Psychological aspects of medical prescription.
Medication possesses a potential for therapeutic efficacy far beyond its chemical capacity if prescribed in ways which enlist patients' personality traits in a therapeutic direction. "Prescription" in this sense includes the physician's attitude (as the patient sees it) and subtleties in the way he fits his instructions to the kind of patient he is dealing with. This presentation deals with four kinds of patients-widely different in what they need from the physician-for whom some therapeutic "placebo" effect of prescription can be brought to bear:1. Patients who are unduly fearful about what is wrong with them, and who look to the physician for calm sureness.2. Systematic, controlled, organized patients, who like to share in their own medical management.3. Patients who are excessively depressed about being sick.4. Patients for whom "nothing works," but who can be helped by a physician who is willing to accept "failure" in dealing with them. For all of them, careful appraisal and sophisticated treatment are necessary.


Intrapartum Management of Sickle Cell Anemia With Rare Antibody and Minimal Blood Availability.
Sickle cell disease (SCD) can pose serious maternal and fetal risk in pregnancy. Transfusion, both during and outside of pregnancy, can improve patient morbidity and mortality but carries risk of alloimmunization, complicating future management. This case describes a 29-year-old gravida 1, para 0 woman with sickle cell anemia and rare red blood cell alloantibody (anti-Rh46) who presented with severe vaso-occlusive crisis at 29 weeks with hemoglobin of 7.6 g/dL. Only one unit of compatible blood existed in the country. Planning for transfusion with least-incompatible blood was made. She ultimately underwent cesarean section at 31 weeks and 2 days for abnormal fetal testing. This case highlights that blood products should be utilized judiciously because their adverse effects, like alloimmunization, can increase patient morbidity and mortality.


Vitrification, in vitro fertilization, and development of Atg7 deficient mouse oocytes.
Autophagy contributes to the clearance and recycling of macromolecules and organelles in response to stress. We previously reported that vitrified mouse oocytes show acute increases in autophagy during warming. Herein, we investigate the potential role of Atg7 in oocyte vitrification by using an oocyte-specific deletion model of the Atg7 gene, a crucial upstream gene in the autophagic pathway. Oocyte-specific Atg7 deficient mice were generated by crossing Atg7 floxed mice and Zp3-Cre transgenic mice. The oocytes were vitrified-warmed and then subjected to in vitro fertilization and development. The rates of survival, fertilization, and development were assessed in the Atg7 deficient oocytes in comparison with the wildtype oocytes. Light chain 3 (LC3) immunofluorescence staining was performed to determine whether this method effectively evaluates the autophagy status of oocytes. The survival rate of vitrified-warmed Atg7(f/f) ;Zp3-Cre (Atg7(d/d) ) metaphase II (MII) oocytes was not significantly different from that of the wildtype (Atg7(f/f) ) oocytes. Fertilization and development in the Atg7(d/d) oocytes were significantly lower than the Atg7(f/f) oocytes, comparable to the Atg5(d/d) oocytes previously described. Notably, the developmental rate improved slightly in vitrified-warmed Atg7(d/d) MII oocytes when compared to fresh Atg7(d/d) oocytes. LC3 immunofluorescence staining showed that this method can be reliably used to assess autophagic activation in oocytes. We confirmed that the LC3-positive signal is nearly absent in Atg7(d/d) oocytes. While autophagy is induced during the warming process after vitrification of MII oocytes, the Atg7 gene is not essential for survival of vitrified-warmed oocytes. Thus, induction of autophagy during warming of vitrified MII oocytes seems to be a natural response to manage cold or other cellular stresses.


[Assessment of risk due to the intake of uranium isotopes in mineral spring waters].
To complement the data of a previous research concerning the evaluation of the lifetime risk of radiation-induced cancer due to the ingestion of 226Ra, 228Ra and 222Rn in mineral spring waters from a natural highly radioactive region of Brazil. The study was performed to evaluate the lifetime risk of radiation-induced cancer due to the ingestion of 238U and 234U in the same spring waters. It is assumed that the risk coefficient for natural U isotopes is the same as for the 226Ra-induced bone sarcomas and that the equilibrium for skeletal content is 25 times the daily ingestion of 226Ra, but 11 times the daily ingestion of long-lived uranium isotopes. Waters samples were collected seasonally over a period of one year at all the spring sites used by the local population of Aguas da Prata, S. Paulo State (Brazil). Concentrations ranging from 2.0 to 28.4 mBq/L and from 4.7 to 143 mBq/L were observed for 238U and 234U, respectively. Based upon the measured concentrations the lifetime risk due to the ingestion of uranium isotopes was estimated. A total of 0.3 uranium-induced cancers per 10(6) exposed persons was predicted, suggesting that chronic ingestion of uranium at the levels observed at these springs will result in an incremental increase of fatal cancers of 0.1%. By taking into account the uncertainties in evaluating the carcinogenic effects, it can be concluded that virtually no cancer would be expected from the ingestion of uranium in the mineral spring waters analyzed.


Role of exercise testing early after myocardial infarction in identifying candidates for coronary surgery.
It has been suggested that ST depression in lead V5 or equivalent on early exercise testing after acute myocardial infarction predicts a high risk of death. To evaluate exercise testing and radionuclide ventriculography in this context 103 consecutive patients with myocardial infarction who were able to undertake a limited exercise test before discharge from hospital were exercised and underwent gated blood pool scanning. No serious complications resulted from exercise testing. Twenty nine patients developed ST depression in lead V5, 19 had exertional hypotension, 31 developed a heart rate of greater than or equal to 130 beats/min, and 15 had complex ventricular arrhythmias. Death during the first year after discharge from hospital was associated with exertional hypotension (p less than 0.001) and a heart rate on exercise testing of greater than or equal to 130 beats/min (p less than 0.05); these two variables identified all nine deaths. Inability to complete the exercise protocol for any reason was also predictive of death (p less than 0.01). Ventricular arrhythmias and ST depression in lead V5 induced by exercise were not significantly associated with an increased risk of death. The mean (SD) radionuclide ejection fraction in the patients who died was 29 (16%) compared with 43 (11)% in the patients who survived (p less than 0.001). ST changes on exercise testing after myocardial infarction appear to be less predictive of later complications than haemodynamic signs, which may indicate left ventricular damage rather than ischaemia.


Wine Consumption and Oral Cavity Cancer: Friend or Foe, Two Faces of Janus.
The health benefits of moderate wine consumption have been extensively studied during the last few decades. Some studies have demonstrated protective associations between moderate drinking and several diseases including oral cavity cancer (OCC). However, due to the various adverse effects related to ethanol content, the recommendation of moderate wine consumption has been controversial. The polyphenolic components of wine contribute to its beneficial effects with different biological pathways, including antioxidant, lipid regulating and anti-inflammatory effects. On the other hand, in the oral cavity, ethanol is oxidized to form acetaldehyde, a metabolite with genotoxic properties. This review is a critical compilation of both the beneficial and the detrimental effects of wine consumption on OCC.


Late effects of a brief psychological intervention in patients with intermittent claudication in a randomized clinical trial.
The authors previously reported the early results of a trial of a brief psychological intervention to increase physical activity in patients with intermittent claudication. After 4 months, participants in the intervention group walked a mean of 1576 more steps per day than control group participants. The present study followed the original participants to determine whether this behaviour change was maintained over 2 years. This was a randomized single-centre parallel-group trial. Fifty-eight patients newly diagnosed with intermittent claudication were assigned randomly to one of two groups. The control group (30 patients) received usual care: lifestyle advice and consultation with a vascular surgeon to agree a treatment plan. The treatment group (28) received usual care plus a brief psychological intervention designed to modify illness and walking beliefs, and develop a personalized walking action plan. The primary outcome was daily steps measured by pedometer. Secondary outcomes included revascularization rate, quality of life and perceived pain-free walking distance. Follow-up was conducted at 1 and 2 years. Between-group differences were analysed by analysis of co-variance. Participants in the brief psychological intervention group walked significantly more than those in the control group. The mean difference at 1 year was 1374 (95 per cent confidence interval 528 to 2220) steps per day and the difference at 2 years was 1630 (495 to 2765) steps per day. Modifying illness and walking beliefs, and assisting patients to develop a personalized walking action plan led to increases in walking behaviour in patients with claudication that were maintained for 2 years. ISRCTN28051878 (http://www.controlled-trials.com).


[Implementation of Brazil's Family Allowance Program: experiences at São Francisco de Itabapoana and Duque de Caxias].
This paper discuss the findings of a study examining the Implementation of Brazil's Family Allowance Program in Rio de Janeiro at São Francisco de Itabapoana and Duque de Caxias, conducted in 2004 - 2005 with the support of the Brazilian Science and Technology Research and Development Council (CNPq) and collaboration among ENSP-FIOCRUZ, UFF and UERJ. Its purpose is to analyze this implementation process and local management practices, identifying the main contours of this program. An examination of its political and institutional dynamics, accountability mechanisms, intersectoral arenas, investments in healthcare and education, and intergovernmental arrangements helps outline some of the conflicts, tensions and challenges associated with conditional cash transfers as a core policy in the battle against poverty and social inequalities.


Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children.
Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.


Protein interactions: mapping interactome networks to support drug target discovery and selection.
Proteins are biomolecular structures that build the microscopic working machinery of any living system. Proteins within the cells and biological systems do not act alone, but rather team up into macromolecular structures enclosing intricate physicochemical dynamic connections to undertake biological functions. A critical step towards unraveling the complex molecular relationships in living systems is the mapping of protein-to-protein physical "interactions". The complete map of protein interactions that can occur in a living organism is called the "interactome". Achieving an adequate atlas of all the protein interactions within a living system should allow to build its interaction network and to identity the "central nodes" that can be critical for the function, the homeostasis, and the movement of such system. Focusing on human studies, the data about the human interactome are most relevant for current biomedical research, because it is clear that the location of the proteins in the interactome network will allow to evaluate their centrality and to redefine the potential value of each protein as a drug target. This chapter presents our current knowledge on the human protein-protein interactome and explains how such knowledge can help us to select adequate targets for drugs.


