Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation.
Metabotropic receptors coupled to Gq/G11 family G proteins critically contribute to nervous system functions by modulating synaptic transmission, often facilitating excitation. We investigated the role of Gq/G11 family G proteins in the regulation of neuronal excitability in mice that selectively lack the alpha-subunits of Gq and G11, G alpha q and G alpha 11, respectively, in forebrain principal neurons. Surprisingly, mutant mice exhibited increased seizure susceptibility, and the activation of neuroprotective mechanisms was impaired. We found that endocannabinoid levels were reduced under both basal and excitotoxic conditions and that increased susceptibility to kainic acid could be normalized by the enhancement of endocannabinoid levels with an endocannabinoid reuptake inhibitor, while the competitive cannabinoid type 1 receptor antagonist SR141716A did not cause further aggravation. These findings indicate that Gq/G11 family G proteins negatively regulate neuronal excitability in vivo and suggest that impaired endocannabinoid formation in the absence of Gq/G11 contributes to this phenotype.


Liquid-liquid/solid three-phase high-speed counter-current chromatography, a new technique for separation of polyphenols from Geranium wilfordii Maxim.
High-speed counter-current chromatography using a new liquid-liquid/solid three-phase system was used for the separation of the polyphenols corilagin and geraniin from a crude extract of Geranium wilfordii Maxim in one step. The optimized three-phase system was composed of n-hexane/ethyl acetate/methanol/acetic acid/water and to which was added 10-μm average diameter microspheres of cross-linked 12% agarose at the ratio of 0.2:10:2:1:5 and 0.1 g/mL, respectively. The purities of geraniin and corilagin were 82 and 90%, which were determined by HPLC at 280 nm. A 14.5 and 7 mg of geraniin and corilagin were purified from 160 mg crude extract with the yields of 70 and 78%, respectively.


Oral insulin in diabetic dogs.
Bovine crystalline insulin, mixed with an absorption enhancer, was loaded by hand into gelatin capsules, which were then coated with an azopolymer designed to deliver the insulin in the upper colon. In 34 experiments with 14 pancreatectomized mongrel dogs of both sexes, the coated capsules were administered orally after a pre-dose period of 1 h. The dogs had cannulae in the portal vein, hepatic vein and femoral artery and Doppler flow probes on the portal vein and hepatic artery. Insulin and food were withdrawn the day before an experiment. Responses measured were plasma glucose, plasma insulin, hepatic glucose production rate, hepatic plasma flow rate and plasma glucagon-like immunoactivity (GLI). Control experiments, with capsules without insulin, produced small changes from 'pre-dose' values. Insulin-containing capsules, without the azopolymer coating, resulted in some early changes consistent with upper gastrointestinal absorption. Single oral doses (66 to 400 nmol/kg) of insulin in completely coated capsules produced peaks of portal plasma insulin and transient decreases in plasma glucose, hepatic glucose production, hepatic plasma flow and plasma GLI. The changes usually began 1.5-2 h after administration of a single dose, and lasted for up to 3 h, but were not significantly related to the dose of insulin. Multiple oral doses of insulin, given at 1.5-h intervals, resulted in multiple peaks of plasma insulin, a continuing dose-dependent fall in plasma glucose to near-euglycaemia with the highest dose, and profound decreases in hepatic glucose production and plasma GLI. These data demonstrate that insulin absorbed from the gastrointestinal tract causes changes in glucose metabolism in the diabetic dog that are consistent with the action of insulin primarily on the liver and that repeated oral doses are necessary to correct the hyperglycaemia.


Brief assessment of diabetes-specific psychological flexibility in racially and income diverse youth with type 1 diabetes.
Diabetes-specific psychological flexibility (the ability to engage in valued behaviors, be open to internal experiences, with present-moment awareness, while living with diabetes) is associated with HbA1c and health-related quality of life in youth with type 1 diabetes (T1D). Having brief diabetes-specific psychological flexibility assessments that perform equivalently across diverse individuals is important for research and clinical work addressing health disparities. The present study aimed to create 9-and 3-item short forms (DAASito-9 and -3) of the Diabetes Acceptance and Action Scale (DAAS-22), and evaluate their validity, reliability, and measurement invariance (MI). Youth with T1D (n = 179, Mage = 14.64, 50% female, 56% Black/African American) completed self-report measures at an endocrinology clinic visit. HbA1c was extracted from medical records. One-half of the sample was used to develop the DAASitos with the highest reliability, McDonald's 𝜔 ≥ 0.75, and convergent validity (r ≥ 0.90 to DASS-22). Confirmatory factor analyses evaluated structural validity. MI was assessed across demographic (race, gender, grade, household income) and disease characteristic (illness duration, HbA1c) groups. Correlations with measures of psychological flexibility assessed additional convergent validity, and latent mean differences across groups were evaluated after confirming MI. MI was supported. The DAASito-9 and -3 were correlated in expected directions with other psychological flexibility measures, HbA1c, and health-related quality of life. The psychometric properties of the DAASito-9 and -3 support their use in research and clinical care of diverse youth with T1D. Significant differences in psychological flexibility across race, income, and glycemic health warrant further research and clinical intervention.


Multidimensional Effects of Solid and Hinged Ankle-Foot Orthosis in Children With Cerebral Palsy.
To compare the effect of solid (SAFO) and hinged (HAFO) ankle-foot orthoses in children with cerebral palsy spastic diplegia and true equinus and jump gait. Participants were 26 children (13 wore SAFO and 13 wore HAFO) aged 4 to 14 years classified as Gross Motor Function Classification System levels I to III. Children were tested on standardized measures of body structure and function, activity, and participation. Children wearing HAFO reached further in standing than those wearing SAFO. Among children who walked without an assistive device, children wearing HAFO had greater stride length and faster velocity. Mean Gross Motor Function Measure and Pediatric Evaluation of Disability Inventory mobility scores did not differ between groups. The cost-to-benefit ratios showed parents preferred HAFO. Among children with true equinus and jump gait, the effects of HAFO were greater in children who walked without an assistive mobility device.


Nutritional intervention influences the bottom line.
Clinical nutrition professionals can influence hospital operating margins by the way they respond to patients who are at risk for protein-calorie malnutrition. Early nutritional intervention can reduce costs associated with at-risk patients, while appropriate documentation and billing can increase revenue from government and private payers.


[Research of influence of stress immobolization on relative mass of reproductive and immunocompetent organs of young and old rats].
Research of influence of stress immobilization on relative mass of reproductive and immunocompetent organs of young and old rats was carried out. The study of age features of correction by alpha-tocopherol of the peroxidation lipid (POL) stress deviations was realized. Specific answer of researched organs and age differences for stress effects was revealed. Tissue and age differences between a physiological level of POL at intact rats, and its change at stress animals fixed. Suppression of POL processes intensity against a background preliminary vitamin E injection and its combination with extreme effects specifies its protective action especially expressed in a liver. Results of researches show the large stress-resistance at young animals and the expressed damaging action of an stress at old animals.


Product distribution from the fast pyrolysis of hemicellulose.
Hemicellulose is one of the major constituents of biomass. Surprisingly, only very limited information regarding its product distribution under fast pyrolysis conditions is available in the literature. In the present study, a combination of several analytical techniques, including micro-pyrolyzer-GC-MS/FID, gas analysis, and capillary electrophoresis, were used to study the primary pyrolysis product distribution of hemicelluloses extracted and purified from switchgrass. A total of 16 products were identified and quantified, which accounted for 85% of the overall mass balance. The pyrolysis behavior of hemicellulose was found to be considerably different than cellulose and was explained on the basis of a proposed mechanism for glycosidic bond cleavage. Further, the effect of minerals and temperature was investigated. The study provides insight into the fast pyrolysis behavior of hemicellulose and provides a basis for developing models that can predict bio-oil composition resulting from overall biomass fast pyrolysis.


[Langerhans cell histiocytosis in anogenital region].
The Langerhans cell histiocytosis (LCH) of the genital tract is rare, with only 48 cases related in the literature. There were reported only 2 cases in the anogenital region. We reported the third case of LCH in the anogenital region; patient was female, 31 years-old, caucasian and the diagnosis was confirmed by electron microscopic magnification. The treatment was local surgical excision and systemic chemotherapy.


[Genetic obesity: new diagnostic options].
- Obesity is an important risk factor for morbidity and premature death, as well as a contributing factor to psychosocial problems. The incidence of obesity has increased dramatically over the last few decades.- Obesity is considered to be a multifactorial condition in which both environmental factors and genetic factors play a part.- In approximately 5% of patients with morbid obesity, a monogenic cause can be identified. Mutations in the MC4R gene are the most frequently occurring monogenic cause of obesity.- The department of Genetics at the VU University Medical Center Amsterdam offers morbidly obese patients a diagnostic analysis of 50 obesity-associated genes. - An underlying obesity-associated genetic defect can influence patient response to certain treatments. Therefore, if the gene defect is known, it can be taken into account when considering treatment options.- The understanding of the genetics of obesity will significantly contribute to research into the development of personalized treatment options.


Timeliness of childhood vaccination in the Federated States of Micronesia.
Vaccination coverage is typically measured as the proportion of individuals who have received recommended vaccine doses by the date of assessment. This approach does not provide information about receipt of vaccines by the recommended age, which is critical for ensuring optimal protection from vaccine-preventable diseases (VPDs). To assess vaccination timeliness in the Federated States of Micronesia (FSM), and the projected impact of suboptimal vaccination in the event of an outbreak. Timeliness of the 4th dose of diphtheria, tetanus, and acellular pertussis vaccine (DTaP) and 1st dose of measles, mumps, and rubella vaccine (MMR) among children 24-35 months was assessed in FSM. Both doses are defined as on time if administered from 361 through 395 days in age. Timeliness was calculated by one-way frequency analysis, and dose delays, measured in months after recommended age, were described using inverse Kaplan-Meier analysis. A time-series susceptible-exposed-infected-recovery (TSEIR) model simulated measles outbreaks in populations with on time and late vaccination. Total coverage for the 4th dose of DTaP ranged from 36.6% to 98.8%, and for the 1st dose of MMR ranged from 80.9% to 100.0% across FSM states. On time coverage for the 4th dose of DTaP ranged from 3.2% to 52.3%, and for the 1st dose of MMR ranged from 21.1% to 66.9%. Maximum and median dose delays beyond the recommended age varied by state. TSEIR models predicted 10.8-13.7% increases in measles cases during an outbreak based on these delays. In each of the FSM states, a substantial proportion of children received DTaP and MMR doses outside the recommended timeframe. Children who receive vaccinations later than recommended remain susceptible to VPDs during the period they remain unvaccinated, which may have a substantial impact on health systems during an outbreak. Immunization programs should consider vaccination timeliness in addition to coverage as a measure of susceptibility to VPDs in young children.


