Study protocol for the optimisation, feasibility testing and pilot cluster randomised trial of Positive Choices: a school-based social marketing intervention to promote sexual health, prevent unintended teenage pregnancies and address health inequalities in England.
Since the introduction of the Teenage Pregnancy Strategy (TPS), England's under-18 conception rate has fallen by 55%, but a continued focus on prevention is needed to maintain and accelerate progress. The teenage birth rate remains higher in the UK than comparable Western European countries. Previous trials indicate that school-based social marketing interventions are a promising approach to addressing teenage pregnancy and improving sexual health. Such interventions are yet to be trialled in the UK. This study aims to optimise and establish the feasibility and acceptability of one such intervention: Positive Choices. Design: Optimisation, feasibility testing and pilot cluster randomised trial.Interventions: The Positive Choices intervention comprises a student needs survey, a student/staff led School Health Promotion Council (SHPC), a classroom curriculum for year nine students covering social and emotional skills and sex education, student-led social marketing activities, parent information and a review of school sexual health services.Systematic optimisation of Positive Choices will be carried out with the National Children's Bureau Sex Education Forum (NCB SEF), one state secondary school in England and other youth and policy stakeholders.Feasibility testing will involve the same state secondary school and will assess progression criteria to advance to the pilot cluster RCT.Pilot cluster RCT with integral process evaluation will involve six different state secondary schools (four interventions and two controls) and will assess the feasibility and utility of progressing to a full effectiveness trial.The following outcome measures will be trialled as part of the pilot:Self-reported pregnancy and unintended pregnancy (initiation of pregnancy for boys) and sexually transmitted infections,Age of sexual debut, number of sexual partners, use of contraception at first and last sex and non-volitional sexEducational attainmentThe feasibility of linking administrative data on births and termination to self-report survey data to measure our primary outcome (unintended teenage pregnancy) will also be tested. This will be the first UK-based pilot trial of a school-wide social marketing intervention to reduce unintended teenage pregnancy and improve sexual health. If this study indicates feasibility and acceptability of the optimised Positive Choices intervention in English secondary schools, plans will be initiated for a phase III trial and economic evaluation of the intervention. ISRCTN registry (ISCTN12524938. Registered 03/07/2017).


Predictors of improvement in an open-trial multisite evaluation of emotion regulation group therapy.
Emotion regulation group therapy (ERGT) is a novel treatment specifically targeting deliberate non-suicidal self-harm (DSH) in individuals with borderline personality disorder (BPD). Identifying robust predictors of positive response to ERGT could aid clinicians in treatment selection; however, to date, only one such study has been conducted. Thus, we aimed to replicate previously identified predictors of treatment response to ERGT by investigating demographic, clinical, and diagnostic predictors in 95 women with BPD or subclinical BPD who had participated in an open-trial evaluation of ERGT. Outcomes evaluated were frequency of DSH and emotion dysregulation. Assessments were conducted at pretreatment, post-treatment, and 6-month follow-up. Multilevel mixed linear models and multilevel negative binomial generalized estimated equations were used to identify significant interactions between the predictors and outcomes. We found that greater pretreatment DSH frequency was associated with greater improvements in DSH during treatment (b = 0.998, SE = 0.00, p = 0.03) and follow-up (b = 0.997, SE = 0.00, p < 0.01) and that greater BPD severity was associated with greater improvements in DSH during treatment (b = 0.84, SE = 0.06, p = 0.02) and in emotion dysregulation at follow-up (b = -3.05, SE = 1.47, p = 0.04). Co-occurring disorders were associated with poorer treatment response during follow-up. Results were generally consistent with a previous study of the predictors of response to ERGT. The findings provide further support for the utility of this treatment across a range of BPD patients, including patients with severe DSH and BPD.