Does a clinical evaluation of oral cleanliness correlate with caries incidence in preschool children? Findings from a cohort study.
The aim of this study was to assess whether a clinical evaluation of oral cleanliness reflects subsequent caries incidence. Oral examination of 180 children (1- to 4-year-olds) was carried out twice in a six-month period. Caries prevalence at baseline (dfs) in 1- to 2-year-olds (group A) and 3- to 4-year-olds (group B) correlated significantly with oral cleanliness as well as salivary mutans streptococci count (MS). Caries increment (delta(dfs)) correlated significantly with oral cleanliness in group A but not in group B, while delta(dfs) significantly correlated with MS in group B and slightly correlated with that in group A. ANCOVA revealed that dfs was significantly higher at the second examination than at baseline in group B, even after adjusting for oral cleanliness. This finding was confirmed by Wilcoxon test when group B was divided in three categories (low, middle and high) based on oral cleanliness. This suggests that the relationship between delta(dfs) and oral cleanliness decreased with age and that the significant positive correlation found in group B by our point-prevalence survey is derived from the remainder of the positive correlation that occurred at a younger age.


Biotransformation and liver-specific functions of human hepatocytes in culture on RGD-immobilized plasma-processed membranes.
In this paper we report on the metabolic response of human hepatocytes grown on polyethersulfone membranes surface modified with a plasma-deposited acrylic acid coating and RGD peptide covalently immobilized through a "spacer arm" molecule. The modified surfaces were characterized by means of X-ray photoelectron spectroscopy and water contact angle measurements. The performance of modified and unmodified membranes was evaluated by assessing the expression of liver specific and biotransformation functions of human hepatocytes. Diclofenac, a non-steroidal anti-inflammatory drug, was used to investigate the biotransformation functions. Surface-modified membranes elicit specific cellular responses and induce hepatocytes to enhance the synthesis rate of albumin and urea, particularly in the presence of diclofenac. Also the biotransformation functions were expressed at high levels.


Conservative full-mouth resin renewal.
The treatment of this patient involved the coordination of periodontal, orthodontic, restorative, and aesthetic considerations. It was unique because it involved only resin as the primary restorative material, which allowed for conservative preparations and restorations. In the posterior, the use of direct and indirect resins resulted in the removal of little or no healthy tooth structure. In the anterior, the use of direct resin veneers required minimal removal of enamel, while still achieving proper function and aesthetics. Resin restorations in this particular case allowed for an acceptable clinical result and a highly satisfied patient.


Magnetic-resonance imaging techniques for detection of elasticity variation.
The relative success of manual palpation in the detection of breast cancer would suggest that a method for remote palpation resulting in a measurement of tissue elasticity could provide a diagnostic tool for detecting cancerous lesions deeper within the breast. This presumption is based in part on the excellent contrast between neoplastic and normal tissue due to the large (orders of magnitude) relative variation in the shear elastic modulus. By comparison, the bulk deformational modulus maintains the same value to within 20% for most soft tissues. A specific method of magnetic-resonance imaging (MRI) which measures tissue displacements has been used in experiments with a phantom containing regions of increased Young's modulus as a demonstration. The spatial modulation of magnetization technique uses the displacement of a spatial grid pattern caused by spin saturation to track regional motion. Mathematical reconstruction of the distribution of elastic moduli is shown for select examples. Any modality, e.g., MRI, ultrasound, etc., which can detect local tissue motion with sufficient spatial resolution can be used and therefore the results presented here should give an indication of the utility of such motion tracking techniques to future measurement of tissue elasticity.


Approaches to the application and removal of compression therapy: A literature review.
Compression therapy is used in the treatment of venous disorders, lymphoedema and burns. Adherence to compression therapy is reported to be poor, due to a number of factors, including difficulty in applying and removing the compression garments. A literature review was conducted to identify aids, equipment and other approaches to ease the application and removal of compression therapy garments. Some 12 studies were identified. Most studies focused on chronic venous insufficiency and venous ulcers. Four methods of easing compression garment application and removal were identified: (1) devices to assist in application and removal; (2) altered compression stocking design; (3) adjustable compression wrap devices; and (4) education. Patients prescribed compression therapy should be educated on how to apply and remove the compression garments, and have application devices made available to them.


Collection of biological samples in forensic toxicology.
Forensic toxicology is the study and practice of the application of toxicology to the purposes of the law. The relevance of any finding is determined, in the first instance, by the nature and integrity of the specimen(s) submitted for analysis. This means that there are several specific challenges to select and collect specimens for ante-mortem and post-mortem toxicology investigation. Post-mortem specimens may be numerous and can endow some special difficulties compared to clinical specimens, namely those resulting from autolytic and putrefactive changes. Storage stability is also an important issue to be considered during the pre-analytic phase, since its consideration should facilitate the assessment of sample quality and the analytical result obtained from that sample. The knowledge on degradation mechanisms and methods to increase storage stability may enable the forensic toxicologist to circumvent possible difficulties. Therefore, advantages and limitations of specimen preservation procedures are thoroughfully discussed in this review. Presently, harmonized protocols for sampling in suspected intoxications would have obvious utility. In the present article an overview is given on sampling procedures for routinely collected specimens as well as on alternative specimens that may provide additional information on the route and timing of exposure to a specific xenobiotic. Last, but not least, a discussion on possible bias that can influence the interpretation of toxicological results is provided. This comprehensive review article is intented as a significant help for forensic toxicologists to accomplish their frequently overwhelming mission.


Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution.
The objective of the study was to explore clinical, electroencephalography (EEG), neuropsychological features and prognosis of myoclonic-astatic epilepsy (MAE). Of 327 children aged between 1 and 9 years with a diagnosis of generalized epilepsy followed between 2000 and 2008, 18 (5.5%) had MAE. Male significantly predominated (88.9%). Age at onset ranged from 2.3 to 4.9 years (mean 3.6 years). Median follow-up period was 6.3 years. In addition to myoclonic-astatic seizures patients had myoclonic seizures (66.7%), drop attacks (72.2%), head drops (77.8%) absences (88.9%), tonic-clonic generalized seizure (77.8%), tonic seizures (38.9%), non-convulsive status epilepticus (16.7%). Seven patients (38.9%) had an epileptic encephalopathy. At onset, interictal epileptiform and slow abnormalities were recorded, respectively, in 100% and 77.8% of patients. EEG abnormalities disappeared in all patients within 4 years since the onset. At long-term follow-up, two patients developed focal abnormalities typical of rolandic epilepsy and two patients photosensitivity. On neuropsychological testing 66.7% of patients had a normal IQ (mean 81.2±17.0, range 47-105, median 84.5) after a mean period of 4.4 years since the last seizure. Sixteen out of 18 patients remitted within 3.5 years since the onset and in two patients tonic seizures persisted. MAE is generalized childhood epilepsy: although cognitive functions might deteriorate, outcome is good regarding seizures.


Comparative in vitro microdosimetric study of murine- and human-derived cancer cells exposed to alpha particles.
Diffusing alpha-emitter radiation therapy (DaRT) is a proposed new form of brachytherapy using α particles to treat solid tumors. The method relies on implantable ²²⁴Ra-loaded sources that continually release short-lived α-particle-emitting atoms that spread inside the tumor over a few millimeters. This treatment was demonstrated to have a significant effect on tumor growth in murine and human-derived models, but the degree of tumor response varied across cell lines. Tumor response was found to correlate with the degree of radionuclide spread inside the tumor. In this work we examined the radiosensitivity of individual cells to determine its relationship to tumor response. Cells were irradiated in vitro by α particles using a ²²⁸Th irradiator, with the mean lethal dose, D₀, estimated from survival curves generated by standard methods. The results were further analyzed by microdosimetric tools to calculate z₀, the specific energy resulting in a survival probability of 1/e for a single cell, which is considered to better represent the intrinsic radiosensitivity of individual cells. The results of the study demonstrate that, as a rule, tumors that respond more favorably to the DaRT treatment are also characterized by higher intrinsic cellular radiosensitivities, with D₀ ranging from 0.7 Gy to 1.5 Gy for the extreme cases and z₀ following the same trend.


Structural arrangement of the intracellular Ca2+ binding domains of the cardiac Na+/Ca2+ exchanger (NCX1.1): effects of Ca2+ binding.
The cardiac Na(+)/Ca(2+) exchanger (NCX1.1) serves as the primary means of Ca(2+) extrusion across the plasma membrane of cardiomyocytes after the rise in intracellular Ca(2+) during contraction. The exchanger is regulated by binding of Ca(2+) to its intracellular domain, which contains two structurally homologous Ca(2+) binding domains denoted as CBD1 and CBD2. NMR and x-ray crystallographic studies have provided structures for the isolated CBD1 and CBD2 domains and have shown how Ca(2+) binding affects their structures and motional dynamics. However, structural information on the entire Ca(2+) binding domain, denoted CBD12, and how binding of Ca(2+) alters its structure and dynamics is more limited. Site-directed spin labeling has been employed in this work to address these questions. Electron paramagnetic resonance measurements on singly labeled constructs of CBD12 have identified the regions that undergo changes in dynamics as a result of Ca(2+) binding. Double electron-electron resonance (DEER) measurements on doubly labeled constructs of CBD12 have shown that the β-sandwich regions of the CBD1 and CBD2 domains are largely insensitive to Ca(2+) binding and that these two domains are widely separated at their N and C termini. Interdomain distances measured by DEER have been employed to construct structural models for CBD12 in the presence and absence of Ca(2+). These models show that there is not a major change in the relative orientation of the two Ca(2+) binding domains as a result of Ca(2+) binding in the NCX1.1 isoform. Additional measurements have shown that there are significant changes in the dynamics of the F-G loop region of CBD2 that merit further characterization with regard to their possible involvement in regulation of NCX1.1 activity.