Ageing in a eusocial insect: molecular and physiological characteristics of life span plasticity in the honey bee.
Commonly held views assume that ageing, or senescence, represents an inevitable, passive, and random decline in function that is strongly linked to chronological age. In recent years, genetic intervention of life span regulating pathways, for example, in Drosophila as well as case studies in non-classical animal models, have provided compelling evidence to challenge these views.Rather than comprehensively revisiting studies on the established genetic model systems of ageing, we here focus on an alternative model organism with a wild type (unselected genotype) characterized by a unique diversity in longevity - the honey bee.Honey bee (Apis mellifera) life span varies from a few weeks to more than 2 years. This plasticity is largely controlled by environmental factors. Thereby, although individuals are closely related genetically, distinct life histories can emerge as a function of social environmental change.Another remarkable feature of the honey bee is the occurrence of reverted behavioural ontogeny in the worker (female helper) caste. This behavioural peculiarity is associated with alterations in somatic maintenance functions that are indicative of reverted senescence. Thus, although intraspecific variation in organismal life span is not uncommon, the honey bee holds great promise for gaining insights into regulatory pathways that can shape the time-course of ageing by delaying, halting or even reversing processes of senescence. These aspects provide the setting of our review.We will highlight comparative findings from Drosophila melanogaster and Caenorhabditis elegans in particular, and focus on knowledge spanning from molecular- to behavioural-senescence to elucidate how the honey bee can contribute to novel insights into regulatory mechanisms that underlie plasticity and robustness or irreversibility in ageing.


Exploring the relationship between ethics committees and the wound care clinician.
Ethics Committees have gained increasing popularity since the mid-1970s. This is likely due to the recognized need to more openly discuss the legal and ethical issues of clinicians and their patients. Wound care clinicians play an important role in the interdisciplinary care of the patient. The typical framework of a hospital-based Ethics Committee is described, Ethics Committees as a resource to the wound care clinician is presented, and the role of the wound care clinician as a consultant to the Ethics Committee, from an interdisciplinary perspective, is illustrated.


Effects of in ovo injection of electrolyte solutions on the pre- and posthatch physiological characteristics of broilers.
Effects of the automated in ovo injection of various concentrations and volumes of physiological electrolyte solutions and a carbohydrate-electrolyte solution (CEN) on broiler embryo development and posthatch chick performance were investigated in 5 individual consecutive trials to test potential diluents for commercial injection. A 200-µL saline solution (117 mM) injection treatment and a noninjected control were included in all trials. For the first 4 trials, solutions were injected into the amnion of embryos on d 16 of incubation, and subsequent percentage incubational egg weight loss, embryo mortality, proportional embryo BW, embryo moisture content, proportional yolk sac weight, and yolk moisture content were evaluated on d 18. In trial 5, solutions were injected into the amnion on d 18, and subsequent hatchability and posthatch performance were investigated. In trial 1, a 200-μL injection of 5 mM tripotassium citrate (C(6)H(5)K(3)O(7)) and a 200-μL injection of CEN at 1:400 and 1:8,000 concentrations had no detrimental effect on proportional embryo BW. However, embryo moisture content was increased by the injection of either solution at all concentrations. In trial 2, 200-μL injections of saline, potassium chloride (KCl), or sodium dihydrogen phosphate (NaH(2)PO(4)) solution at various physiological concentrations did not affect any of the parameters examined. In trial 3, the injection of 2,000 µL of 117 mM saline reduced 0 to 18 d percentage egg weight loss. In trial 4, percentage egg weight loss was reduced and embryo moisture was increased by a 200-μL saline (117 mM) injection, but not by 200 μL of solutions of CEN (1:400), C(6)H(5)K(3)O(7) (5.0 mM), or NaH(2)PO(4) (1.0 mM) in 5.5 mM KCl. Compared with controls in trial 5, plasma refractive index was increased by CEN-KCl (1:400-5.5 mM) and saline (117 mM) injections, but not by C(6)H(5)K(3)O(7)-KCl (5 mM-5.5 mM). The current study indicated that 5.5 mM KCl and 5 mM C(6)H(5)K(3)O(7) have the greatest potential for use individually or in combination for the commercial injection of broiler hatching eggs.


Invited Commentary: Drug Checking for Novel Insights Into the Unregulated Drug Supply.
Tobias et al. (Am J Epidemiol. 2022;191 (2):241-247) present a novel analysis of time trends in fentanyl concentrations in the unregulated drug supply in British Columbia, Canada. The preexisting knowledge about unregulated drugs had come from law-enforcement seizures and postmortem toxicology. As both of these data sources are subject to selection bias, large-scale drug-checking programs are poised to be a crucial component of the public health response to the unrelenting increase in overdose in North America. As programs expand, we offer 2 guiding principles. First, the primary purpose of these programs is to deliver timely results to people who use drugs to mitigate health risks. Second, innovation is needed to go beyond criminal justice paradigms in laboratory analysis for a more nuanced understanding of health concerns. We provide examples of the role adulterants play in our understanding of drug harms. We also describe the applications and limitations of common laboratory assays, with implications for epidemiologic surveillance. While the research and direct service teams in British Columbia have taken groundbreaking steps, there is still a need to establish best practices for communicating results to sample donors in an approachable yet nonalarmist tone.


A cost-analysis comparison of laparoscopic radical prostatectomy versus open radical prostatectomy: the McMaster Institute of Urology experience.
The objective of this study was to identify and compare the costs of laparoscopic radical prostatectomy (LRP) and radical retropubic prostatectomy (RRP) at our centre. We conducted a retrospective chart review of our first 70 consecutive LRP cases and 70 consecutive RRP cases at St. Joseph's Healthcare in Hamilton, Ontario, Canada. We performed cost analysis, including operating room costs, disposable instruments, blood transfusions, analgesic requirements and length of hospital stay. Overall expenses were then analyzed and compared. Preoperative patient demographics and disease stages were comparable between the LRP and RRP groups. On a per procedure basis, large discrepancies were found in mean disposable instrument costs (LRP = $659.18 vs. RRP = $236.59), operating room costs (LRP = $4278.00 vs. RRP = $3139.00), mean cost of blood transfusions (LRP = $21.00 vs. RRP = $394.34), mean analgesia requirements (LRP = $12.94 vs. RRP = $41.06) and mean hospital stay bed costs (LRP = $3690.00 vs. RRP = $5027.14). Overall, costs for all patients in the LRP and RRP groups, respectively, were $606 307.29 and $618 721.57 with a cost saving of $12 414.28 in favour of the LRP arm. At our institution, we found that LRP costs are slightly less than those for RRP. Higher operative time and disposable instrument expenses are offset by the shorter hospital stays, fewer blood transfusions and less analgesic requirements for the LRP group. Further financial advantages for LRP will likely be achieved with additional reduction of operating room time and by minimizing disposables.


Aberrant expression of a hemidesmosomal protein, bullous pemphigoid antigen 2, in human squamous cell carcinoma.
Through yet unidentified mechanisms, squamous epithelial cells become committed to terminal differentiation after detachment from the basement membrane. In squamous cell carcinoma, these mechanisms seem to be disturbed. A murine monoclonal antibody, designated NCC-Lu-226 (IgG1, K), which recognizes an antigen expressed in basal cells of squamous epithelium at the epithelio-connective tissue border, was obtained. A cDNA clone encoding the antigen was isolated from a cDNA library by immunoselection. DNA sequencing and a database search revealed that this cDNA clone was identical to a hemidesmosomal transmembrane protein, bullous pemphigoid antigen 2 (BPA-2; also known as BPAG2, BP180, or type XVII collagen). Immunoelectron microscopy validated the specific reactivity of this monoclonal antibody with skin hemidesmosomes. Enhanced expression and abnormal distribution of BPA-2 was revealed immunohistochemically in various precancerous and cancerous tissues, including solar keratosis (4 of 5), Bowen's disease (3 of 5), invasive squamous cell carcinoma (7 of 7) of the skin, and squamous cell carcinoma of the lung (14 of 14), esophagus (12 of 13), and cervix (14 of 17). The specific expression of BPA-2 protein in squamous cell carcinoma was confirmed by RT-PCR and Northern hybridization. BPA-2 has possible phosphorylation sites and is actually phosphorylated in cultured keratinocytes and squamous cell carcinoma. The aberrant expression of BPA-2 may reflect dysfunction of the hemidesmosome that occurs as a relatively early event in multistep carcinogenesis of squamous epithelium.


Prevalence of varicose veins of the lower limbs in the women working at a department store.
The prevalence of varicose veins of the lower limbs and their risk factors were investigated in the group of 696 women working at a large department store. It was found that 421 of them suffered from varicose veins with the following prevalence of individual clinical types: trunk varices--14.4%, reticular varices--15.4%, and hyphenwebs--30.7%. In our study women with VV of all types compared to women without VV were older (p less than 0.05), more often obese (p less than 0.05), had the positive family history for VV (p less than 0.01), higher systolic and diastolic blood pressure and lower levels of physical activity (not significantly). Women with at least one pregnancy had significantly higher prevalence of VV (p less than 0.001) and women standing at their work had a higher prevalence of trunk varices than those who were sitting at the work (p less than 0.05).