Mitral valve replacement in a Jehovah's Witness with dextrocardia and situs solitus.
Dextrocardia with situs solitus and mitral valve insufficiency requiring surgical treatment is a rare presentation. Jehovah's Witnesses (JW), a specific religious group, deny any blood transfusion and for this reason the cardiac surgeon has to plan his operation well in advance, particularly in the case of adhesions from previous thoracic procedures. A 50-year-old white female Jehovah's Witness with dextrocardia and situs solitus was referred for surgical treatment of massive mitral valve insufficiency of rheumatic etiology. Due to multiple adhesions from previous bilateral thoracotomies and the inverted position of the heart, cardiopulmonary bypass (CPB) was initiated with an aortic and a left common femoral vein cannulae. CPB was completed with an additional SVC cannula. The surgeon, having excellent exposure from the opposite side of the table, was able to perform a mitral valve replacement (MVR) with a 31 mm St. Jude Medical valve prosthesis, through a giant left atrium under moderate hypothermia and crystalloid cardioplegia. The operation was bloodless, with only two units of autotransfused blood being used with a postoperative hematocrit of 34%. The patient had an uneventful recovery and has been in NYHA class I for 24 months now. The case is presented for the safety of the approach, the excellent exposure from the left side in a dextrocardia case and the avoidance of blood transfusion in a Jehovah's patient.


[Loss of visual acuity caused by ethmoidal mucocele cured after endonasal surgery: report of a case].
A posterior and/or ethmoidal mucocele remains a rare occurrence. The condition usually follows a past history of sinonasal surgery. Extension of the lesion may have ophtalmological implications, with the possibility of causing visual impairment. The predilection for a site of origin in the posterior sinuses explains the frequent absence of nasal symptoms, and the usual pattern of discovery by the ophtalmologist. Modern imaging techniques, especially scanning, allows the diagnosis to be made immediately after the first orbital symptoms. By the same token, recent techniques of endoscopic endonasal surgery have radically changed the treatment. Early complete surgical removal holds out hope for remission of the symptoms that led originally to discovery of the mucocele. We report here a case of posterior ethmoidal mucocele causing a visual field defect which reversed completely after endoscopic treatment.


Optimization of a 1,4,7-Triazacyclononane-1,4-diacetic acid (NODA) Derivative Radiofluorination by Al18 F Complexation Using a Design of Experiments Approach.
Fluorine-18 (18 F) is the most favorable positron emitter for radiolabeling Positron Emission Tomography (PET) probes. However, conventional 18 F labeling through covalent C-F bond formation is challenging, involving multiple steps and stringent conditions unsuitable for sensitive biomolecular probes whose integrity may be altered. Over the past decade, an elegant new approach has been developed involving the coordination of an aluminum fluoride {Al18 F} species in aqueous media at a late-stage of the synthetic process. The objective of this study was to implement this method and to optimize radiolabeling efficiency using a Design of Experiments (DoE). To assess the impact of various experimental parameters on {Al18 F} incorporation, a pentadentate chelating agent NODA-MP-C4 was prepared as a model compound. This model carried a thiourea function present in the final conjugates resulting from the grafting of the chelating agent onto the probe. The formation of the radioactive complex Al18 F-NODA-MP-C4 was studied to achieve the highest radiochemical conversion. A complementary "cold" series study using the natural isotope 19 F was also conducted to guide the radiochemical operating conditions. Ultimately, Al18 F-NODA-MP-C4 was obtained with a reproducible and satisfactory radiochemical conversion of 79±3.5 % (n=5).


An update on the management of hepatitis C virus-infected patients with stage 4-5 chronic kidney disease while awaiting the revised KDIGO Guidelines.
The treatment of hepatitis C virus (HCV) infection has progressed markedly over the last 2 decades, with a dramatic acceleration the last 3 years. The combination of two or three direct-acting antiviral drugs (DAAs) targeting viral proteins [NS3/4A protease inhibitors, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase inhibitors, NS5A replication complex inhibitors], with or without ribavirin but without interferon (interferon-free regimen), for 8-24 weeks, achieved high sustained virological response (>90%), whatever fibrosis stage, genotype and subtype, baseline viral load, prior therapeutic history of the patient (naïve or experienced) and pre-existing resistance-associated variants with a fair tolerance and reduced pill burden. International guidelines recommend to ideally treat all infected patients even if a prioritization of the most severe patients (extensive fibrosis or cirrhosis, symptomatic cryoglobulinaemic vasculitis…) appears to be the best cost-effective and urgent policy. Patients with stage 4-5 chronic kidney disease (CKD) have to be considered as priority patients. Updating of the Kidney Disease: Improving Global Outcomes recommendations is due to start soon, but awaiting their availability, we present here an overview of recent developments in the field.