Carbon-ion Radiotherapy for Isolated Lymph Node Metastasis After Surgery or Radiotherapy for Lung Cancer.
Purpose: Mediastinal and hilar lymph node metastasis is one of the recurrence patterns after definitive treatment of lung cancer. Salvage radiotherapy (RT) can be a treatment option for lymph node metastasis. However, the usefulness of additional RT remains unclear after surgery or RT for the primary lung tumor. We retrospectively evaluated the efficacy and safety of hypofractionated carbon-ion RT for isolated lymph node metastasis. Methods and Materials: Between April 2013 and August 2016, 15 consecutive patients with isolated lymph node metastasis underwent carbon-ion RT. The pretreatment evaluations confirmed the isolated lymph node metastasis and the absence of local recurrence or distant metastasis, which was oligometastatic disease. The median age was 72 (range, 51-83) years, with 11 male patients. The first treatments for primary lung tumors were carbon-ion RT for 8 patients and surgery for 7 patients. There were 9 adenocarcinomas, 4 squamous cell carcinomas, 1 adenosquamous cell carcinoma, and 1 mucoepidermoid carcinoma. Most patients (93%) were irradiated with 52.8 Gy relative biological effectiveness in 12 fractions for 3 weeks. There were no patients treated with concurrent or adjuvant therapy such as chemotherapy, molecular-targeted therapy, or immunotherapy. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0). Results: The median follow-up for surviving patients was 28 months. One patient experienced local lymph node recurrence, and the 2-year local control rate was 92% for all patients. Distant metastasis was observed in 7 patients, and 2-year progression-free survival rate was 47%. During follow-up, there were 4 deaths from lung cancer, and the 2-year overall survival rate was 75%. There were 2 patients with acute grade 2 esophagitis and 2 with late grade 2 cough, which were improved by conservative therapy. There were no other grade 2 or higher adverse events. Conclusions: Hypofractionated carbon-ion RT showed excellent local control and overall survival without severe toxicities in lung cancer patients with isolated lymph node metastasis after surgery or carbon-ion RT for primary lung tumors. A multi-institutional prospective study is required to establish the efficacy and safety of carbon-ion RT.


[Unexplained sterility: practical management].
The treatment of unexplained sterility is a gamble, since by definition it is sterility in which investigation does not show any abnormality in the couple. Sterility cannot be regarded as "unexplained" until after an investigation of which the author describes the progression from the simplest to the most complicated. Uncertainties, paradoxes and controversies will still trouble the unexplained sterilities, within the limits of our means of investigation, for a long time to come.


Development of physician networks.
This article provides a brief overview of the development of physician networks. The continued progression of managed care and the advent of managed care-based health care reform at the state and national level have escalated the development of physician networks. This article reviews the potential purposes and objectives for forming a physician network as well as the different desired characteristics such as geographic access, network size and composition, and targeted physician characteristics that are important in the network's development.


Strengthening children's oral health: views from the field.
Low-income children and adolescents continue to bear a heavy burden of untreated pain and complications from dental disease. To explore why proposals to remediate this problem have not gained traction, the authors interviewed experts involved in efforts to improve the oral health status of low-income and minority children during the past decade. Key informants believe that success requires addressing both consumer demand and provider supply factors. They especially cite the lack of public outcry for more accessible oral health care and the undervaluing of oral health, relative to medical care. Informants were cautiously optimistic that strategies such as health literacy and outreach campaigns, which have helped increase children's physical activity and improve their diets, offer unexplored opportunities for progress.


Manage your energy, not your time.
As the demands of the workplace keep rising, many people respond by putting in ever longer hours, which inevitably leads to burnout that costs both the organization and the employee. Meanwhile, people take for granted what fuels their capacity to work--their energy. Increasing that capacity is the best way to get more done faster and better. Time is a finite resource, but energy is different. It has four wellsprings--the body, emotions, mind, and spirit--and in each, it can be systematically expanded and renewed. In this article, Schwartz, founder of the Energy Project, describes how to establish rituals that will build energy in the four key dimensions. For instance, harnessing the body's ultradian rhythms by taking intermittent breaks restores physical energy. Rejecting the role of a victim and instead viewing events through three hopeful lenses defuses energy-draining negative emotions. Avoiding the constant distractions that technology has introduced increases mental energy. And participating in activities that give you a sense of meaning and purpose boosts the energy of the spirit. The new workday rituals succeed only if leaders support their adoption, but when that happens, the results can be powerful. A group of Wachovia Bank employees who went through an energy management program outperformed a control group on important financial metrics like loans generated, and they reported substantially improved customer relationships, productivity, and personal satisfaction. These findings corroborated anecdotal evidence gathered about the effectiveness of this approach at other companies, including Ernst & Young, Sony, and Deutsche Bank. When organizations invest in all dimensions of their employees' lives, individuals respond by bringing all their energy wholeheartedly to work -and both companies and their people grow in value.


Amyloid-beta oligomers impair fear conditioned memory in a calcineurin-dependent fashion in mice.
Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice.


Coarse-grained Monte Carlo simulations of nanogel-polyelectrolyte complexes: electrostatic effects.
Coarse-grained Monte-Carlo simulations of nanogel-polyelectrolyte complexes have been carried out. The results presented here capture two phenomena reported in experiments with real complexes: (i) the reduction in size after absorbing just a few chains and (ii) the charge inversion detected through electrophoretic mobility data. Our simulations reveal that charge inversion occurs if the polyelectrolyte charge is large enough. In addition, the distribution of chains inside the nanogel strongly depends on whether charge inversion takes place. It should also be stressed that the chain topology has little influence on most of the properties studied here.


Rural-Urban Differences in Colorectal Cancer Screening Barriers in Nebraska.
Nebraska ranks 36th nationally in colorectal cancer screening. Despite recent increases in CRC screening rates, rural areas in Nebraska have consistently shown lower rates of CRC screening uptake, compared to urban areas. The objective of this study was to investigate reasons for lower CRC screening rates among Nebraska residents, especially among rural residents. We developed a questionnaire based on Health Belief Model (HBM) constructs to identify factors associated with the use of CRC screening. The questionnaire was mailed in 2014 to adults aged 50-75 years in an urban community in the east and a rural community in the west regions of the state. Multiple logistic regression models were created to assess the effects of HBM constructs, rural residence, and demographic factors on CRC screening use. Of the 1200 surveys mailed, 393 were returned (rural n = 200, urban n = 193). Rural respondents were more likely to perceive screening cost as a barrier. Rural residents were also more likely to report that CRC cannot be prevented and it would change their whole life. In multiple regression models, rural residence, perceived embarrassment, and perceived unpleasantness about screening were significantly associated with reduced odds of receiving colonoscopy. Older age (62 years and older), having a personal doctor, and perceived risk of getting CRC were significantly associated with increased odds of receiving colonoscopy. Interventions to increase uptake of colorectal cancer screening in rural residents should be tailored to acknowledge unique perceptions of screening methods and barriers to screening.


An automated RNA extraction procedure and application for 16S rRNA sequencing of Leuconostoc amelobiosum.
The determination of 16S ribosomal ribonucleic acid (16S rRNA) primary structures by in vitro reverse transcription requires the extraction of rRNA in pure form. Although a number of high reliable techniques have been developed for the purpose most are fairly complex, involving numerous steps and the wasting of large volumes. It describes here a RNA extraction and purification method, suitable for automatic extractors, which consistently yields reasonable amounts of pure total RNA from prokaryotes, free of DNA and RNases. The rRNA from the type strain Leuconostoc amelobiosum was isolated using this procedure. Its 16S rRNA sequence was determined and a comparative analysis with those from all currently described leuconostocs, including several atypical lactobacilli, revealed very high sequence homology with Leuconostoc citreum confirming Leuconostoc amelobiosum is phylogenetically a member of the genus Leuconostoc sensu stricto.


The cost of gastro-oesophageal reflux disease, dyspepsia and peptic ulcer disease in Sweden.
Dyspepsia, peptic ulcer disease (PUD) and gastro-oesophageal reflux disease (GORD) involve a substantial cost to Swedish society. There is a lack of up-to-date nationwide cost estimates after 1985. This study was conducted to present a comprehensive and updated cost analysis and study the change over time of the national cost of these disorders. Primarily, data from National Swedish databases and secondly, data from databases from the County of Uppsala for 1997 were used for the calculations and estimations. Swedish societal perspective. The total cost to Swedish society of dyspepsia, PUD and GORD in 1997 was $US424 million, or $US63 per adult. Direct costs totalled $US258 million (61%) while indirect costs totalled $US166 million (39%). The highest proportions of costs were due to drugs and sick leave, these being 37 and 34%, respectively. The cost of dyspepsia and GORD is substantial for patients, health providers and society. Since 1985, drug costs have increased substantially while the cost of sick leave has decreased.