Comparison of multiplex PCR with serogrouping and PCR-RFLP of fliC gene for the detection of enteropathogenic Escherichia coli (EPEC).
Enteropathogenic Escherichia coli (EPEC) comprise one of the six categories of diarrhoeagenic E. coli (DEC). EPEC is subgrouped into typical (tEPEC) and atypical (aEPEC). The identification of DEC cannot be based only on cultural and biochemical criteria, since they are indistinguishable from the non-pathogenic E. coli commonly found in human feces. Several PCR methods, with both single and multiple target genes, have been reported for detecting the different DEC pathotypes. In the present study five hundred E. coli isolates from children with diarrhea were subjected into multiplex PCR. Furthermore the strains were typed serologically with O antisera and their fliC gene was characterized by PCR-RFLP. The results obtained revealed that overall 41 (8.2%) isolates could be detected as EPEC by this multiplex PCR assay. Of these isolates; 27 (66%) were typical (escv+, bfp+) and 14 (34%) atypical EPEC (escv+, bfp-). None of these 41 isolates contained the Stx1 and Stx2 genes. Among 37 (90%) typeable strains, nine different serogroups were present. The most common serogroups were O111, followed by O86, O55 and O119 and 10 different H types were found among these isolates. The multiplex PCR assay was found to be rapid and reliable in comparison to serological test; especially when screening the large number of isolates.


Dot pattern processing using voronoi neighborhoods.
A sound notion of the neighborhood of a point is essential for analyzing dot patterns. The past work in this direction has concentrated on identifying pairs of points that are neighbors. Examples of such methods include those based on a fixed radius, k-nearest neighbors, minimal spanning tree, relative neighborhood graph, and the Gabriel graph. This correspondence considers the use of the region enclosed by a point's Voronoi polygon as its neighborhood. It is argued that the Voronoi polygons possess intuitively appealing characteristics, as would be expected from the neighborhood of a point. Geometrical characteristics of the Voronoi neighborhood are used as features in dot pattern processing. Procedures for segmentation, matching, and perceptual border extraction using the Voronoi neighborhood are outlined. Extensions of the Voronoi definition to other domains are discussed.


A wild wolf attack and its unfortunate outcome: rabies and death.
Wild animal attacks are potential occurrences in rural areas of Turkey. Wolf attacks, however, are rare this century, but there are many anecdotal reports from previous times. Attacks by wolves are generally directed against animals, such as cows and sheep, and for feeding purposes. Wolf attacks on humans are a little known and unexpected phenomenon. A 60-year-old man was brought to the emergency department with facial injuries caused by a wolf emerging from a rural area and leaping at his face as he was sitting in his garden. During the incident, the patient strangled the wolf to death. Despite postexposure prophylaxis the patient likely died because of rabies.


The association between blood pressure and long-term outcomes of patients with ischaemic cardiomyopathy with and without surgical revascularization: an analysis of the STICH trial.
Hypertension (HTN) is a well-known contributor to cardiovascular disease, including heart failure (HF) and coronary artery disease, and is the leading risk factor for premature death world-wide. A J- or U-shaped relationship has been suggested between blood pressure (BP) and clinical outcomes in different studies. However, there is little information about the significance of BP on the outcomes of patients with coronary artery disease and left ventricular dysfunction. This study aimed to determine the relationship between BP and mortality outcomes in patients with ischaemic cardiomyopathy. The influence of BP during a median follow-up of 9.8 years was studied in a total of 1212 patients with ejection fraction ≤35% and coronary disease amenable to coronary artery bypass grafting (CABG) who were randomized to CABG or medical therapy alone (MED) in the STICH (Surgical Treatment for Ischaemic Heart Failure) trial. Landmark analyses were performed starting at 1, 2, 3, 4, and 5 years after randomization, in which previous systolic BP values were averaged and related to subsequent mortality through the end of follow-up with a median of 9.8 years. Neither a previous history of HTN nor baseline BP had any significant influence on long-term mortality outcomes, nor did they have a significant interaction with MED or CABG treatment. The landmark analyses showed a progressive U-shaped relationship that became strongest at 5 years (χ2 and P-values: 7.08, P = 0.069; 8.72, P = 0.033; 9.86; P = 0.020; 8.31, P = 0.040; 14.52, P = 0.002; at 1, 2, 3, 4, and 5-year landmark analyses, respectively). The relationship between diastolic BP (DBP) and outcomes was similar. The most favourable outcomes were observed in the SBP range 120-130, and DBP 75-85 mmHg, whereas lower and higher BP were associated with worse outcomes. There were no differences in BP-lowering medications between groups. A strong U-shaped relationship between BP and mortality outcomes was evident in ischaemic HF patients. The results imply that the optimal SBP might be in the range 120-130 mmHg after intervention, and possibly be subject to pharmacologic action regarding high BP. Further, low BP was a marker of poor outcomes that might require other interactions and treatment strategies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.


Wastewater network infrastructure in public health: Applications and learnings from the COVID-19 pandemic.
Accurate estimates of COVID-19 burden of infections in communities can inform public health strategy for the current pandemic. Wastewater based epidemiology (WBE) leverages sewer infrastructure to provide insights on rates of infection by measuring viral concentrations in wastewater. By accessing the sewer network at various junctures, important insights regarding COVID-19 disease activity can be gained. The analysis of sewage at the wastewater treatment plant level enables population-level surveillance of disease trends and virus mutations. At the neighborhood level, WBE can be used to describe trends in infection rates in the community thereby facilitating local efforts at targeted disease mitigation. Finally, at the building level, WBE can suggest the presence of infections and prompt individual testing. In this critical review, we describe the types of data that can be obtained through varying levels of WBE analysis, concrete plans for implementation, and public health actions that can be taken based on WBE surveillance data of infectious diseases, using recent and successful applications of WBE during the COVID-19 pandemic for illustration.


Antibody testing as a diagnostic tool in autonomic disorders.
Some forms of peripheral autonomic dysfunction (especially enteric neuropathy and subacute panautonomic failure) occur as autoimmune phenomena either in isolation or in the context of cancer. Autoimmune autonomic ganglionopathy is an example of a severe, but potentially treatable, antibody-mediated form of autonomic failure. Diagnostic evaluation of autonomic disorders can be supplemented by testing for paraneoplastic antibodies and antibodies against membrane receptors. The diagnostic antibodies most commonly associated with dysautonomia are paraneoplastic antibodies (anti-Hu and CRMP-5) and ganglionic acetylcholine receptor antibodies.


Novel Approaches to Hasten Detection of Pathogens and Antimicrobial Resistance in the Intensive Care Unit.
Antibiotic resistance is recognized as a key determinant of outcome in patients with serious infections influencing empiric antibiotic practices especially for critically ill patients. Within the intensive care unit (ICU), nosocomial infections and increasingly community-onset infections are caused by multidrug-resistant bacteria. Escalating rates of antibiotic resistance adds substantially to the morbidity, mortality, and cost related to infections treated in the ICU. Both gram-positive organisms, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter species, carbapenem-resistant Enterobacteriaceae, and extended spectrum β-lactamase producing organisms, are urgent threats. The rising rates of antimicrobial resistance have resulted in routine empiric administration of broad-spectrum antibiotics by clinicians to critically ill patients even when bacterial infection is microbiologically absent. Moreover, new broad-spectrum antibiotics are a challenge to use effectively while avoiding emergence of further resistance. Use of rapid diagnostic technologies (RDTs) will likely provide an important methodology for achieving this important balance. There is an urgent need for integrating the administration of new and existing antibiotics with RDTs in a way that is safe, cost-effective, applicable in all countries, and sustainable.


Enabling nursing students to focus on the Ottawa Charter and the nurses role in tackling inequalities in health through international exchange.
Student nurses in a transatlantic exchange program explored the role of registered nurses in five countries' public health systems. The Ottawa Charter provided a framework for students to examine the nurse's responsibilities in public health. Students took practice placements in geographically rural a reason another continent and explored inequalities in health care. If nurses are to understand their role in the health care system then they must be taught the scope of their practice including their role in health promotion,public health practice and community development. For this project nursing instructors developed an assignment relevant to the aims and suitable for students in all five nursing programs. Only three of 48 students offered an assignment which focused on building healthy public policy. Nurse educators need to explore this further to ensure nurses of the future are aware of their role and responsibilities in this area and have skills to work effectively to influence and build healthy policy. The international student exchange supported the students' developing understanding of the breadth of initiatives around the globe where nurses are actively engaged in addressing inequalities of health. Findings from an analysis of their assignments are presented in this evaluative report.


Sexual satisfaction among married women age 50 and older.
Correlates of sexual satisfaction were identified in a sample of older married women. A 70-item questionnaire was mailed to an age-stratified sample of 5,000 married persons, including 1,000 married women over the age of 50. Usable questionnaires were received from 148 participants (14.8% return rate). Hierarchical multiple regression analysis, using sexual satisfaction as the dependent variable, yielded five predictor variables that accounted for a significant portion of the variation in sexual satisfaction (Cumulative R2 = .73). These results serve as a reminder that sexual interactions cannot be compartmentalized but must be considered within the context of the overall marriage relationship. Given the low return rate, interpretations should be limited until replication with an adequate sample has been completed.


Faster recovery in central than in peripheral auditory system following a reversible cochlear deafferentation.
Included among the exciting findings in auditory neuroscience are (i) central plasticity after peripheral injury and (ii) regeneration of auditory nerve fibres following excitotoxic damage. The present study extends our understanding of auditory system plasticity by examining changes in peripheral and central physiology as the cochlea recovers from temporary deafferentation due to excitotoxicity. Application of kainic acid (60 mM) to the round window membrane substantially depressed responses from both auditory nerve and brain stem (inferior colliculus), without affecting distortion-product otoacoustic emissions from the inner ear. The auditory nerve input/output functions recovered over a 30-day period whereas recovery of brainstem response amplitudes occurred within five days. In contrast to amplitudes, thresholds at both peripheral and central levels recovered simultaneously, within five days after kainic acid application. The results indicate that (i) cochlear afferent neurons can recover after excitotoxic damage; (ii) response threshold itself, either central or peripheral, is not sufficient to assess the integrity of the auditory periphery; (iii) the central auditory system can recover more rapidly than the periphery; and (iv) the system can maintain its function in the normal range as peripheral function continues to improve.