Metformin-Associated Lactic Acidosis in a Diabetic Patient with Normal Kidney Function and Occult Cirrhosis.
Lactic acidosis is a well-known complication of metformin accumulation in diabetic patients with kidney failure. However, it is not usual to raise the diagnosis of metformin-associated lactic acidosis when patients have normal kidney function. The causes of metformin-induced high lactate include the accumulation of normal doses of metformin in chronic kidney disease, an overdose of this drug without kidney failure, or an increase in lactate production due to the inhibition of liver gluconeogenesis. Case Presentation. We report the case of a 61-year-old diabetic man who was brought to the emergency room in a comatose state. His family reported abdominal pain with diarrhea in the last two days. He was found to have severe lactic acidosis with normal serum creatinine. He was on a regular dose of metformin, and his family denied any other medical history or any alcohol abuse. He showed no signs of infection, his liver enzymes were slightly elevated, and he had severe anemia. His hemodynamics deteriorated quickly within hours, and an abdominal computed tomography scan revealed no abnormalities. He underwent a laparotomy that ruled out mesenteric ischemia and revealed an abnormal liver. The liver biopsy later confirmed the diagnosis of cirrhosis. We discuss here the probable causes of severe lactic acidosis and the role of metformin in exacerbating this acid-base disturbance in cirrhotic patients. Future research is needed to determine whether these patients might benefit from dialysis.


OSMOTIC PROPERTIES OF HUMAN RED CELLS.
The hematocrit method as a technique for determining red cell volume under anisotonic conditions has been reexamined and has been shown, with appropriate corrections for trapped plasma, to provide a true measure of cell volume. Cell volume changes in response to equilibration in anisotonic media were found to be much less than those predicted for an ideal osmometer; this anomalous behavior cannot be explained by solute leakage or by the changing osmotic coefficient of hemoglobin, but is quantitatively accounted for by the hypothesis that 20 per cent of intracellular water is bound to hemoglobin and is unavailable for participation in osmotic shifts.


Distribution and excretion of sumatriptan in human milk.
1. The excretion of a 6 mg subcutaneous dose of sumatriptan in breast milk was studied in five lactating volunteer subjects with a mean age of 27.6 years and a mean body weight of 75 kg. Drug concentrations in milk and plasma over the ensuing 8 h were measured by high-performance liquid chromatography. 2. The mean milk:plasma ratio estimated from the areas under the milk and plasma concentration-time curves (AUC) was 4.9 (95% CI 4.1-5.7), indicating a significant transfer of sumatriptan into the milk compartment. 3. The mean total recovery of drug in milk was estimated to be only 14.4 micrograms (95% CI 6.1-22.7 micrograms), or 0.24% of the 6 mg administered dose. On a weight-adjusted basis this corresponded to a mean infant exposure of 3.5% of the maternal dose (95% CI 0.3-6.7%). 4. If oral bioavailability in the infant is similar to that in adults (14%), the weight-adjusted infant dose is reduced to 0.49%. Furthermore, allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in a very premature neonate to 0.7% in a 30 week old infant. 5. Since sumatriptan is usually administered as a single dose at infrequent intervals, the low level of excretion in breast milk suggests that continued breast feeding following its use will not pose a significant risk to the suckling infant. Even this minor exposure could be largely avoided by expressing and discarding all milk for 8 h after the dose.