Involvement of cell surface glycans in adhesion of human colon carcinoma cells to liver tissue in a frozen section assay: role of endo-beta-galactosidase-sensitive structures.
Adhesion of human colon carcinoma variant cell lines expressing different levels of the cell surface sialyl Lewis X (sLeX) antigen to frozen sections of mouse liver was examined. KM12-HX cells that bound the monoclonal antibody (mAb) FH6 (anti-sLeX) and thus expressed a high level of sLeX demonstrated a greater degree of adhesion to liver sections than their low-binding counterparts, KM12-LX cells. The adhesion of KM12-HX cells to liver sections was partially blocked by mAb FH6, but not by another anti-sLeX mAb, KM93. The adhesion was Ca2+ dependent but was not inhibited by anti-E-selectin. Endo-beta-galactosidase treatment significantly reduced adhesion and resulted in the loss of cell surface binding sites for mAb FH6. O-linked oligosaccharides from KM12-HX cells incubated in the presence of p-nitrophenyl-N-acetylgalactosaminide were fractionated by a combination of gel filtration, anion exchange chromatography, and normal phase high-performance liquid chromatography. The structure of a mAb FH6-reactive and endo-beta-galactosidase-sensitive glycan was estimated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry in a post source decay mode and by glycosidase digestions to be NeuAc alpha2-3Gal beta1-4GlcNAc beta1-3Gal beta1-4Glc-NAc beta1-3Gal beta1-4(+/-Fuc alpha1-3)GlcNAc beta1-6(NeuAc alpha2-3Gal beta1-3)GalNAc-pNP. Mild detergent lysates of mouse liver surface-labeled with sulfo-NHS biotin were incubated with glutaraldehyde-fixed monolayers of KM12-HX cells, and bound components were isolated after EDTA treatment. A Mr 49,000 component that bound only to KM12-HX cells and not to KM12-LX cells was identified.


An empirical model for megavoltage x-ray output factors.
An empirical model of the factors that determine the central axis dose at 10 cm depth in water for 4 MV, 6 MV and 18 MV photon beams is presented. Backscattering from the variable collimators into the dose monitoring ionization chamber can cause a variation of -0.5% to +1.8% in the dose per monitor unit in accelerators with an electron facility. Forward emission towards the isocentre from the beam flattening filter and upper collimators is more dependent on the position of the upper variable collimator blades than the lower blades, so that they are not interchangeable in determining output factors, which can differ by up to 2%. The model includes the product of the monitor backscatter factor, normalized phantom scatter factor, normalized head scatter factor and inverse square law, corrected for the displacement of the virtual x-ray focus from the target. It can predict the dose to -/+0.83% for 4 MV, -/+0.80% for 6 MV photons and -/+0.82% for 18 MV photons. The normalized head scatter factor is a second-order polynomial of the modified equivalent square collimator, whose coefficients do not vary significantly with x-ray energy. The model was tested by comparison with independent measurements of output factor and generally agreed to around 1%.


[Process of bile formation and bile composition in albino rats in acute adrenal cortex insufficiency and adrenal gland autologous transplantation].
Experiments were conducted on 84 male albino rats. A study was made of the state of the bile forming process 7, 14 and 30 days after bilateral adrenalectomy and adrenal gland autotransplantation. Investigations carried out showed inhibition of the bile formation with the corresponding changes in the chemical composition of bile to occur both in adrenalectomized animals and the rats with adrenal autotransplantation; in the second case, however, these changes were less pronounced. A gradual suppression of the intensity of bile production, cholate formation, bilirubin- and cholesterol secretion occurred in the adrenalectomized rats, whereas in the animals a significant shift in the direction of restoration took place as soon as in 7 days after autotransplantation. The first to become restored is the cholesterin secretory function in the liver, then the intensity of the cholate formation, particularly the glycocholic and desoxycholic acids, and bilirubin secretion. The intensity of bile secretion, as well as the sum total content of cholates in the bile, chiefly on account of taurocholic acid, failed to reach the initial level even by the 30th day after the adrenal gland autotransplantation.


Microwave plasma-based direct synthesis of free-standing N-graphene.
Free-standing N-graphene was synthesized using a microwave plasma-based method at atmospheric pressure conditions through a single step and in a controllable manner. Using ethanol and ammonia as precursors, N-graphene with low relative amount of bonded oxygen and low level of saturated sp3 carbon bonds was produced. Adjusting the injection position of the nitrogen precursor in the plasma medium leads to selectivity in terms of doping level, nitrogen configuration and production yield. A previously developed theoretical model, based on plasma thermodynamics and chemical kinetics, was further updated to account for the presence of nitrogen precursor. The important role of HCN attachment to the graphene sheets as the main process of N-graphene formation is elucidated. The model predictions were validated by experimental results. Optical Emission Spectroscopy was used to detect the emission of plasma generated "building units" and to determine the gas temperature. The plasma outlet gas was analyzed by Fourier-Transform Infrared Spectroscopy to detect the generated gaseous by-products. The synthesized N-graphene was characterized by Scanning Electron Microscopy, Raman and X-ray photoelectron spectroscopies.


Effects of Olympic Combat Sports on Health-Related Quality of Life in Middle-Aged and Older People: A Systematic Review.
Olympic combat sports are unconventional physical activity strategies to train middle-aged and older people with and without health problems. This systematic review aimed to assess the available body of published peer-reviewed articles related to the effects of Olympic combat sports interventions (boxing, fencing, judo, karate, taekwondo, wrestling) on health-related quality of life in adults aged 45 and older. The search was carried out in five generic databases until July 2021 and the protocol was registered in PROSPERO (code: CRD42021244161). The PRISMA guidelines were followed and the Downs and Black checklist was used to assessed the methodological quality of the studies. After reviewing 1,151 records, only seven studies met the inclusion criteria, adding 212 participants (43.4% female) with a mean age of 63.7 years. Six studies (two with middle-aged participants and four with older people) provided data to calculate the effect size (ES) in the Olympic combat sports groups (No research that used taekwondo or wrestling as an intervention modality was found). Three studies reported beneficial changes with a small ES for the total score (d < 0.40) of the health-related quality of life. Two studies reported a beneficial change with a small ES (d = 0.49) and strong ES (d = 4.45) for physical health. One study reported improvements with a small ES for emotional (d = 0.23) and functional (d = 0.26) well-being. In conclusion, interventions based on Olympic combat sports produce beneficial effects with a small and moderate ES on health-related quality of life in male and female aged 45 and older who are healthy participants, participants with Parkinson's disease, and participants with breast cancer. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, PROSPERO: CRD42021244161.


Development of a stable isotope dilution analysis with liquid chromatography-tandem mass spectrometry detection for the quantitative analysis of di- and trihydroxybenzenes in foods and model systems.
A straightforward stable isotope dilution analysis (SIDA) for the quantitative determination of the di- and trihydroxybenzenes catechol (1), pyrogallol (2), 3-methylcatechol (3), 4-methylcatechol (4), and 4-ethylcatechol (5) in foods by means of liquid chromatography-tandem mass spectrometry was developed. With or without sample preparation involving phenylboronyl solid phase extraction, the method allowed the quantification of the target compounds in complex matrices such as coffee beverages with quantification limits of 9 nmol/L for 4-ethylcatechol, 24 nmol/L for catechol, 3-methyl-, and 4-methylcatechol, and 31 nmol/L for pyrogallol. Recovery rates for the analytes ranged from 97 to 103%. Application of the developed SIDA to various commercial food samples showed that quantitative analysis of the target compounds is possible within 30 min and gave first quantitative data on the amounts of di- and trihydroxybenzenes in coffee beverage, coffee powder, coffee surrogate, beer, malt, roasted cocoa powder, bread crust, potato crisps, fruits, and cigarette smoke and human urine. Model precursor studies revealed the carbohydrate/amino acid systems as well as the plant polyphenols catechin and epicatechin as precursors of catechol and 5-O-caffeoylquinic acid, caffeic acid as a precursor of catechol and 4-ethylcatechol, and gallocatechin, epigallocatechin, and gallic acid as precursors of pyrogallol.


Status of patients presently living 9 to 13 years after orthotopic heart transplantation.
Heart transplantation has a dramatic impact on both life expectancy and quality of life in patients with terminal heart failure. The aim of the study was to evaluate psychologic, social, occupational, and somatic status of patients living long-term, 9 to 13 years after orthotopic heart transplantation. Seventy-seven of 182 patients who received transplants between July 1983 and January 1988 in Hannover (1983-1985; n = 69 patients) and Berlin (1986-1988; n = 113 patients) have survived up to now, 9 to 13 years after transplantation (mean, 10 years 4 months). The patients and their medical records (eg, cardiac catheter studies, echocardiography) were examined to assess their somatic status. Psychologic, social, and occupational status and quality of life data were assessed by combination of self-rating questionnaires (the Short Form Health Survey Questionnaire, Giessener Beschwerdebogen [the Giessen Subjective Complaints List], the Sickness Impact Profile, and the Hospital Anxiety and Depression Scale) and semistructured interviews. Ninety-one percent of the patients were in New York Heart Association functional class I (70%) or II (21%). The results of the psychologic investigation revealed a definite impact of the side effects of chronic immunosuppression; however, overall, the quality of life rating was within the normal range. Sixty-seven (86%) patients were married, 51 (66%) patients were retired, 17 (22%) worked full-time or part-time, and 9 (12%) were housewife or houseman. Four male patients have fathered five healthy children 1 to 10 years after the transplantation. More than 75% of the patients had normal systolic ventricular function (mean left ventricular ejection fraction, 0.63). Coronary angiograms were normal or with minor wall irregularities in 86% (n = 66 patients), and revealed severe obstructions in 14% (n = 11). Normal function of all valves was found in one-third of the patients, tricuspid valve incompetence was not found or was insignificant in 87% (n = 67 patients) and severe in 8% (n = 10). Six patients had undergone tricuspid valve replacement, invariably for structural valve defects attributable to biopsy injuries. Fifty-eight patients (75%) exhibited various degrees of compensated renal insufficiency, 7 of them were on chronic hemodialysis, and 2 patients have undergone kidney transplantation. Hepatic function was normal in 68% (n = 52) of the patients, and 1 patient has developed liver cirrhosis. Osteoporosis was diagnosed of the discrete form in 7 (9%) and of a significant degree in 24 patients (31%); 38.5% (n = 30) complained of symptoms of polyneuropathy. The patients surviving 9 to 13 years after orthotopic heart transplantation are mostly in good physical status, the quality of life is comparable to the general population, and only a few of them have significantly limited in their life style. They do show the substantial chronic side effects of long-term immunosuppression, remaining treatment-dependent for a lifetime.