High Incidence of Chikungunya Virus and Frequency of Viremic Blood Donations during Epidemic, Puerto Rico, USA, 2014.
Chikungunya virus (CHIKV) caused large epidemics throughout the Caribbean in 2014. We conducted nucleic acid amplification testing (NAAT) for CHIKV RNA (n = 29,695) and serologic testing for IgG against CHIKV (n = 1,232) in archived blood donor samples collected during and after an epidemic in Puerto Rico in 2014. NAAT yields peaked in October with 2.1% of donations positive for CHIKV RNA. A total of 14% of NAAT-reactive donations posed a high risk for virus transmission by transfusion because of high virus RNA copy numbers (10 (4) -10 (9) RNA copies/mL) and a lack of specific IgM and IgG responses. Testing of minipools of 16 donations would not have detected 62.5% of RNA-positive donations detectable by individual donor testing, including individual donations without IgM and IgG. Serosurveys before and after the epidemic demonstrated that nearly 25% of blood donors in Puerto Rico acquired CHIKV infections and seroconverted during the epidemic.


A guide for monitoring child development in low- and middle-income countries.
In low- and middle-income countries, methods for clinicians to address difficulties in language, social-emotional, cognitive, behavioral, or neuromotor development during early childhood are lacking. To fill this gap, we designed, in Turkey, the Guide for Monitoring Child Development, which aims to aid clinicians in monitoring and supporting child development and the early detection and management of developmental difficulties. The Guide for Monitoring Child Development monitoring component is a practical, open-ended interview that catalyzes communication between clinicians and caregivers and obtains a portrayal of the child's development. We report on the development and psychometric properties of the Guide for Monitoring Child Development monitoring component for children aged 0 to 24 months. We examined the ages of attainment of Guide for Monitoring Child Development milestones and internal consistency in a cross-sectional study of healthy children receiving well-child care (study 1). In 2 clinical samples, we studied the interrater reliability between medical students and a child development specialist administering the guide (study 2), as well as the concurrent validity of the guide administered during a health visit and a comprehensive developmental assessment (study 3). In study 1 (N = 510), item-total scale correlations ranged from 0.28 to 0.91. An age-dependent attainment pattern was seen in all of the milestones. In study 2 (N = 92), interrater reliability between medical-student pairs and between the child development specialist and students was high (kappa scores were 0.83-0.88). In study 3 (N = 79), the sensitivity, specificity, and positive and negative predictive values were 0.88, 0.93, 0.84, and 0.94, respectively. The Guide for Monitoring Child Development is an innovative method for monitoring child development that is designed specifically for use by health care providers in low- and middle-income countries. Studies in Turkey provide preliminary evidence for its reliability and validity.


Sildenafil citrate after radical retropubic prostatectomy.
Erectile dysfunction continues to be a significant problem for men after radical retropubic prostatectomy despite nerve sparing techniques. Sildenafil citrate (Viagra) has proved effective for erectile dysfunction in many men. We determine the efficacy of sildenafil in men with erectile dysfunction after radical retropubic prostatectomy and examine variables that may impact the response to treatment. A total of 84 men were prescribed sildenafil after radical retropubic prostatectomy and asked to complete a series of questionnaires, including the International Index of Erectile Function (IIEF), on erectile function before and after sildenafil administration. The importance of factors, such as patient age, time since surgery, degree of cavernous nerve sparing, preoperative prostate specific antigen, Gleason score, clinical and pathological stage, and baseline postoperative erectile function, was examined. Of the 84 patients 45 (53%) had improved erections and 34 (40%) had improved ability for intercourse while taking sildenafil. Mean IIEF score for the erectile function domain increased from 9 to 14 (p <0.001). Orgasmic function (p = 0.004) and intercourse satisfaction (p = 0.009) also significantly improved. The degree of nerve sparing and baseline postoperative erectile dysfunction had a significant impact on the ability of sildenafil to improve erectile function (p = 0.010 and p <0.001, respectively) and total IIEF questionnaire responses (p = 0.031 and p <0.001, respectively). Age and pathological stage also appeared to have a significant effect. Sildenafil improved erectile function and the ability to have intercourse in more than half of men after radical retropubic prostatectomy. Baseline postoperative erectile function, which is dependent on the degree of nerve sparing technique, significantly impacts the likelihood that patients will respond to sildenafil.


Reconstruction of a large external hemipelvectomy defect after chordoma resection using a 5-component chimeric rotational flap.
Management of complex lumbosacral neoplastic disease presents unique challenges and requires a multidisciplinary approach. Large pelvic tumors may require external hemipelvectomy where an entire lower extremity including the hemipelvis is removed with disarticulation of the sacroiliac joint and symphysis pubis. When external hemipelvectomy is performed, the reconstructive surgeon must consider osseous reconstruction for structural pelvic support, the elimination of dead space, protection of implanted hardware, intra-abdominal support, and skin coverage. Reconstruction must minimize wound healing morbidity, operative time and the number of operative sites, and maximize the potential for rehabilitation. We present a case demonstrating use of a rotational chimeric flap for the reconstruction of an external hemipelvectomy defect.


Systematic Comparison of the Structural and Dynamic Properties of Commonly Used Water Models for Molecular Dynamics Simulations.
Water is a unique solvent that is ubiquitous in biology and present in a variety of solutions, mixtures, and materials settings. It therefore forms the basis for all molecular dynamics simulations of biological phenomena, as well as for many chemical, industrial, and materials investigations. Over the years, many water models have been developed, and it remains a challenge to find a single water model that accurately reproduces all experimental properties of water simultaneously. Here, we report a comprehensive comparison of structural and dynamic properties of 30 commonly used 3-point, 4-point, 5-point, and polarizable water models simulated using consistent settings and analysis methods. For the properties of density, coordination number, surface tension, dielectric constant, self-diffusion coefficient, and solvation free energy of methane, models published within the past two decades consistently show better agreement with experimental values compared to models published earlier, albeit with some notable exceptions. However, no single model reproduced all experimental values exactly, highlighting the need to carefully choose a water model for a particular study, depending on the phenomena of interest. Finally, machine learning algorithms quantified the relationship between the water model force field parameters and the resulting bulk properties, providing insight into the parameter-property relationship and illustrating the challenges of developing a water model that can accurately reproduce all properties of water simultaneously.


Renal involvement follows cardiac enlargement in essential hypertension.
To assess the relationship between early clinically detectable involvement of hypertensive vascular disease in heart and kidneys, we obtained systemic and renal hemodynamic and M-mode echocardiographic measurements in 65 patients with essential hypertension. The results indicate that patients with and without left ventricular hypertrophy had similar renal hemodynamic findings. In contrast, patients with altered renal hemodynamic measurements (ie, reduced renal distribution of cardiac output and, therefore, absolute renal blood flow with increased renal vascular resistance) and increased serum uric acid levels also had increased left ventricular posterior and septal wall thicknesses and mass index. Moreover, these data also demonstrated that in patients with altered renal hemodynamics, the lower the renal distribution of cardiac output and the higher the serum uric acid levels, the greater were the indexes of cardiac enlargement. These results demonstrated that the pathophysiological and hemodynamic effects of essential hypertension in the heart precede those in the kidneys.


Renin-Angiotensin-Aldosterone Profiles in Pregnant Women With Chronic Hypertension.
Pregnant women with chronic hypertension are at risk for increased blood pressure and superimposed preeclampsia (SPE) in late pregnancy. Alterations in the renin-aldosterone system are a feature of normal pregnancy; however, their role in chronic hypertension with and without SPE is less clear. We performed a prospective, longitudinal trial of 108 women with chronic hypertension and measured plasma renin activity (PRA), 24-hour urine sodium, urine potassium, and urine aldosterone (Ualdo) at 12, 20, 28, and 36 weeks and postpartum. SPE developed in 34% of pregnancies. PRA was lower in women who developed SPE at weeks 28 (5.99 versus 6.22 ng/mL per hour; P<0.001) and 36 (5.71 versus 7.74 ng/mL per hour; P=0.002). Ualdo was lower in women with SPE compared with those without SPE at 28 weeks (59.6 versus 81.3 μg/d; P=0.039). Mean arterial pressure was inversely related to both PRA (r=-0.23; P<0.0001) and Ualdo (r=-0.11; P=0.029). PRA and Ualdo were positively associated with each other (r=0.5327; P<0.0001) after adjusting for urine potassium, urine sodium, serum potassium, and mean arterial pressure. PRA and Ualdo were lower in women of black race compared with other racial groups (P<0.001). Our results demonstrate that in women with chronic hypertension PRA and Ualdo increase in early pregnancy and subsequently decrease in women who develop SPE. These findings are consistent with the hypothesis that sodium retention may contribute to the elevation in blood pressure in SPE.


Absolute survival after cardiac resynchronization therapy according to baseline QRS duration: a multinational 10-year experience: data from the Multicenter International CRT Study.
In the major trials of cardiac resynchronization therapy (CRT), the survival benefit of the therapy, relative to control subjects, increases with QRS duration. In the non-CRT heart failure population, however, a wide QRS duration is associated with a shorter survival. Relative survival benefit from a therapy, however, is not synonymous with a longer absolute survival. We sought to determine whether baseline QRS duration relates to the absolute survival after CRT. In this prospective, longitudinal, observational study, 3,319 consecutive patients undergoing CRT (QRS 120-149 ms 26%, QRS 150-199 ms 58%, and QRS ≥200 ms 16%) were assessed in relation to mortality over 10 years. Overall mortality rates (per 100 patient-years) were 9.2%, 9.3%, and 13.3% in the 3 groups, respectively (all P < .001). Cardiac mortality rates were 6.2, 6.0, and 9.9 per 100 patient-years, respectively (all P < .001). Compared with the QRS 120-149 ms group, cardiac mortality was highest in the QRS ≥200 ms group (hazard ratio [HR] 1.72 [95% CI 1.35-2.19], P < .001), independent of age, gender, New York Heart Association class, presence of atrial fibrillation, heart failure etiology, and left ventricular ejection fraction. Median survival after CRT was longest in patients with a width of QRS 120-149 ms and shortest in patients with a QRS ≥200 ms (P < .001). In multivariable analyses, a QRS ≥200 ms emerged as a powerful independent predictor of both overall (HR 1.44 [95% CI 1.07-1.94], P = .017) and cardiac mortality (HR 1.59 [95% CI 1.14-2.24], P = .007). At long-term follow-up, absolute overall and cardiac survival after CRT is similar in patients with a preimplant QRS duration of 120 to 149 ms and 150 to 199 ms but markedly shorter in patients with a QRS ≥200 ms.