Beat-ID: Towards a computationally low-cost single heartbeat biometric identity check system based on electrocardiogram wave morphology.
In recent years, safer and more reliable biometric methods have been developed. Apart from the need for enhanced security, the media and entertainment sectors have also been applying biometrics in the emerging market of user-adaptable objects/systems to make these systems more user-friendly. However, the complexity of some state-of-the-art biometric systems (e.g., iris recognition) or their high false rejection rate (e.g., fingerprint recognition) is neither compatible with the simple hardware architecture required by reduced-size devices nor the new trend of implementing smart objects within the dynamic market of the Internet of Things (IoT). It was recently shown that an individual can be recognized by extracting features from their electrocardiogram (ECG). However, most current ECG-based biometric algorithms are computationally demanding and/or rely on relatively large (several seconds) ECG samples, which are incompatible with the aforementioned application fields. Here, we present a computationally low-cost method (patent pending), including simple mathematical operations, for identifying a person using only three ECG morphology-based characteristics from a single heartbeat. The algorithm was trained/tested using ECG signals of different duration from the Physionet database on more than 60 different training/test datasets. The proposed method achieved maximal averaged accuracy of 97.450% in distinguishing each subject from a ten-subject set and false acceptance and rejection rates (FAR and FRR) of 5.710±1.900% and 3.440±1.980%, respectively, placing Beat-ID in a very competitive position in terms of the FRR/FAR among state-of-the-art methods. Furthermore, the proposed method can identify a person using an average of 1.020 heartbeats. It therefore has FRR/FAR behavior similar to obtaining a fingerprint, yet it is simpler and requires less expensive hardware. This method targets low-computational/energy-cost scenarios, such as tiny wearable devices (e.g., a smart object that automatically adapts its configuration to the user). A hardware proof-of-concept implementation is presented as an annex to this paper.


Advances in quality of life measurements in oncology patients.
Accurate assessment of the quality of life (QOL) of patients can provide important clinical information to physicians, especially in the area of oncology. Changes in QOL are important indicators of the impact of a new cytotoxic therapy, can affect a patient's willingness to continue treatment, and may aid in defining response in the absence of quantifiable endpoints such as tumor regression. Because QOL is becoming an increasingly important aspect in the management of patients with malignant disease, it is vital that the instruments used to measure QOL are reliable and accurate. Assessment of QOL involves a multidimensional approach that includes physical, functional, social, and emotional well-being, and the most comprehensive instruments measure at least three of these domains. Instruments to measure QOL can be generic (eg, the Nottingham Health Profile), targeted toward specific illnesses (eg, Functional Assessment of Cancer Therapy - Lung), or be a combination of generic and targeted. Two of the most widely used examples of the combination, or hybrid, instruments are the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items and the Functional Assessment of Chronic Illness Therapy. A consequence of the increasing international collaboration in clinical trials has been the growing necessity for instruments that are valid across languages and cultures. To assure the continuing reliability and validity of QOL instruments in this regard, item response theory can be applied. Techniques such as item response theory may be used in the future to construct QOL item banks containing large sets of validated questions that represent various levels of QOL domains. As QOL becomes increasingly important in understanding and approaching the overall management of cancer patients, the tools available to clinicians and researchers to assess QOL will continue to evolve. While the instruments currently available provide reliable and valid measurement, further improvements in precision and application are anticipated.


Are We Missing Out on Something?
Suicide risk is very high in the patients suffering from advanced cancer. Around 60% of patients with advanced cancer suffer from cancer related pain and this further accentuates the risk of psychiatric disorders as well as suicide. A fifty year old male who was a known case of carcinoma of floor of mouth, post chemotherapy and post radiotherapy came in the outpatient clinic with complains of throat pain which increased on swallowing. On further probing, it was revealed, that he consumed poison in the recent past while being agitated and upset with the severe throat pain. The recent radiotherapy had only made the pain worse. Cancer pain is an important symptom which should be adequately addressed while reviewing patients in the palliative care / oncologist clinic.


Improving Clinical Performance of an Interprofessional Emergency Medical Team Through a One-day Crisis Resource Management Training.
Errors are frequent in health care and Emergency Departments are one of the riskiest areas due to frequent changes of team composition, complexity and variety of the cases and difficulties encountered in managing multiple patients. As the majority of clinical errors are the results of human factors and not technical in nature or due to the lack of knowledge, a training focused on these factors appears to be necessary. Crisis resource management (CRM), a tool that was developed initially by the aviation industry and then adopted by different medical specialties as anesthesia and emergency medicine, has been associated with decreased error rates. To assess whether a single day CRM training, combining didactic and simulation sessions, improves the clinical performance of an interprofessional emergency medical team. Seventy health professionals with different qualifications, working in an emergency department, were enrolled in the study. Twenty individual interprofessional teams were created. Each team was assessed before and after the training, through two in situ simulated exercises. The exercises were videotaped and were evaluated by two assessors who were blinded as to whether it was the initial or the final exercise. Objective measurement of clinical team performance was performed using a checklist that was designed for each scenario and included essential assessment items for the diagnosis and treatment of a critical patient, with the focus on key actions and decisions. The intervention consisted of a one-day training, combining didactic and simulation sessions, followed by instructor facilitated debriefing. All participants went through this training after the initial assessment exercises. An improvement was seen in most of the measured clinical parameters. Our study supports the use of combined CRM training for improving the clinical performance of an interprofessional emergency team. Empirically this may improve the patient outcome.