Phase I study of nivolumab combined with IFN-β for patients with advanced melanoma.
The efficacy of nivolumab is greater than that of other anti-melanoma drugs, so nivolumab-based combined therapies that enhance anti-tumor immune responses in patients with metastatic melanoma are of great interest to dermato-oncologists. As we have previously reported, IFN-β enhances the anti-tumor immune response of anti-PD-1 antibodies against B16F10 melanoma in vivo. To explore the potential of this property of IFN-β as part of a combination therapy for the treatment of metastatic melanoma patients, we performed a phase 1 trial, using a traditional rule-based 3 + 3 design, on patients with advanced melanoma. The nivolumab dose was fixed at 2 mg/kg, every 3 weeks. IFN-β was administered to three groups at doses of 1 million, 2 million, and 3 million units, respectively. Dose-limiting toxicities were defined as any grade 3-5 adverse events occurring between day 0 and day 42 that might possibly be related to nivolumab and IFN-β. Of the nine patients who received this combined therapy, none experienced dose-limiting toxicities, and all completed the treatment phase of the study. Patient follow-up continued for 6 months following the final treatment. There were two complete responses (22%) and one partial response (11%), all of which occurred in patients who had received monthly IFN-β immediately prior to the study. In this study, we determined the safe dose of IFN-β, when combined with nivolumab, to be 3 million units. To determine the efficacy of this combination therapy, further phase II trials are required.


Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: a population-based case-control study.
Dysfunction of the protein C anticoagulant system is associated with venous thromboembolism (VTE) and thrombomodulin (TM) is a critical cofactor within the protein C system. The aim of this study was to test the hypotheses that polymorphisms or haplotypes within the TM gene are common risk factors for VTE. We screened the TM putative promoter, exon and 3'-untranslated region for sequence variations in a random sample (n = 266) of consecutive idiopathic, objectively confirmed non-Olmsted County VTE patients referred to the Mayo Clinic. We then genotyped a sample of Olmsted County, MN residents with a first lifetime, objectively confirmed VTE in the 25-year period, 1966-90 (n = 223), and a sample of Olmsted County residents without VTE (n = 237) for polymorphisms either discovered in the screening population or previously published, and tested for an association of VTE with TM genotype or haplotypes using unconditional logistic regression and generalized linear models, respectively. We also genotyped these Olmsted County cases and controls at 20 'null' genetic maker loci and tested for population admixture. Nine novel and three previously described mutations were identified in the screening population. Mutations within the TM promoter, EGF(1-5), serine/threonine-rich, transmembrane, and cytoplasm regions were absent or uncommon. TM845G-->A (Ala25Thr; lectin region), TM2136T-->C (Ala455Val; EGF(6) region), TM2470C deletion (3'-untranslated region), and 4363A-->G (3'-flanking region) were more common, but were not associated with VTE by genotype or haplotype. Null genetic marker allele frequencies did not differ significantly among cases and controls. We conclude that polymorphisms or haplotypes within the TM gene are not common risk factors for incident VTE.


Characterization of lip expression in Salmonella typhimurium: analysis of lip::lac operon fusions.
Strains of Salmonella typhimurium which have an auxotrophic requirement for lipoic acid were isolated by mutagenesis with the transposable element Mu dJ. The chromosomal location of these insertion mutations was determined to be at 14 map units by bacteriophage P22-mediated cotransduction. The lip gene is transcribed in the clockwise direction relative to the S. typhimurium genetic map. Strains with lip::lac operon fusions were used to characterize the transcriptional activity of the lip promoter. Transcription of the lip gene is not regulated by catabolite repression or lipoic acid concentration. The data indicate that the lip gene product is expressed constitutively at a low level.


An expression signature classifies chemotherapy-resistant pediatric osteosarcoma.
Osteosarcoma is the most common malignant bone tumor in children. Osteosarcoma patients who respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome. Therefore, it was the aim of this study to identify prognostic factors at the time of diagnosis to characterize the genes predictive of poor survival outcome and to identify potential novel therapeutic targets. Expression profiling of 30 osteosarcoma diagnostic biopsy samples, 15 with inferior necrosis following induction chemotherapy (Huvos I/II) and 15 with superior necrosis following induction chemotherapy (Huvos III/IV), was conducted using Affymetrix U95Av2 oligonucleotide microarrays. One hundred and four genes were found to be statistically significant and highly differentially expressed between Huvos I/II and III/IV patients. Statistically significant genes were validated on a small independent cohort comprised of osteosarcoma xenograft tumor samples. Markers of Huvos I/II response predominantly were gene products involved in extracellular matrix (ECM) microenvironment remodeling and osteoclast differentiation. A striking finding was the significant decrease in osteoprotegerin, an osteoclastogenesis inhibitory factor. Additional genes involved in osteoclastogenesis and bone resorption, which were statistically different, include annexin 2, SMAD, PLA2G2A, and TGFbeta1. ECM remodeling genes include desmoplakin, SPARCL1, biglycan, and PECAM. Gene expression of select genes involved in tumor progression, ECM remodeling, and osteoclastogenesis were validated via quantitative reverse transcription-PCR in an independent cohort. We propose that osteosarcoma tumor-driven changes in the bone microenvironment contribute to the chemotherapy-resistant phenotype and offer testable hypotheses to potentially enhance therapeutic response.


Methods of studying the planar distribution of objects in histological sections of brain tissue.
This article reviews the statistical methods that have been used to study the planar distribution, and especially clustering, of objects in histological sections of brain tissue. The objective of these studies is usually quantitative description, comparison between patients or correlation between histological features. Objects of interest such as neurones, glial cells, blood vessels or pathological features such as protein deposits appear as sectional profiles in a two-dimensional section. These objects may not be randomly distributed within the section but exhibit a spatial pattern, a departure from randomness either towards regularity or clustering. The methods described include simple tests of whether the planar distribution of a histological feature departs significantly from randomness using randomized points, lines or sample fields and more complex methods that employ grids or transects of contiguous fields, and which can detect the intensity of aggregation and the sizes, distribution and spacing of clusters. The usefulness of these methods in understanding the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Creutzfeldt-Jakob disease is discussed.


Is the foot structure of preschool children moderated by gender?
Although boys are frequently reported to have flatter feet than girls, there has been little systematic research to confirm or explain this structural difference between the genders. The objective of this study was to determine whether flat-footedness was moderated by gender in Australian preschool children and, if so, to determine the cause of this between-gender difference in structure of the plantar surface of the foot. Foot anthropometry, Arch Index derived from plantar footprints, and midfoot plantar fat pad thickness measured by ultrasound were obtained for the left and right feet of 52 girls and 36 boys (mean age, 4.2 +/- 0.6 years). The children were recruited from 10 randomly selected preschools from the Illawarra region of New South Wales, Australia. In agreement with previous research, the preschool boys displayed significantly flatter feet than the girls (P < or = 0.04). Although there were no between-gender differences in structural foot dimensions, the boys had a significantly thicker midfoot fat pad than the girls by approximately 0.4 and 0.5 mm on both the right and left feet, respectively. The increased incidence of flat-footedness in boys compared with girls of the same age seems to be caused by a thicker plantar fat pad in the medial midfoot in boys. This suggests that the development of the medial longitudinal arch may be progressing at a slower rate in boys than in girls, and that intervention for a flexible flat foot, particularly for young boys, may be unnecessary.


Prophylaxis of oral mucositis in irradiated head-and-neck cancer patients: a proposed classification scheme of interventions and meta-analysis of randomized controlled trials.
To identify, classify, and evaluate agents used in the prophylaxis of oral mucositis in irradiated head and neck cancer patients. Data sources included multiple databases and manual citation review of relevant literature. Based on the eligibility criteria, 59 studies were independently reviewed by two reviewers. Forty-two studies were included in the classification scheme, of which 15 met the criteria for inclusion in the meta-analysis. Data were extracted by duplicate independent review, with disagreement resolved by consensus. Overall, the interventions reduced the odds of developing severe oral mucositis, when assessed by clinicians, by 36% (OR: 0.64; 95% CI: 0.46, 0.88). Subgroup analysis suggested that only the narrow-spectrum antibacterial lozenges were effective (OR: 0.45; 95% CI: 0.23, 0.86); however, the power of the aggregated data in the other classes may have been insufficient to detect differences. When the outcome was assessed by patients, no significant difference was seen in the outcome between the treatment and the control groups (OR: 0.79; 95% CI: 0.56-1.12). Overall, interventions chosen on a sound biologic basis to prevent severe oral mucositis are effective. In particular, when oral mucositis is assessed by clinicians, narrow-spectrum antibiotic lozenges appear to be beneficial. Methodologic limitations were evident in many of the studies. Further research using validated measurement tools in larger, methodologically sound trials is warranted.


Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo.
The metabolic needs for postnatal growth of the human nervous system are vast. Recessive loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2) in humans cause postnatal undergrowth of brain, and cognitive and motor disability. We demonstrate that GPT2 governs critical metabolic mechanisms in neurons required for neuronal growth and survival. These metabolic processes include neuronal alanine synthesis and anaplerosis, the replenishment of tricarboxylic acid (TCA) cycle intermediates. We performed metabolomics across postnatal development in Gpt2-null mouse brain to identify the trajectory of dysregulated metabolic pathways: alterations in alanine occur earliest; followed by reduced TCA cycle intermediates and reduced pyruvate; followed by elevations in glycolytic intermediates and amino acids. Neuron-specific deletion of GPT2 in mice is sufficient to cause motor abnormalities and death pre-weaning, a phenotype identical to the germline Gpt2-null mouse. Alanine biosynthesis is profoundly impeded in Gpt2-null neurons. Exogenous alanine is necessary for Gpt2-null neuronal survival in vitro but is not needed for Gpt2-null astrocytes. Dietary alanine supplementation in Gpt2-null mice enhances animal survival and improves the metabolic profile of Gpt2-null brain but does not alone appear to correct motor function. In surviving Gpt2-null animals, we observe smaller upper and lower motor neurons in vivo. We also observe selective death of lower motor neurons in vivo with worsening motor behavior with age. In conclusion, these studies of the pathophysiology of GPT2 Deficiency have identified metabolic mechanisms that are required for neuronal growth and that potentially underlie selective neuronal vulnerabilities in motor neurons.


Exercise in people with comorbidity or multimorbidity.
Exercise is effective in producing a wide range of beneficial health outcomes. To ensure safe and effective exercise, guidance has been developed for seemingly healthy people and for people with a single disease. Unfortunately, similar guidance is not yet available for people with comorbidity in addition to the index disease or for people with multimorbidity. However, researchers have recently started to explore the application of exercise in people with comorbidity or multimorbidity, and these innovative applications of exercise have produced encouraging results: Exercise was shown to be safe and effective. The objective of the present article is to identify the underlying principles of exercise in people with comorbidity or multimorbidity. We perform a narrative review of applications of exercise in people with comorbidity or multimorbidity. Principles of exercise in people with comorbidity or multimorbidity appear to include (a) a rigorous assessment of health status, (b) the adaptation of exercise to comorbidity or multimorbidity, (c) the application and integration of behavior change techniques into the exercise plan, and (d) clinical reasoning to support the application of exercise by health professionals. We posit that these 4 principles provide a framework for the successful development of exercise guidance for people with comorbidity or multimorbidity. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Sample size calculations for randomized controlled trials with repeatedly measured continuous variables as primary outcomes need improvements: a cross-sectional study.
Randomized controlled trials (RCTs) with repeatedly measured continuous variables as primary outcomes are common. Although statistical methodologies for calculating sample sizes in such trials have been extensively investigated, their practical application remains unclear. This study aims to provide an overview of sample size calculation methods for different research questions (e.g., key time point treatment effect, treatment effect change over time) and evaluate the adequacy of current practices in trial design. We conducted a comprehensive search of PubMed to identify RCTs published in core journals in 2019 that utilized repeatedly measured continuous variables as their primary outcomes. Data were extracted using a predefined questionnaire including general study characteristics, primary outcomes, detailed sample size calculation methods, and methods for analyzing the primary outcome. We re-estimated the sample size for trials that provided all relevant parameters. A total of 168 RCTs were included, with a median of 4 repeated measurements (interquartile range (IQR) 3-6) per outcome. In 48 (28.6%) trials, the primary outcome used for sample size calculation differed from the one used in defining the primary outcomes. There were 90 (53.6%) trials exhibited inconsistencies between the hypotheses specified for sample size calculation and those specified for primary analysis. The statistical methods used for sample size calculation in 158 (94.0%) trials did not align with those used for primary analysis. Additionally, only 6 (3.6%) trials accounted for the number of repeated measurements, and 7 (4.2%) trials considered the correlation among these measurements when calculating the sample size. Furthermore, of the 128 (76.2%) trials that considered loss to follow-up, 33 (25.8%) used an incorrect formula (i.e., N*(1+ lose rate) for sample size adjustment. In 53 (49.5%) out of 107 trials, the re-estimated sample size was larger than the reported sample size. The practice of sample size calculation for RCTs with repeatedly measured continuous variables as primary outcomes displayed significant deficiencies, with a notable proportion of trials failed to report essential parameters about repeated measurement required for sample size calculation. Our findings highlight the urgent need to use optimal sample size methods that align with the research hypothesis, primary analysis method, and the form of the primary outcome.


Determinants of estimated insulin resistance and beta-cell function in Indian, Creole and Chinese Mauritians. The Mauritius NCD Study Group.
Associations with insulin resistance and islet beta-cell function have been studied cross-sectionally in a population-based sample of 4278 Mauritians comprising Asian Indian, Creole and Chinese subjects. Insulin resistance and beta-cell function were estimated by a computer solved model based on fasting plasma glucose and insulin concentrations. Insulin resistance increased with declining glucose tolerance, whereas beta-cell function was highest in subjects with impaired glucose tolerance (IGT) and lowest in those with non-insulin-dependent diabetes mellitus (NIDDM). Indian subjects had the highest beta-cell function, while ethnic differences in insulin sensitivity were less marked. This may indicate that deranged beta-cell function rather than insulin resistance is the primary determinant of hyperinsulinaemia and glucose intolerance in Asian Indians. beta-Cell function declined with age more sharply than did insulin sensitivity, suggesting that the age-related decline in glucose tolerance is primarily related to loss of beta-cell function. Body mass index, waist/hip ratio, physical inactivity and female sex were independently associated with insulin resistance and beta-cell function. Subjects with a family history of diabetes had increased insulin resistance, irrespective of glucose tolerance. This or similar models may have application in longitudinal population-based studies which seek to determine the relative contributions of insulin resistance and beta-cell function to the aetio-pathogenesis of NIDDM.


Basic understanding of gonadotropin-releasing hormone-agonist triggering.
A single bolus of human chorionic gonadotropin (hCG) at midcycle has been the gold standard for triggering final oocyte maturation and ovulation in assisted reproductive technology cycles. More recently, gonadotropin-releasing hormone (GnRH)-agonist (GnRH-a) triggering has been introduced. The GnRH-a trigger may allow a more physiologic surge of both luteinizing hormone (LH) and follicle-stimulating hormone, although whether the combined surge will result in improved oocyte and embryo quality remains to be seen. However, the short duration of the LH surge with the GnRH-a trigger (approximately 34 hours) has been shown to be beneficial for preventing ovarian hyperstimulation syndrome in GnRH antagonist in vitro fertilization (IVF) cycles when compared with the prolonged elevation of hCG (≥6 days) after exposure to an hCG bolus. This review discusses the physiologic basis for the use of a GnRH-a trigger in IVF cycles.


In situ analysis of trifluorothymidine-resistant (TFTr) mutants of L5178Y/TK+/- mouse lymphoma cells.
TFTr mutants of L5178Y/TK+/- mouse lymphoma cells are analyzed as they appear in situ following cloning and incubation for 9-11 days in soft agar cloning medium. These TFTr mutants can be divided by colony size into sigma, small colony, and lambda, large colony, mutants. The use of a size discriminator on an automatic colony counter allows the production of histograms to evaluate the size distribution of colonies on a plate. The evaluation of these size distribution curves provides insight into the properties of sigma and lambda mutants. From these analyses several conclusions may be drawn. The sigma phenotype is preferentially associated with the TFTr subpopulation of a treated culture. The sigma phenotype is not an artifact of delayed toxicity following treatment. The frequency of quantifiable sigma mutants is not affected by agar concentrations between 0.20% and 0.45% in the cloning medium. TFTr sigma mutants are produced spontaneously and can be induced by a variety of mutagens. The decline in overall detectable mutants frequency observed for some mutagens with increasing time after treatment is due to the decline in sigma mutant frequency. The quantitation of both sigma and lambda mutants is thus useful in obtaining maximum utility of the information provided by the L5178Y/TK+/- mouse lymphoma assay.


Musculotendinous stiffness of triceps surae, maximal rate of force development, and vertical jump performance.
The relationships between ankle plantar flexor musculotendinous stiffness (MTS) and performance in a countermovement vertical jump (CMJ) and maximal rate of torque development (MRTD) were studied in 27 active men. MTS was studied by means of quick releases at 20 (S0.2), 40 (S0.4), 60 (S0.6), and 80% (S0.8) of maximal voluntary torque (T(MVC)). CMJ was not correlated with strength indices but was positively correlated with MRTD/BM, S 0.4/BM. The slope α 2 and intercept β 2 of the torque-stiffness relationships from 40 to 80% T(MVC) were correlated negatively (α 2) and positively (β 2) with CMJ. The different stiffness indices were not correlated with MRTD. The prediction of CMJ was improved by the introduction of MRTD in multiple regressions between CMJ and stiffness. CMJ was also negatively correlated with indices of curvature of the torque-stiffness relationship. The subjects were subdivided in 3 groups in function of CMJ (groups H, M, and L for high, medium, and low performers, resp.). There was a downward curvature of the torque-stiffness relationship at high torques in group H or M and the torque-stiffness regression was linear in group L only. These results suggested that torque-stiffness relationships with a plateau at high torques are more frequent in the best jumpers.


Unleashing the global potential of public health: A framework for future pandemic response.
Public health emergencies, especially pandemics, need to be managed globally, and on several levels, emphasizing the importance of leadership, communication, and synchronization of measures, data, and management plans in contrast to the management of the Coronavirus-19 pandemic, which illustrated diverse strategies employed by various nations. This paper aims to review and discuss whether globalized diseases in a globalized world should be managed by globalized public health. Using a systematic literature search, followed by a non-systematic literature review, selected studies were grouped into topics, and analyzed, using content analysis to enhance the conclusive results. The results present a roadmap towards a re-envisioned framework highlighting key areas of focus: data-driven decision-making, robust technology infrastructure, global cooperation, and ongoing public health education, as part of a coordinated global response. This article reveals the weaknesses of current pandemic management systems and recommends new steps to further strengthen the management of future pandemics.