Early sepsis bundle compliance for non-hypotensive patients with intermediate versus severe hyperlactemia.
To compare the association of 3-h sepsis bundle compliance with hospital mortality in non-hypotensive sepsis patients with intermediate versus severe hyperlactemia. This was a cohort study of all non-hypotensive, hyperlactemic sepsis patients captured in a prospective quality-improvement database, treated October 2014 to September 2015 at five tertiary-care centers. We defined sepsis as 1) infection, 2) ≥2 SIRS criteria, and 3) ≥1 organ dysfunction criterion. "Time-zero" was the first time a patient met all sepsis criteria. systolic blood pressure>90 mmHg, mean arterial pressure>65 mmHg, and serum lactate≥2.2 mmol/L. Primary exposures: 1) intermediate(2.2-3.9 mmol/L) versus severe(≥4.0 mmol/L) hyperlactemia and 2) full 3-h bundle compliance. Bundle elements: The primary outcome was 60-day in-hospital mortality. 2417 patients met inclusion criteria. 704(29%) had lactate≥4.0 mmol/L versus 1775 patients with lactate 2.2-3.9 mmol/L. Compliance was 75% for antibiotics and 53% for fluids. Full-compliance was comparable between lactate groups (n=200(29%) and 488(28%), respectively). We observed 424(17.5%) mortalities: intermediate/non-compliant - 182(14.9%), intermediate/compliant - 41(8.4%), severe/non-compliant - 147(29.2%), severe/compliant - 54(27.0%) [difference-of-differences=4.3%, CI=2.6-5.9%]. In multivariable regression, mortality predictors included severe hyperlactemia (OR=1.99, CI=1.51-2.63) and bundle compliance (OR=0.62, CI=0.42-0.90), and their interaction was significant: p(interaction)=0.022. We observed a significant interaction between 3-h bundle compliance and initial hyperlactemia. Bundle compliance may be associated with greater mortality benefit for non-hypotensive sepsis patients with less severe hyperlactemia.


Lost in translation: methodological considerations in cross-cultural research.
In cross-cultural child development research there is often a need to translate instruments and instructions to languages other than English. Typically, the translation process focuses on ensuring linguistic equivalence. However, establishment of linguistic equivalence through translation techniques is often not sufficient to guard against validity threats. In addition to linguistic equivalence, functional equivalence, cultural equivalence, and metric equivalence are factors that need to be considered when research methods are translated to other languages. This article first examines cross-cultural threats to validity in research. Next, each of the preceding factors is illustrated with examples from the literature. Finally, suggestions for incorporating each factor into research studies of child development are given.


Thyroid hormone specifically inhibits prolactin synthesis and decreases prolactin messenger ribonucleic acid levels in cultured pituitary cells.
Electrophoretic analysis of soluble proteins from pituitary cells pulse labeled with [35S]methionine demonstrated that 10 nM T3 inhibited PRL synthesis, but did not affect the synthesis of most other pituitary proteins. The effects of T3 were somewhat slow, requiring about 3 days for a 50% reduction in PRL synthesis. PRL synthesis slowly returned toward control levels after the removal of T3 from the culture medium. In serum-free medium, a concentration of about 0.6 nM T3 was required for half-maximal inhibition of PRL synthesis. In medium containing 5% fetal calf serum, only slightly higher concentrations of T3 were required to inhibit PRL synthesis. The Kd for the binding of [125]T3 to pituitary cell nuclei was 0.2 nM. Analysis of PRL mRNA levels by hybridization of total cellular RNA to PRL cDNA demonstrated that there was a good correspondence between T3 effects on PRL synthesis and PRL mRNA. These findings demonstrate that T3 can specifically inhibit PRL synthesis and PRL mRNA levels in cultured pituitary cells and suggest that T3 may have a physiological role in the regulation of PRL synthesis.


Identification and Validation of a Novel Pyroptosis-Related Gene Signature for Prognosis Prediction in Soft Tissue Sarcoma.
Soft tissue sarcoma (STS) represents an uncommon and heterogenous group of malignancies, and poses substantial therapeutic challenges. Pyroptosis has been demonstrated to be related with tumor progression and prognosis. Nevertheless, no studies exist that delineated the role of pyroptosis-related genes (PRGs) in STS. In the present study, we comprehensively and systematically analyzed the gene expression profiles of PRGs in STS. The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were utilized to identify differentially expressed PRGs. In total, 34 PRGs were aberrantly expressed between STS and normal tissues. Several PRGs were validated with RT-qPCR. Consensus clustering analysis based on PRGs was conducted to divide STS patients into two clusters, and significant survival difference was observed between two distinct clusters (p = 0.019). Differentially expressed genes (DEGs) were identified between pyroptosis-related clusters. Based on the least absolute shrinkage and selection operator (LASSO) COX regression analysis, the pyroptosis-related gene signature with five key DEGs was constructed. The high pyroptosis-related risk score group of TCGA cohort was characterized by poorer prognosis (p < 0.001), with immune infiltration and function significantly decreased. For external validation, STS patients from Gene Expression Omnibus (GEO) were grouped according to the same cut-off point. The survival difference between two risk groups of GEO cohort was also significant (p < 0.001). With the combination of clinical characteristics, pyroptosis-related risk score was identified to serve as an independent prognostic factor for STS patients. In conclusion, this study provided a comprehensive overview of PRGs in STS and the potential role in prognosis, which could be an important direction for future studies.


Photoacoustic Effect of Near-Infrared Absorbing Organic Molecules via Click Chemistry.
Near-infrared dyes were developed to be contrast agents due to their ability to improve the productivity of photoacoustic (PA) imaging and photothermal therapy (PTT) treatments. During the article, we described in detail the PA and PT effects of a category of organic molecules. F4-TCNQ could potentially cause a red-shift in the peak PA intensity. The results show that the PTT intensity of the near-infrared dyes with phenyl groups were higher than near-infrared dyes with thiophene groups. We also investigated the photodynamic treatment effect of C1b to demonstrate that these dyes are highly desirable in biochemistry. The high photoacoustic intensity of the organic molecules and the good yield of reactive oxygen species could indicate that these dyes have good potential for a wide range of imaging applications. Finally, we embedded the dye (C1b) in a liposomal hydrophobic phospholipid bilayer (C1b⊂L) to facilitate the application of hydrophobic dyes in biomedical applications, which can be absorbed by cells with good compatible and high stability for the imaging of cellular PA.


Recent Advances in C-H Functionalisation through Indirect Hydrogen Atom Transfer.
The functionalisation of C-H bonds has been an enormous achievement in synthetic methodology, enabling new retrosynthetic disconnections and affording simple synthetic equivalents for synthons. Hydrogen atom transfer (HAT) is a key method for forming alkyl radicals from C-H substrates. Classic reactions, including the Barton nitrite ester reaction and Hofmann-Löffler-Freytag reaction, among others, provided early examples of HAT. However, recent developments in photoredox catalysis and electrochemistry have made HAT a powerful synthetic tool capable of introducing a wide range of functional groups into C-H bonds. Moreover, greater mechanistic insights into HAT have stimulated the development of increasingly site-selective protocols. Site-selectivity can be achieved through the tuning of electron density at certain C-H bonds using additives, a judicious choice of HAT reagent, and a solvent system. Herein, we describe the latest methods for functionalizing C-H/Si-H/Ge-H bonds using indirect HAT between 2018-2023, as well as a critical discussion of new HAT reagents, mechanistic aspects, substrate scopes, and background contexts of the protocols.


Isolation and characterization of an IGROV-1 human ovarian cancer cell line made resistant to Ecteinascidin-743 (ET-743).
By exposing Igrov-1 human ovarian cancer cells to increasing concentrations of Ecteinascidin-743 (ET-743), either for a short or prolonged time, we obtained sublines resistant to ET-743 which overexpress Pgp. The most resistant clone (Igrov-1/25 ET) was evaluated for biological and pharmacological characterizations. The increased Pgp levels of Igrov-1/25 ET were not due to amplification of the mdr-1 gene but to increased mRNA levels. No increase in other multidrug resistance-related proteins such as MRP or LRP was observed in Igrov-1/25 ET. The IC50 values of ET-743 against Igrov-1/25 ET was approximately 50 times higher than the parental cell line. Resistance was not reversed while maintaining the cell line in drug-free medium for at least 24 months. Igrov-1/25 ET was cross-resistant to Doxorubicin and VP16 while it was equally sensitive to L-PAM, MNNG, CPT and only marginally less sensitive to Cis-DDP and Oxaliplatin compared to the parental cell line. Igrov-1/25 ET exposed to Doxorubicin retained this drug much less, mainly because of a more efficient drug efflux. The cyclosporine analogue SDZ PSC-833 reversed the resistance of Igrov-1/25 ET to ET-743, without any enhancement of the drug activity against the parental Igrov-1 cell line. Igrov-1/25 ET exhibits typical features of cell lines overexpressing the mdr-1 gene and can be a potentially useful tool in selecting ET-743 non-cross-resistant analogues as well as to investigate methods to counteract resistance to this drug.


Impact of iron overload in myelodysplastic syndromes.
Anaemia is prevalent in patients with myelodysplastic syndromes (MDS), and most patients with MDS receive regular red blood cell transfusions, which can lead to iron overload. Some patients may already have iron overload before transfusions begin, as a result of ineffective erythropoiesis. Iron overload has been linked to hepatic, cardiac, and endocrine dysfunction, although its exact contribution to cardiac failure and other complications is difficult to determine due to the advanced age of MDS patients and the prevalence of comorbidities. In addition, in patients with lower-risk MDS, a high serum ferritin level has been associated with an increased risk of leukaemic evolution independent of other prognostic factors, possibly related in part to the accumulation of free iron radicals. Finally, iron overload has been associated with poorer outcome after allogeneic stem cell transplantation and possibly with increased risk of infection. Thus, iron overload may negatively influence survival in patients with MDS, especially those with lower-risk disease. Iron chelation therapy may be beneficial in these patients.


