebo. All 5 had a history of MDD; 3 were women. Four had a history of substance abuse and attained at least 3 consecutive biochemically verified weeks of smoking abstinence. Those who developed MDD after treatment scored significantly higher on measures of depressed mood at baseline than those who did not develop MDD after smoking-cessation treatment. The results from this descriptive study suggest that a subset of smokers may be at risk for developing MDD after smoking cessation.


Tiazofurine ICN Pharmaceuticals.
Tiazofurine is a nucleoside analog with oncolytic activity being developed by Ribapharm (formerly ICN Pharmaceuticals) as a potential treatment for leukemia. It is metabolized to TAD (thiazole-4-carboxamide adenine dinucleotide), an inhibitor of IMP dehydrogenase. This inhibition results in the reduction of guanylate levels and the halting of neoplastic proliferation. The compound is in phase II/III trials [215553]. It is expected that Ribapharm will file an orphan drug application for tiazofurine, as a treatment for myelogenous leukemia, following the drug's completion of phase III trials by the end of 2002. The company has reported that phase III trials will begin by the end of 2000. Preliminary studies involving 21 patients have been carried out and the results reported by the company. During these studies, seven patients with chronic myelogenous leukemia had a complete hematologic response and two patients had a partial response. Of the patients with a complete response, six had marrow and peripheral responses. Ribapharm, through a Russian subsidiary of ICN, is also planning to conduct phase II studies of tiazofurine involving patients suffering from advanced ovarian cancer or multiple myeloma which is resistant to conventional therapy. The company has reported that the multiple myeloma limited phase II study is still undergoing planning, with an intended start date in late 2000 [381453]. In March 2000, Chase Hambrecht & Quist predicted that first approval could be towards the end of 2001 [384894].


Heritable disorders of oxygen sensing.
Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O2 availability and play critical roles in development, physiology, and disease pathogenesis. Mutations that dysregulate HIF activity are the genetic basis for tumor predisposition in the von Hippel-Lindau syndrome and excess red blood cell production in hereditary erythrocytosis.


The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages.
We use findings from the behavior genetics literature about how genetic factors (latently) influence alcohol dependence and related disorders to develop and test hypotheses about the risk associated with a specific gene, GABRA2, across different developmental stages. This gene has previously been associated with adult alcohol dependence in the Collaborative Study of the Genetics of Alcoholism (COGA) sample [Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O., Crowe, R., Goate, A., Hesselbrock, V., Jones, K. A., Kwon, J., Li, T. K., Nurnberger Jr., J. I., O'Connor, S. J., Reich, T., Rice, J., Schuckit, M., Porjesz, B., Foroud, T., and Begleiter, H. (2004). Am. J. Hum. Genet. 74:705-714] and other studies [Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., and Kranzler, H. R. (2004). Am. J. Med. Genet. B Neuropsychiatr. Genet. 129B:104-109; Lappalainen, J., Krupitsky, E., Remizov, M., Pchelina, S., Taraskina, A., Zvartau, E., Somberg, L. K., Covault, J., Kranzler, H. R., Krystal, J., and Gelernter, J. (2005). Alcohol. Clin. Exp. Res. 29:493-498]. In a sample of children and adolescents ascertained as part of the COGA project, we find that GABRA2 is significantly associated with childhood conduct disorder symptoms, but not with childhood alcohol dependence symptoms. A consistent elevation in risk for alcohol dependence associated with GABRA2 is not evident until the mid-20s and then remains throughout adulthood. GABRA2 is also associated with other drug dependence in our sample, both in adolescence and adulthood.


A resolution of the mutation load paradox in humans.
Current information on the rate of mutation and the fraction of sites in the genome that are subject to selection suggests that each human has received, on average, at least two new harmful mutations from its parents. These mutations were subsequently removed by natural selection through reduced survival or fertility. It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation () for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10's or even 100's of new deleterious mutations per genome each generation.


Role of Patient Maximizing-Minimizing Preferences in Thyroid Cancer Surveillance.
To understand the effect of patient preferences on thyroid cancer surveillance intensity. Eligible patients diagnosed with thyroid cancer between January 1, 2014, and December 31, 2015, from the Georgia and Los Angeles County SEER registries were surveyed between February 2017 and October 2018 (N = 2,632; response rate, 63%). Patient reports on health care utilization in the past year and responses to the validated Medical Maximizer-Minimizer Scale were linked to SEER data in the 2,183 disease-free patients. Ordered logistic regression was performed using a cumulative logit with nonproportional odds. Of disease-free patients, 31.6% were classified as minimizers, 42.5% as moderate maximizers, and 25.9% as strong maximizers. In the past year, 25.2%, 27.3%, and 38.5% of minimizers, moderate maximizers, and strong maximizers, respectively, had ≥ 4 doctor visits, and 18.3%, 24.9%, and 29.5%, respectively, had ≥ 2 neck ultrasounds. When controlling for age, sex, race and ethnicity, comorbidity, stage, and SEER site, strong maximizers (compared with minimizers) were significantly more likely to report ≥ 4 doctor visits (odds ratio [OR], 1.45; 95% CI, 1.10-1.92), ≥ 2 neck ultrasounds (OR, 1.58; 95% CI, 1.17-2.14), ≥ 1 radioactive iodine scan (OR, 1.73; 95% CI, 1.19-2.50), and ≥ 1 additional imaging study (OR, 2.06; 95% CI, 1.56-2.72). Among patients with thyroid cancer who have been declared disease free, preference for a more maximal versus minimal approach to medical care is associated with increased number of physician visits and imaging tests. Because increased surveillance does not clearly correlate with improved outcomes, poses potential risks to patients, and contributes to increased healthcare costs, stronger consideration of the role of patient preferences is necessary when framing discussions on surveillance.


Double-stranded RNA targeting fungal ergosterol biosynthesis pathway controls Botrytis cinerea and postharvest grey mould.
Pathogenic fungi cause major postharvest losses. During storage and ripening, fruit becomes highly susceptible to fungi that cause postharvest disease. Fungicides are effective treatments to limit disease. However, due to increased public concern for their possible side effects, there is a need to develop new strategies to control postharvest fungal pathogens. Botrytis cinerea, a common postharvest pathogen, was shown to uptake small double-stranded RNA (dsRNA) molecules from the host plant. Such dsRNA can regulate gene expression through the RNA interference system. This work aimed to develop a synthetic dsRNA simultaneously targeting three essential transcripts active in the fungal ergosterol biosynthesis pathway (dsRNA-ERG). Our results show initial uptake of dsRNA in the emergence zone of the germination tube that spreads throughout the fungus and results in down-regulation of all three targeted transcripts. Application of dsRNA-ERG decreased B. cinerea germination and growth in in vitro conditions and various fruits, leading to reduce grey-mould decay. The inhibition of growth or decay was reversed by the addition of ergosterol. While dual treatment with dsRNA-ERG and ergosterol-inhibitor fungicide reduced by 100-fold the required amount of fungicide to achieve the same protection rate. The application of dsRNA-ERG induced systemic protection as shown by decreased decay development at inoculation points distant from the treatment point in tomato and pepper fruits. Overall, this study suggests that dsRNA-ERG can effectively control B. cinerea growth and grey-mould development suggesting its efficacy as a future method for postharvest control of fungal pathogens.