Using BODIPY FL-Sphingolipid Analogs to Study Sphingolipid Metabolism in Mouse Embryonic Stem Cells.
Sphingolipids are important structural components of cellular membranes. They also function as prominent signaling molecules to control a variety of cellular events, such as cell growth, differentiation, and apoptosis. Impaired sphingolipid metabolism, particularly defects in sphingolipid degradation, has been associated with many human diseases. Fluorescence sphingolipid analogs have been widely used as efficient probes to study sphingolipid metabolism and intracellular trafficking in living mammalian cells. Compared with nitrobenzoxadiazole fluorophores (NBD FL), the boron dipyrromethene difluoride fluorophores (BODIPY FL) have much higher absorptivity and fluorescence quantum. These features allow more intensive labeling of cells for fluorescence microscopy imaging and flow cytometry analysis. Here, we describe a protocol employing BODIPY FL-labeled sphingolipid analogs to elucidate sphingolipid internalization, trafficking, and endocytosis in mouse embryonic stem cells. This protocol was validated in: eLife (2022), DOI: 10.7554/eLife.67452 Graphical abstract.


Fundamental bound on epidemic overshoot in the SIR model.
We derive an exact upper bound on the epidemic overshoot for the Kermack-McKendrick SIR model. This maximal overshoot value of 0.2984 · · · occurs at [Formula: see text]. In considering the utility of the notion of overshoot, a rudimentary analysis of data from the first wave of the COVID-19 pandemic in Manaus, Brazil highlights the public health hazard posed by overshoot for epidemics with R0 near 2. Using the general analysis framework presented within, we then consider more complex SIR models that incorporate vaccination.


Pet ownership and psychological well-being during the COVID-19 pandemic.
The question of pet ownership contributing to human well-being has received mixed empirical evidence. This contrasts with the lay intuition that pet ownership contributes positively to wellness. In a large representative sample, we investigate the differences that may exist between pet vs. non-pet owners in terms of their well-being during the COVID-19 pandemic, and examine among different sociodemographic strata, for whom pet ownership can be more vs. less beneficial. A cross-sectional questionnaire survey was conducted among Canadian adults (1220 pet owners, 1204 non-pet owners). Pet owners reported lower well-being than non-pet owners on a majority of well-being indicators; this general pet ownership effect held when accounting for pet species (dogs, cats, other species) and number of pets owned. Compared to owners of other pets, dog owners reported higher well-being. When examining the effect of pet ownership within different socioeconomic strata, being a pet owner was associated with lower well-being among: women; people who have 2 + children living at home; people who are unemployed. Our results offer a counterpoint to popular beliefs emphasising the benefits of pets to human wellness during the COVID-19 pandemic and confirm the importance of accounting for sociodemographic factors to further understand the experience of pet ownership.


Association between event-free survival and overall survival after neoadjuvant treatment for non-small cell lung cancer: a systematic review and meta-analysis.
We wanted to evaluate if event-free survival (EFS) is a reliable surrogate for overall survival (OS) in patients with resectable non-small cell lung cancer (r-NSCLC) receiving neoadjuvant therapy. We conducted a systematic literature review and meta-analysis to investigate the statistical association between EFS and OS. Electronic databases were searched on 30 July 2021 to identify sources reporting both EFS and OS data in patients with stage I-IIIB r-NSCLC receiving neoadjuvant therapy. Correlation and regression analyses evaluated the association between the effect of treatment on EFS and OS using log-hazard ratios (HRs). Sources in which the entire population had epidermal growth factor receptor mutations were excluded from the analyses. We identified 74 sources, of which 8 reported EFS and OS HRs from randomized controlled trials. Based on these, we found a positive linear correlation and a strong association between EFS and OS log-HRs (weighted Pearson's correlation coefficient r = 0.864; 95% confidence interval 0.809-0.992; P = 0.006; random-effects meta-regression, R2 = 0.777). We found a strong association between treatment effects for EFS and OS, indicating that improvements in EFS are likely to be predictive of improvements in OS. EFS may therefore be a reliable surrogate for OS after neoadjuvant therapy in r-NSCLC.


Gunshot fatalities in children and adolescents in New York City.
We reviewed the case records of all fatalities due to gunshot wounds in children and adolescents under 19 years of age in New York City from 1996 to 2000. The epidemiological profile, circumstances, toxicology results, location, and injuries were examined. There were 263 deaths: 242 homicides, 17 suicides, and 4 accidents. Among the homicides, 96% involved Black or Hispanic and 68% involved 17 and 18-year-old decedents. There were 11 times as many male as female homicides. The detection of ethanol and/or illicit drugs was 56% in the homicide and 53% in the suicide groups. Suicide notes were found in 18% of suicides, and an additional 35% verbally expressed a plan to commit suicide. Most suicides (77%) were in the home and half of the homicides occurred on the street.


IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma.
Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical responses in a subset of Ewing sarcoma (ES) patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to the IGF-1R/mTOR blockade are still undefined. To elucidate predominant mechanism(s) of acquired drug resistance while identifying synergistic drug combinations that improve clinical efficacy, we generated more than 18 ES cell lines resistant to IGF-1R- or mTOR-targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Reverse-phase protein lysate arrays (RPPAs) revealed proteomic changes linked to IGF-1R/mTOR resistance, and selected proteins were validated in cell-based assays, xenografts, and within human clinical samples. All statistical tests were two-sided. Novel mechanisms of resistance (MOR) emerged after dalotuzumab-, NVP-ADW-742-, and OSI-906-based targeting of IGF-1R. MOR to dalotuzumab included upregulation of IRS1, PI3K, and STAT3, as well as p38 MAPK, which was also induced by OSI-906. pEIF4E(Ser209), a key regulator of Cap-dependent translation, was induced in ridaforolimus-resistant ES cell lines. Unique drug combinations targeting IGF-1R and PI3K-alpha or Mnk and mTOR were synergistic in vivo and vitro (P < .001) as assessed respectively by Mantel-Cox and isobologram testing. We discovered new druggable targets expressed by chemoresistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets, in concert with IGF-1R or mTOR blockade, should improve clinical outcomes.


Living-Donor Liver Transplantation for Patients With Extrahepatic Malignancy: A Series of 14 Patients in a Single Institution.
Extrahepatic malignancy is a relative contraindication for liver transplant in many countries. Nevertheless, the indications for living-donor liver transplantation (LDLT) for such patients vary by institution. Our aim was to reevaluate the indications for LDLT in patients with extrahepatic malignancy. We retrospectively reviewed data for 609 patients who underwent adult LDLT from May 1997 to January 2018 and analyzed patients with a history of extrahepatic malignancies or concurrent malignancies. Fourteen patients had extrahepatic malignancies concurrent with or before LDLT. Malignancies in 9 patients were detected during their systematic screening for LDLT. The mean duration between surgeries was 70 days (range, 20-209 days). Five patients had a history of extrahepatic malignancies before considering LDLT. The estimated 5-year survival rate was 100%. Although the risk and long-term prognosis of patients with extrahepatic malignancy are not well known, such patients can be candidates for LDLT if they undergo curative surgery for the malignancy, and if the prognosis of the malignancy is the same or superior to that of LDLT.


Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response.
Helicobacter hepaticus infection in A/JCr mice results in chronic active hepatitis characterized by perivascular, periportal, and parenchymal infiltrates of mononuclear and polymorphonuclear cells. This study examined the development of hepatitis and the immune response of A/JCr mice to H. hepaticus infection. The humoral and cell-mediated T helper immune response was profiled by measuring the postinfection (p.i.) antibody response in serum, feces, and bile and by the production of cytokines and proliferative responses by splenic mononuclear cells to H. hepaticus antigens. Secretory immunoglobulin A (IgA) and systemic IgG2a antibody developed by 4 weeks p.i. and persisted through 12 months. Splenocytes from infected mice proliferated and produced more gamma interferon (IFN-gamma) than interleukin-4 (IL-4) or IL-5 when cultured with H. hepaticus outer membrane proteins. The predominantly IgG2a antibody response in serum and the in vitro production of IFN-gamma in excess of IL-4 or IL-5 are consistent with a Th1 immune response reported in humans and mice infected with Helicobacter pylori and Helicobacter felis, respectively. Mice infected with H. hepaticus developed progressively severe perivascular, periportal, and hepatic parenchymal lesions consisting of lymphohistiocytic and plasmacytic cellular infiltrates. In addition, transmural typhlitis was observed at 12 months p.i. The characterization of a cell-mediated Th1 immune response to H. hepaticus infection in the A/JCr mouse should prove valuable as a model for experimental regimens which manipulate the host response to Helicobacter.


Quality control in scRNA-Seq can discriminate pacemaker cells: the mtRNA bias.
Single-cell RNA-sequencing (scRNA-seq) provides high-resolution insights into complex tissues. Cardiac tissue, however, poses a major challenge due to the delicate isolation process and the large size of mature cardiomyocytes. Regardless of the experimental technique, captured cells are often impaired and some capture sites may contain multiple or no cells at all. All this refers to "low quality" potentially leading to data misinterpretation. Common standard quality control parameters involve the number of detected genes, transcripts per cell, and the fraction of transcripts from mitochondrial genes. While cutoffs for transcripts and genes per cell are usually user-defined for each experiment or individually calculated, a fixed threshold of 5% mitochondrial transcripts is standard and often set as default in scRNA-seq software. However, this parameter is highly dependent on the tissue type. In the heart, mitochondrial transcripts comprise almost 30% of total mRNA due to high energy demands. Here, we demonstrate that a 5%-threshold not only causes an unacceptable exclusion of cardiomyocytes but also introduces a bias that particularly discriminates pacemaker cells. This effect is apparent for our in vitro generated induced-sinoatrial-bodies (iSABs; highly enriched physiologically functional pacemaker cells), and also evident in a public data set of cells isolated from embryonal murine sinoatrial node tissue (Goodyer William et al. in Circ Res 125:379-397, 2019). Taken together, we recommend omitting this filtering parameter for scRNA-seq in cardiovascular applications whenever possible.