A versatile route to C-6 arylmethyl-functionalized S-DABO and related analogues.
Since their discovery in 1992, 3,4-dihydro-2-alkoxy-6-benzyl-4-oxypyrimidines (DABOs) have been subjected to many structural modifications in order to obtain better non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of AIDS. Herein, we report a straightforward and versatile route for the synthesis of novel C-6 arylmethyl-functionalized S-DABO, a poorly explored class of derivatives. Finally, biological evaluation of the synthesized derivatives led to the identification of a promising anti-HIV-1 lead compound.


Posaconazole and amphotericin B combination therapy against Cryptococcus neoformans infection.
To investigate the effects of posaconazole (POS) and amphotericin B (AMB) combination therapy in cryptococcal infection, we established an experimental model of systemic cryptococcosis in CD1 mice by intravenous injection of three distinct clinical isolates of Cryptococcus neoformans. Therapy was started 24 h after the infection and continued for 10 consecutive days. POS was given at 3 and 10 mg/kg of body weight/day, while AMB was given at 0.3 mg/kg/day. Combination therapy consisted of POS given at a low (combo 3) or at a high (combo 10) dose plus AMB. Survival studies showed that combo 3 was significantly more effective than POS at 3 mg/kg for two isolates tested (P value, < or = 0.001), while combo 10 was significantly more effective than POS at 10 mg/kg for all three isolates (P values ranging from <0.001 to 0.005). However, neither combination regimen was more effective than AMB alone. For two isolates, combination therapy was significantly more effective than each single drug at reducing the fungal burden in the brain (P values ranging from 0.001 to 0.015) but not in the lungs. This study demonstrates that the major impact of POS and AMB combination therapy is on brain fungal burden rather than on survival.


Effect of vitamin A acid on papillomas induced by irradiated bed bugs in rabbit skin.
The preventive effect of vitamin A acid (13-cis-retinoic acid) on skin papillomas induced in rabbits (Oryctolagus cuniculus) by the bite of bed bugs (Cimex lectularius) pre-irradiated with gamma rays was investigated. Painting the papillomas with an oily 13-cis-retinoic acid suspension twice a week in a dose of 25 mg/kg body weight leads to significant regression of these structures.


The sensing of nutritional status and the relationship to filamentous growth in Saccharomyces cerevisiae.
Heterotrophic organisms rely on the ingestion of organic molecules or nutrients from the environment to sustain energy and biomass production. Non-motile, unicellular organisms have a limited ability to store nutrients or to take evasive action, and are therefore most directly dependent on the availability of nutrients in their immediate surrounding. Such organisms have evolved numerous developmental options in order to adapt to and to survive the permanently changing nutritional status of the environment. The phenotypical, physiological and molecular nature of nutrient-induced cellular adaptations has been most extensively studied in the yeast Saccharomyces cerevisiae. These studies have revealed a network of sensing mechanisms and of signalling pathways that generate and transmit the information on the nutritional status of the environment to the cellular machinery that implements specific developmental programmes. This review integrates our current knowledge on nutrient sensing and signalling in S. cerevisiae, and suggests how an integrated signalling network may lead to the establishment of a specific developmental programme, namely pseudohyphal differentiation and invasive growth.


The impact of bivalirudin on percutaneous coronary intervention-related bleeding.
We studied the clinical and economic impact of bivalirudin in clinical practice. Consecutive patients undergoing PCI via the common femoral artery for stable, unstable, or atypical angina, silent ischaemia, or non-ST-elevation myocardial infarction indications during 2007-2008 were prospectively studied. In-hospital bleeding events were systematically assessed and classified as either major or minor. Use of bivalirudin, vascular closure devices, heparin and/or glycoprotein (GP) IIb/IIIa inhibitor was at the operator's discretion. Among 1,364 patients, 503 received bivalirudin and 861 received usual care consisting of either heparin monotherapy (n=687) or heparin+GP IIb/IIIa (n=174). Any post-PCI bleeding occurred in 356 (26.1%) patients, including 32 (2.3%) major and 324 (23.8%) minor events. Compared with usual care, bivalirudin was associated with reduced bleeding before adjustment (any: 17.3% vs. 31.2%, P<0.001; major: 1.2% vs. 3.0%, P=0.03; minor: 16.1% vs. 28.2%, P<0.01) and after propensity-matching (OR 0.46, 95% CI 0.34-0.63, P<0.001). Use of vascular closure devices was associated with an increase in any bleeding (32.2% vs. 17.7%, P<0.001), primarily due to an increase in minor bleeding (30.8% vs. 14.1%, P<0.001) while there was a significant decrease in major bleeding (1.4% vs. 3.7%, P=0.007). Bivalirudin was associated with total hospitalisation costs that were lower than usual care (mean cost savings, $463/patient; 95% CI 1,594 less to 621 more). In this prospective PCI cohort, bivalirudin was associated with reduced major and minor bleeding without a significant increase in hospital costs compared with other anticoagulation regimens. Closure device use was associated with decreased major but increased minor bleeding.


Analysis of behavior of sodiated sugar hemiacetals under low-energy collision-induced dissociation conditions and application to investigating mutarotation and mechanism of a glycosidase.
Analysis of anomericity is one of the most important issues in the structure elucidation of carbohydrates. Mass spectrometry (MS)-based methods are of particular interest and important to address the issue related to resolving anomericity of monosaccharide units in a glycan. However, direct analysis of hemiacetals has not been possible by MS because of the nonavailability of information regarding the gas-phase behavior of such ion species. We addressed this issue by using stage-discriminated energy-resolved mass spectrometry (ERMS) at the stages of MS(n) and MS(n+1) and showed that such analysis can be made. This was achieved by proving that individual anomers can be identified and that the equilibrium of sodium adducted ion species of alpha- and beta-anomers can be negated in the gas phase under collision-induced dissociation (CID) conditions. On the basis of these results, we could 1) observe the mutarotation of lactose and 2) speculate the hydrolysis mechanism of endo-glycosylceramidase by using mass spectrometry.


Importance of early endoscopic and clinical evaluation of children with caustics ingestion.
Accidental ingestion of caustics in pediatrics continues to be a frequent problem that can lead to severe injuries and permanent sequelae that require esophageal rehabilitation programs. This study aimed to describe the medical care experience of children who ingested caustic substances in a tertiary hospital in Mexico City. We conducted a descriptive and analytical study. We described age, sex, type of caustics, clinical and endoscopic findings, and the radiological evolution of 284 patients who arrived during the acute phase. The records of 336 children with a history of caustic ingestion were reviewed. The median age was 1.7 years, and the predominant sex was male. Caustic soda was the most accidentally ingested substance. We found an association between the severity of the esophageal injury with the presence of more than four symptoms at diagnosis (χ², p < 0.001) and with the finding of oral lesions, sialorrhea, and vomiting (χ², p < 0.05). Forty percent (n = 114) showed normal gastrointestinal endoscopy. In children with caustic ingestion, upper gastrointestinal endoscopy should be performed within 72 hours to evaluate the extent of the lesions. In this study, we found that more than four symptoms at admission, and oral lesions, sialorrhea, and vomiting are associated with the severity of the esophageal injury.


Hormonal changes in severely malnourished children.
Hormonal changes during the acute phase of protein-energy malnutrition (PEM) and at recovery have been examined in thirty-four severely malnourished subjects (twenty-four kwashiorkor and ten marasmus) all of whom were aged 3 years and below. It was observed that except for cortisol, the hormonal values were different between the marasmic and kwashiorkor children. Serum insulin levels were depressed and growth hormone (GH) elevated among the kwashiorkor children most especially among the kwashiorkor sub-groups II and III cases who had the greatest deficit in body weight. Although the GH values were also elevated in the marasmic patients, the levels were much lower than those for the kwashiorkor children. There was no statistically significant difference in the mean serum concentration of both cortisol and thyroxine among the different sub-groups of kwashiorkor and the marasmic subjects. The identical serum levels of cortisol in both the marasmic and kwashiorkor children may have been due to similar extent of exposure of infections. With improved dietary intake and some degree of anthropometric recovery, GH concentration fell steadily while insulin rose especially among the kwashiorkor cases. The reasons for these hormonal changes, their functions during the acute phase of PEM and at recovery are discussed.


Contribution of basophil/mast cell and eosinophil growth and differentiation to the allergic tissue inflammatory response.
The mechanisms underlying allergic tissue basophil/mast cell (BMC) or eosinophil (Eo) accumulation are unclear, especially since chemotaxis or IgE levels do not offer a sufficient explanation. We have found that a formaldehyde-blockable, steroid-responsive nasal metachromatic cell (NMC) population predominates in epithelium and correlates well with symptoms and signs in patients with allergic rhinitis. Circulating BMC and Eo progenitors (colony-forming cells in culture; CFU-c) are increased in atopic patients, inversely related to NMC counts, and fall as NMC numbers rise during seasonal allergen (ragweed pollen) stimulation. The metachromatic cell progeny of these CFU-c are also formaldehyde-blockable in their staining reaction and thus may correspond to NMC. Human nasal polyps yield BMC CFU-c. Nasal polyp epithelial scrapings or mononuclear cells, T lymphocytes or keratinocytes in vitro all produce potent BMC or Eo colony-stimulating activities (CSA) as well as an interleukin-3-like activity, each of which is partially separable from the others. Nasal epithelial cells cultured from scrapings of atopic, as opposed to nonatopic, patients also produce BMC or Eo CSA with an enhanced effect of the former on atopic peripheral blood CFU-c growth. These studies support the hypothesis that BMC and Eo accumulate in allergic inflammation as a result of in situ growth and differentiation of progenitors stimulated by soluble hemopoietic factors derived from mucosal cell populations.