Impact of isoelectronic substitution and hydrostatic pressure on the quantum critical properties of CeRhSi3.
There is an ongoing dispute in the community about the absence of a magnetic quantum critical point (QCP) in the noncentrosymmetric heavy fermion compound CeRhSi3. In order to explore this question we prepared single crystals of CeRh(Si1-x Ge x )3 with x = 0.05 and 0.15 and determined the temperature-pressure (T-p) phase diagram by means of measurements of the electrical resistivity. The substitution of isoelectronic but large Ge enforces a lattice volume increase resulting in a weakening of the Kondo interaction. As a result, the x = 0.05 and x = 0.15 compound exhibit a transition into the antiferromagnetic (AFM) at higher temperatures being T N = 4.7 K and T N1 = 19.7 K, respectively. Application of pressure suppresses T N (T N1) monotonically and pressure induced superconductivity is observed in both Ge-substituted compounds above p ⩾ 2.16 GPa (x = 0.05) and p ⩾ 2.93 GPa (x = 0.15). Extrapolation of T N(p) → 0 of CeRh(Si0.95Ge0.05)3 yields a critical pressure of p c ≈ 3.4 GPa (in CeRh(Si0.85Ge0.15)3 p c ≈ 3.5 GPa) pointing to the presence of an AFM QCP located deep inside the superconducting state.


Bioconversion of lignocellulose: inhibitors and detoxification.
Bioconversion of lignocellulose by microbial fermentation is typically preceded by an acidic thermochemical pretreatment step designed to facilitate enzymatic hydrolysis of cellulose. Substances formed during the pretreatment of the lignocellulosic feedstock inhibit enzymatic hydrolysis as well as microbial fermentation steps. This review focuses on inhibitors from lignocellulosic feedstocks and how conditioning of slurries and hydrolysates can be used to alleviate inhibition problems. Novel developments in the area include chemical in-situ detoxification by using reducing agents, and methods that improve the performance of both enzymatic and microbial biocatalysts.


Treatment of focal segmental glomerulosclerosis.
The prognosis of untreated patients with focal segmental glomerulosclerosis is poor, as the disease progress to end-stage renal disease in approximately 50--70% of nephrotic patients. Although focal segmental glomerulosclerosis was initially considered to be a steroid-resistant disease, several studies have shown a better responsiveness to more prolonged courses of steroids. For patients with steroid-resistant or -dependent focal segmental glomerulosclerosis, cyclosporine A and cytotoxic agents have shown efficacy in clinical trials. Plasmapheresis or LDL-apheresis may represent a rescue treatment in patients who do not respond to other therapies. The role of other agents used in focal segmental glomerulosclerosis, including azathioprine, mycophenolate mofetil, tacrolimus, pefloxacin or vitamin E is still poorly defined.


Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.
Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. Here, we analyzed the RNA expression patterns of more than 76,000 individual microglia in mice during development, in old age, and after brain injury. Our analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states-including chemokine-enriched inflammatory microglia-persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human multiple sclerosis lesions. These distinct microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.


COVID-19 and food systems in Pacific Island Countries, Papua New Guinea, and Timor-Leste: Opportunities for actions towards the sustainable development goals.
The COVID-19 pandemic has impacted global food systems. This has led to different strategies by communities, governments, and businesses involved in food systems to mitigate and adapt to the unfolding pandemic. Small Island Developing States are particularly exposed to the conflation of risks from COVID-19 disease, economic downturns, underlying climate vulnerabilities and biosecurity risks. Our study aimed to identify the food systems vulnerabilities, impacts, and opportunities for supporting resilience and sustainable development in selected Pacific Island countries, Papua New Guinea, and Timor-Leste. The study focused on the impacts from the first six months of the pandemic (February-July 2020), with remote data collection and analysis done between May and July 2020. We conducted 67 interviews, and triangulated information with desktop and news sources emerging at the time. We present results on the effect on smallholder livelihoods, supply chains, governance, communities and employment. Overall, the major impacts of COVID-19 have been on economies, posing risks to future food security and further hampering progress towards key Sustainable Development Goals. We found that unemployment and economic contraction have been the most severe effects to date, with long-term consequences for food value chains and smallholder farmers. Disruptions to tourism, labour migration, and remittances have led to varying socio-economic impacts throughout the region. Vulnerable groups, notably women, urban poor, and youth, have been disproportionately affected by unemployment. Timor-Leste has had some social protection measures, whereas in Pacific Countries these have been varied. The lockdowns and State of Emergency initially influenced the distribution and marketing of food, but local food economies are starting to stabilise. The continued functioning of international food supply chains reduced the risk of food insecurity in high import dependent nations, notably import dependent countries like Tuvalu and Kiribati. The results have significance for three recovery pathways. The first recovery pathway relates to revisiting value chains in light of restricted travel. The second recovery pathway exists through leveraging the adaptive capacities of communities to stimulate innovative agriculture that also integrates climate adaptation and nutrition. The third recovery pathway relates to addressing the structural challenges that perpetuate inequalities and poverty while finding new ways of implementing inclusive policies and research. Our study presents a set of comparative examples of managing a food system shock that can inform future systems-oriented research and policy for sustainable development.


A Need for Better Understanding Is the Major Determinant for Public Perceptions of Human Gene Editing.
The CRISPR/Cas system could provide an efficient and reliable means of editing the human genome and has the potential to revolutionize modern medicine; however, rapid developments are raising complex ethical issues. There has been significant scientific debate regarding the acceptability of some applications of CRISPR/Cas, with leaders in the field highlighting the need for the lay public's views to shape expert discussion. As such, we sought to determine the factors that influence public opinion on gene editing. We created a 17-item online survey translated into 11 languages and advertised worldwide. Topic modeling was used to analyze textual responses to determine what factors influenced respondents' opinions toward human somatic or embryonic gene editing, and how this varied among respondents with differing attitudes and demographic backgrounds. A total of 3,988 free-text responses were analyzed. Respondents had a mean age of 32 (range, 11-90) years, and 37% were female. The most prevalent topics cited were Future Generations, Research, Human Editing, Children, and Health. Respondents who disagreed with gene editing for health-related purposes were more likely to cite the topic Better Understanding than those who agreed to both somatic and embryonic gene editing. Respondents from Western backgrounds more frequently discussed Future Generations, compared with participants from Eastern countries. Religious respondents did not cite the topic Religious Beliefs more frequently than did nonreligious respondents, whereas Christian respondents were more likely to cite the topic Future Generations. Our results suggest that public resistance to human somatic or embryonic gene editing does not stem from an inherent mistrust of genome modification, but rather a desire for greater understanding. Furthermore, we demonstrate that factors influencing public opinion vary greatly amongst demographic groups. It is crucial that the determinants of public attitudes toward CRISPR/Cas be well understood so that the technology does not suffer the negative public sentiment seen with previous genetic biotechnologies.


Improving the lives of millions through new double fortification of salt technology.
Micronutrient deficiencies (including iodine and iron deficiency) is a global health problem affecting one third of the world's population. Salt is an ideal carrier for food fortification as it is universally consumed at equal rates, independently of economic status, and it is industrially processed. Addressing iron and iodine deficiencies together is a challenge, due to interaction between iodine and iron, negating the effect of added iodine. This paper explains the development of an improved microencapsulation-based technology to produce iron premix, which, when added to iodized salt, is stable and organoleptically indistinguishable. Ferrous fumarate was extruded, followed by cutting, sieving to achieve a size of 300-710 μm (salt grain size). Agglomerated extrudates were microencapsulated (5% hydroxypropyl methylcellulose and 5% soy stearin) to form iron premix. Microencapsulation ensures that the added micronutrients are stable without interaction or degradation. Double Fortified Salt is formed by blending iron premix with iodized salt (1:200 ratio). This technology was transferred to India for industrial scale-up. The public distribution system was utilized to establish and monitor an efficient distribution network for DFS in a transparent manner. The scale-up process was initially demonstrated in the state of Uttar Pradesh, following its success two more Indian states have started distribution of DFS. At present, the DFS with iron and iodine is reaching 60 million people in India. This important health intervention technology through food fortification has the potential to be scaled globally to ensure a world free from iron deficiency anemia.


Cysteine-independent polymerization of metallothioneins in solutions and in crystals.
Polymerization of metallothioneins is one of the usually encountered puzzles during the research process of metallothioneins' structure and function. Our work focuses on the cysteine independently occurred polymerization from metallothioneins monomers in different milieus, while it leaves out the aggregation caused by the oxidation of cysteine, because the latter circumstance is the result of purification lapsus. After the purification of metallothioneins monomers, a dynamic light-scattering technique is used to detect the polymerized states of rabbit liver metallothionein I and II in different buffers, which is the first systematical detection of polymerized states of metallothioneins in solutions. The effects of different compositions of each buffer are discussed in details. Steric complementarity, hydrophobic, and electrostatic interaction characteristics are studied, following the modeling of monomers and relevant polymers of rat metallothionein II, rabbit liver metallothionein I and II. These theoretical calculations are the first complete computer simulations on different factors affecting metallothioneins' polymerization. A molecular recognition mechanism of metallothioneins' polymerization in solutions is proposed on the bases of experimental results and theoretical calculations. Preliminary X-ray studies of two crystal forms of rabbit liver metallothionein II are compared with the crystal structure of rat metallothionein II, and the polymerized states in crystal packing are discussed with the knowledge of polymerization of metallothioneins in solutions. The hypothesis, which is consistent with theoretical calculations and experimental results, is expected to construct a connection between the biochemical characteristics and physiological functions of metallothioneins, and this research may give some enlightenment to the topics of protein polymerizations.