Elevated expression of the AF1q gene, an MLL fusion partner, is an independent adverse prognostic factor in pediatric acute myeloid leukemia.
The AF1q gene, a mixed-lineage leukemia fusion partner, is highly expressed in hematopoietic progenitor cells but has low expression in differentiated cells. We determined the expression of the AF1q gene by reverse transcriptase-polymerase chain reaction in 64 pediatric acute myeloid leukemia (AML) patients treated on Children's Cancer Group clinical trial CCG-2891 and correlated its expression level to clinical characteristics and outcome. AF1q expression in patients varied from 0- to 154-fold compared with normal marrow, and increasing expression level was associated with worsening survival, with a hazard ratio of 1.02 per fold increase in AF1q expression (P = .032). We divided patients into tertile groups based on AF1q expression level. Patients with high AF1q expression (top tertile) had a higher predominance of French-American-British M1 compared to patients with lower 2 tertiles of AF1q expression (43% vs 9%, P = .003). High AF1q expression was associated with poor survival in univariate and multivariate models. Overall survival at 8 years for patients with the high AF1q expression was 19% versus 50% in patients with low AF1q expression, (P = .01). AF1q expression may correlate with clinical outcome in pediatric AML, although it is not clear if AF1q is simply a marker of a more primitive phenotype or contributes directly to leukemogenesis.


Acute toxicity of ochratoxins A and B in chicks.
Ochratoxins A and B were given to 1-day-old Babcock B-300 cockerels to evaluate acute toxic effects. Two trials with ochratoxin A gave 7-day oral median lethal dose estimates of 116 mug (3.3 mg/kg) and 135 mug (3.9 mg/kg) per chick. Chicks given daily oral doses of 100 mug of ochratoxin A died on the second day. Single subcutaneous doses of 400 mug of ochratoxin A were also lethal. The 7-day oral median lethal dose of B was estimated at 1,890 mug (54 mg/kg) per chick. Chicks given oral doses of 100 mug of ochratoxin B daily for 10 days survived. Sublethal doses of both ochratoxins A and B resulted in growth suppression which was proportional to the amount of ochratoxin given. Visceral gout was the principal gross finding. Microscopic examinations revealed acute nephrosis, hepatic degeneration or focal necrosis, and enteritis. Suppression of hematopoiesis in the bone marrow and depletion of lymphoid elements from the spleen and bursa of Fabricius were frequently seen. Both ochratoxins appeared to have similar pathological effects. This is the first report on the toxicity of ochratoxin B.


Phenotypic differentiation of bifidobacteria of human and animal origins.
The phenotypes of 153 strains belonging or related to the genus Bifidobacterium were studied. These organisms included 38 collection strains and 115 wild strains (41 strains of human origin, 56 strains of animal origin, and 18 strains obtained from rivers or sewage). Our phenotypic analysis revealed seven main groups that were subdivided into 20 subgroups. Seven subgroups contained no type or collection strain. Among the human strains, the type strains of Bifidobacterium pseudocatenulatum and B. catenulatum fell into group I, which contained the type strains of B. adolescentis (subgroup Ib), B. dentium (subgroup Ic), and B. angulatum (ungrouped). The type strain of B. breve belonged to subgroup IIIa1, and the type strains of B. infantis and B. longum fell into subgroup IIIb1. Group VII comprised only wild strains that were isolated from human infant feces. Among the animal strains, group II consisted mainly of bifidobacteria that were isolated from pig feces and contained the type strains of B. suis (subgroup IIb), B. thermophilum (subgroup IIf), B. choerinum, and B. boum (ungrouped). Wild strains belonging to group V were isolated from pig, calf, cow, and chicken feces; this included the type strains of B. animalis (subgroup Va), B. magnum (subgroup Vb), B. pseudolongum, and B. globosum (subgroup Vc). The strains of human origin (groups I, III, and VII) were well separated from the animal strains (groups II, IV, and V). It was not surprising that the wild strains isolated from surface water or sewage were distributed in the animal groups as well as the human groups. Thus, bifidobacteria can be considered to be successful indicators of human or animal fecal pollution when they are correctly classified. The acidification patterns were not adequate to differentiate Bifidobacterium species, as determined previously by Mitsuoka (Bifidobacteria Microflora 3:11-28, 1984) and Scardovi (p. 1418-1434, in P. H. A. Sneath, N. S. Mair, M. E. Sharpe, and J. G. Holt, ed., Bergey's Manual of Systematic Bacteriology, vol. 2, 1986). However, enzymatic tests furnished new taxonomic criteria for the genus.


Is There a Community Microbial Community? A Comparison of Pathogens Between Two Hospital Surgical Intensive Care Units in a Single City.
Background: Nosocomial and health-care-associated infections drive increased healthcare costs and negatively affect patient outcomes. The human microbiome has been heavily explored in recent years with incomplete data regarding hospital-specific and community-specific microbial communities. Although bacterial species differ between intensive care units in the same hospital, it is unclear if they differ between similar units in similar hospitals in the same community. Our hypothesis is that pathogens in surgical intensive care units (SICUs) are distinct between hospitals, even in the same community. Methods: From 2017 to 2021, data were collected prospectively from the SICUs of two 400-bed hospitals located three miles apart in the same city (Hospital A and Hospital B). Infections defined using U.S. Centers for Disease Control and Prevention (CDC) criteria were recorded for trauma and general surgery patients, as well as patient demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and causative organism. Results: Overall, Escherichia coli was the most commonly isolated pathogen in Hospital A, whereas Staphylococcus aureus was most commonly isolated at Hospital B. Enterococci were more common in Hospital A, and Haemophilus influenzae and Enterobacter spp. were more common in Hospital B. After stratification between trauma and non-trauma patients, however, these differences disappeared, with the exception of more overall gram-positive organisms and fewer gram-negative organisms among Hospital A trauma patients compared to Hospital B. There were no differences in rates of isolation of either fungi or resistant bacteria between hospitals. Conclusions: At a species level, admission diagnosis appears to be a greater determinant of pathogen isolation than hospital when comparing similar intensive care units (ICUs) in the same geographic area, but a larger body of data is needed to flesh out a distinct microbial map of the organisms occupying a certain geographic region. Further areas for investigation include comparison between hospital units, specific anatomic sites, and ICU versus floor patients.


Expanding the Informatics Competencies of Nurse Practitioners Through Online Learning.
Nurse practitioners' informatics competencies are not well-understood. Limited evidence alludes to the potential need to improve the informatics competencies of nurse practitioners. The primary purpose of this study was to analyze the informatics competencies of nurse practitioners, including nurses training to become nurse practitioners, before and after completing an online learning module in nursing informatics. Six topics were covered in the investigator-developed learning module. A pretest-posttest, one-group, quasi-experimental design was used in the study. The link to the study was emailed to members of a local nurse practitioners' association in California and graduate nursing students at a public university in Missouri. The study was also shared on a professional networking Web site, LinkedIn. Data were collected from 15 nurse practitioners and two nurse practitioner students, using a demographic questionnaire and an 18-item self-assessment of informatics competency scale. A related-samples Sign test was conducted to compare the pretest and posttest scores. Statistically significant median increases ( P = .001 to <.001) were found in five areas. Findings suggest that the online learning module expanded the participants' competencies in specific areas of informatics. The results also provide an initial understanding of nurse practitioners' informatics competencies and inform future iterations of the study.


Relativistic cyclotron resonance shape in magnetic bottle geonium.
The thermally excited axial oscillation of the electron through the weak magnetic bottle needed for the continuous Stern-Gerlach effect modulates the cyclotron frequency and produces a characteristic approximately 12-kHz-wide vertical rise-exponential decline line shape of the cyclotron resonance. At the same time the relativistic mass shift decreases the frequency by approximately 200 Hz per cyclotron motion quantum level n. Nevertheless, our analysis of the complex line shape shows that it should be possible to produce an abrupt rise in the cyclotron quantum number n from 0 to approximately 20 over a small fraction of 200 Hz, when the 160-GHz microwave drive approaches the n = 0 --> 1 transition, and a jump of 14 levels over a frequency increment of 200 Hz has already been observed in preliminary work. This realizes an earlier proposal to generate a very sharp cyclotron resonance feature by quasithermal excitation with a square noise band and should provide a way to detect spin flips when a weak bottle is used to reduce the broadening of the g - 2 resonance by a factor of 20.


[Medico-genetic study of myopathies in a population of Pamir and Karategin valley of the Tadzhik SSR].
The clinic-genealogical and population-genetical studies were undertaken to reveal the myopathia patients. The frequency of myopathies in a population of Tajiks, their clinical polymorphism and the course of the pathologic process, depending on factors of environment were studied. In the population of Pamir people, who were exposed to external conditions, 25 patients with the neural amyotrophy, 8 patients with shoulder, shoulder-blade and face form of progressive muscle distrophy, 4 patients with Erba's PMD and 3 with the pseudohypertrophic Dushen form were revealed. High frequency of the neural amyotrophy was connected with the marriage election of the population, its isolation and accumulation of heterozygote carriers. Earlier onset of progressive muscle distrophy was connected with sharp change in climate and great physical burdens which led to the disarrangement of the adaptation system. It was established that 17 patients with the shoulder-blade and face form of the PMD, 5 patients with the sporadic form of the neural amyotrophy, 3 patients with the Dushen's PMD, 2 patients with the Erba's PMD and 1 patient with the spinal amyotrophy inhabited Karategin valley having the continental climate. The high level of migration of these populations resulted in dissemination of the gene in the valley regions. The quantity of abortions and still-borns in families suffering from myopathy is fewer than in Pamir.


Perspectives of carriers of X-linked retinal diseases on genetic testing and gene therapy: A global survey.
Female carriers of X-linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease-causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self-identified carriers worldwide. Two hundred and twenty-eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy.


Molecular Engineering of Rylene Diimides via Sila-Annulation Toward High-Mobility Organic Semiconductors.
The continuous innovation of captivating new organic semiconducting materials remains pivotal in the development of high-performance organic electronic devices. Herein, a molecular engineering by combining sila-annulation with the vertical extension of rylene diimides (RDIs) toward high-mobility organic semiconductors is presented. The unilateral and bilateral sila-annulated quaterrylene diimides (Si-QDI and 2Si-QDI) are designed and synthesized. In particular, the symmetrical bilateral 2Si-QDI exhibits a compact, 1D slipped π-π stacking arrangement through the synergistic combination of a sizable π-conjugated core and intercalating alkyl chains. Combining the appreciable elevated HOMO levels and reduced energy gaps, the single-crystalline organic field-effect transistors (SC-OFETs) based on 2Si-QDI demonstrate exceptional ambipolar transport characteristics with an impressive hole mobility of 3.0 cm2 V-1 s-1 and an electron mobility of 0.03 cm2 V-1 s-1 , representing the best ampibolar SC-OFETs based on RDIs. Detailed theoretical calculations rationalize that the larger transfer integral along the π-π stacking direction is responsible for the achievement of the superior charge transport. This study showcases the remarkable potential of sila-annulation in optimizing carrier transport performances of polycyclic aromatic hydrocarbons (PAHs).


MarkVCID cerebral small vessel consortium: I. Enrollment, clinical, fluid protocols.
The concept of vascular contributions to cognitive impairment and dementia (VCID) derives from more than two decades of research indicating that (1) most older individuals with cognitive impairment have post mortem evidence of multiple contributing pathologies and (2) along with the preeminent role of Alzheimer's disease (AD) pathology, cerebrovascular disease accounts for a substantial proportion of this contribution. Contributing cerebrovascular processes include both overt strokes caused by etiologies such as large vessel occlusion, cardioembolism, and embolic infarcts of unknown source, and frequently asymptomatic brain injuries caused by diseases of the small cerebral vessels. Cerebral small vessel diseases such as arteriolosclerosis and cerebral amyloid angiopathy, when present at moderate or greater pathologic severity, are independently associated with worse cognitive performance and greater likelihood of dementia, particularly in combination with AD and other neurodegenerative pathologies. Based on this evidence, the US National Alzheimer's Project Act explicitly authorized accelerated research in vascular and mixed dementia along with frontotemporal and Lewy body dementia and AD itself. Biomarker development has been consistently identified as a key step toward translating scientific advances in VCID into effective prevention and treatment strategies. Validated biomarkers can serve a range of purposes in trials of candidate interventions, including (1) identifying individuals at increased VCID risk, (2) diagnosing the presence of cerebral small vessel disease or specific small vessel pathologies, (3) stratifying study participants according to their prognosis for VCID progression or treatment response, (4) demonstrating an intervention's target engagement or pharmacodynamic mechanism of action, and (5) monitoring disease progression during treatment. Effective biomarkers allow academic and industry investigators to advance promising interventions at early stages of development and discard interventions with low success likelihood. The MarkVCID consortium was formed in 2016 with the goal of developing and validating fluid- and imaging-based biomarkers for the cerebral small vessel diseases associated with VCID. MarkVCID consists of seven project sites and a central coordinating center, working with the National Institute of Neurologic Diseases and Stroke and National Institute on Aging under cooperative agreements. Through an internal selection process, MarkVCID has identified a panel of 11 candidate biomarker "kits" (consisting of the biomarker measure and the clinical and cognitive data used to validate it) and established a range of harmonized procedures and protocols for participant enrollment, clinical and cognitive evaluation, collection and handling of fluid samples, acquisition of neuroimaging studies, and biomarker validation. The overarching goal of these protocols is to generate rigorous validating data that could be used by investigators throughout the research community in selecting and applying biomarkers to multi-site VCID trials. Key features of MarkVCID participant enrollment, clinical/cognitive testing, and fluid biomarker procedures are summarized here, with full details in the following text, tables, and supplemental material, and a description of the MarkVCID imaging biomarker procedures in a companion paper, "MarkVCID Cerebral small vessel consortium: II. Neuroimaging protocols." The procedures described here address a range of challenges in MarkVCID's design, notably: (1) acquiring all data under informed consent and enrollment procedures that allow unlimited sharing and open-ended analyses without compromising participant privacy rights; (2) acquiring the data in a sufficiently wide range of study participants to allow assessment of candidate biomarkers across the various patient groups who might ultimately be targeted in VCID clinical trials; (3) defining a common dataset of clinical and cognitive elements that contains all the key outcome markers and covariates for VCID studies and is realistically obtainable during a practical study visit; (4) instituting best fluid-handling practices for minimizing avoidable sources of variability; and (5) establishing rigorous procedures for testing the reliability of candidate fluid-based biomarkers across replicates, assay runs, sites, and time intervals (collectively defined as the biomarker's instrumental validity). Participant Enrollment Project sites enroll diverse study cohorts using site-specific inclusion and exclusion criteria so as to provide generalizable validation data across a range of cognitive statuses, risk factor profiles, small vessel disease severities, and racial/ethnic characteristics representative of the diverse patient groups that might be enrolled in a future VCID trial. MarkVCID project sites include both prospectively enrolling centers and centers providing extant data and samples from preexisting community- and population-based studies. With approval of local institutional review boards, all sites incorporate MarkVCID consensus language into their study documents and informed consent agreements. The consensus language asks prospectively enrolled participants to consent to unrestricted access to their data and samples for research analysis within and outside MarkVCID. The data are transferred and stored as a de-identified dataset as defined by the Health Insurance Portability and Accountability Act Privacy Rule. Similar human subject protection and informed consent language serve as the basis for MarkVCID Research Agreements that act as contracts and data/biospecimen sharing agreements across the consortium. Clinical and Cognitive Data Clinical and cognitive data are collected across prospectively enrolling project sites using common MarkVCID instruments. The clinical data elements are modified from study protocols already in use such as the Alzheimer's Disease Center program Uniform Data Set Version 3 (UDS3), with additional focus on VCID-related items such as prior stroke and cardiovascular disease, vascular risk factors, focal neurologic findings, and blood testing for vascular risk markers and kidney function including hemoglobin A1c, cholesterol subtypes, triglycerides, and creatinine. Cognitive assessments and rating instruments include the Clinical Dementia Rating Scale, Geriatric Depression Scale, and most of the UDS3 neuropsychological battery. The cognitive testing requires ≈60 to 90 minutes. Study staff at the prospectively recruiting sites undergo formalized training in all measures and review of their first three UDS3 administrations by the coordinating center. Collection and Handling of Fluid Samples Fluid sample types collected for MarkVCID biomarker kits are serum, ethylenediaminetetraacetic acid-plasma, platelet-poor plasma, and cerebrospinal fluid (CSF) with additional collection of packed cells to allow future DNA extraction and analyses. MarkVCID fluid guidelines to minimize variability include fasting morning fluid collections, rapid processing, standardized handling and storage, and avoidance of CSF contact with polystyrene. Instrumental Validation for Fluid-Based Biomarkers Instrumental validation of MarkVCID fluid-based biomarkers is operationally defined as determination of intra-plate and inter-plate repeatability, inter-site reproducibility, and test-retest repeatability. MarkVCID study participants both with and without advanced small vessel disease are selected for these determinations to assess instrumental validity across the full biomarker assay range. Intra- and inter-plate repeatability is determined by repeat assays of single split fluid samples performed at individual sites. Inter-site reproducibility is determined by assays of split samples distributed to multiple sites. Test-retest repeatability is determined by assay of three samples acquired from the same individual, collected at least 5 days apart over a 30-day period and assayed on a single plate. The MarkVCID protocols are designed to allow direct translation of the biomarker validation results to multicenter trials. They also provide a template for outside groups to perform analyses using identical methods and therefore allow direct comparison of results across studies and centers. All MarkVCID protocols are available to the biomedical community and intended to be shared. In addition to the instrumental validation procedures described here, each of the MarkVCID kits will undergo biological validation to determine whether the candidate biomarker measures important aspects of VCID such as cognitive function. Analytic methods and results of these validation studies for the 11 MarkVCID biomarker kits will be published separately. The results of this rigorous validation process will ultimately determine each kit's potential usefulness for multicenter interventional trials aimed at preventing or treating small vessel disease related VCID.


Observation of clinical efficacy of yousiyue for endometrium regeneration after superconducting visual abortion and its nursing.
Present study is carried out to observe and analyze the curative effect of Yousiyue (Drospirenone and Ethinylestradiol tablets) on endometrium regeneration after superconducting visual abortion and explore the nursing mode. A total of 150 patients who underwent superconducting visual abortion in our hospital were enrolled and divided into study and reference groups with 75 patients each according to random grouping. Both groups were treated with vaginal ultrasonography-mediated abortion. The study group was treated with Yousiyue after the operation plus comprehensive nursing intervention program. The reference group only received general routine nursing and treatment. The treatment outcomes of the two groups were compared. Comparison of endometrial thickness, menses return time and menstrual reduction rate reveals significant advantage of study group over reference group, p<0.05; study group has an overall satisfaction significantly higher than the reference group, p<0.05. The implementation of Yousiyue in endometrium regeneration after superconducting visual abortion can receive good results, which is worthy of popularization and application.


Non-pharmacological interventions for cognitive difficulties in ADHD: A systematic review and meta-analysis.
Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children and is associated with significant risk of educational failure, interpersonal problems, mental illness, and delinquency. Despite a number of comparative and comprehensive reviews on the effects of ADHD treatments on ADHD core symptoms, evidence synthesizing the effects of ADHD interventions on cognitive difficulties is limited. In this meta-analysis, the neuropsychological effects of non-pharmacological interventions for ADHD were examined across studies published between 1980 and 2017. Data were extracted from studies that used objective cognitive measures (either computerized or pencil-and-paper), and multiple meta-analyses were conducted to compare the effectiveness across these interventions. Publication bias was assessed, as well as quality of the evidence, using Cochrane risk of bias tool for randomized control trials studies. Our final meta-analysis included 18 studies with interventions that were categorized into four categories: neurofeedback, cognitive-behavioral therapy, cognitive training, and physical exercises. Physical exercises demonstrated the highest average effect size (Morris d = 0.93). A further evaluation of cognitive functions yielded 49 effect sizes for the five categories, including attention, inhibition, flexibility, and working memory. Analyses demonstrated a homogenous, medium to large, effect size of improvement across interventions, with inhibition demonstrating the largest average effect size (Morris d = 0.685). This study highlights the positive effect of psychological interventions on ADHD cognitive symptomology and supports the inclusion of non-pharmacological interventions in conjunction with the commonly used pharmacological treatments.