Axial optical trapping efficiency through a dielectric interface.
Axial trapping through a dielectric interface is investigated in the framework of the angular spectrum representation and of the generalized Lorenz-Mie theory. We determine the optical force for an arbitrarily polarized non-paraxial, strongly aberrated, axially symmetric focusing beam and apply this description to the case of an arbitrarily positioned dielectric microsphere, commonly employed in optical tweezers, not taking into account the contribution of evanescent waves at the interface. We derive the analytical expression of the force profile, finding that the incident polarization does not affect the axial optical force. In addition, we derive an approximated expression for the axial force as a function of beam displacement just outside the microsphere and we show how the information provided by the ripple structure of the optical trapping efficiency versus sphere displacement curve, due to the aberration effect, could be exploited to calibrate the bead axial position versus the experimental beam positioning controls.


Towards Smart City Governance. Case Study: Improving the Interpretation of Quantitative Traffic Measurement Data through Citizen Participation.
Citizens play a core role in sustainable cities as users of the services delivered by cities and as active participants in initiatives aimed at making cities more sustainable. This paper considers the role of citizens as information providers and discusses the conditions under which citizens can participate in the development of sustainable cities. The objective of this study is to document the sustainability of an urban transit system and evaluate its compliance, with citizen participation as a major contributor. The methodology used is intensive field visits, interviews, and a mixed analysis of Sant Andreu de Palomar District in Barcelona city. The circulating vehicles are quantitatively monitored, qualitative problems are detected, and the typology of vehicles and other aspects identified and detailed in the study are indicated. All this information is contrasted with that of the technological sensors in the sectors. The results indicate that vehicles in the current pattern of urban density planned under incorrect sensor operation influence sustainable behavior through agglomerative clustering. This paper provides recommendations for future urban sustainability assessment research, including the employment of mixed-methods research, among other strategies. This article is intended to assist policymakers and traffic engineers in evaluating the sustainability of urban transportation infrastructure projects considering citizens as sensors.


Antibiotic stewardship in the newborn surgical patient: A quality improvement project in the neonatal intensive care unit.
There is significant diversity in the utilization of antibiotics for neonates undergoing surgical procedures. Our institution standardized antibiotic administration for surgical neonates, in which no empiric antibiotics were given to infants with surgical conditions postnatally, and antibiotics are given no more than 72 hours perioperatively. We compared the time periods before and after implementation of antibiotic protocol in an institution review board-approved, retrospective review of neonates with congenital surgical conditions who underwent surgical correction within 30 days after birth. Surgical site infection at 30 days was the primary outcome, and development of hospital-acquired infections or multidrug-resistant organism were secondary outcomes. One hundred forty-eight infants underwent surgical procedures pre-protocol, and 127 underwent procedures post-protocol implementation. Surgical site infection rates were similar pre- and post-protocol, 14% and 9% respectively, (P = .21.) The incidence of hospital-acquired infections (13.7% vs 8.7%, P = .205) and multidrug-resistant organism (4.7% vs 1.6%, P = .143) was similar between the 2 periods. Elimination of empiric postnatal antibiotics did not statistically change rates of surgical site infection, hospital-acquired infections, or multidrug-resistant organisms. Limiting the duration of perioperative antibiotic prophylaxis to no more than 72 hours after surgery did not increase the rate of surgical site infection, hospital-acquired infections, or multidrug-resistant organism. Median antibiotic days were decreased with antibiotic standardization for surgical neonates.


Cell fusion between L-forms and protoplasts of Staphylococcus aureus.
Mixtures of various combinations of Lysostaphin protoplasts and stable L-forms of Staphylococcus aureus, which have different markers for drug resistance, were treated with polyethylene glycol (PEG) to examine the development of doubly resistant fusion products (fusants). To recover doubly resistant colonies as L-forms, they were incubated in 4.5% NaCl-brain heart infusion (BHI) broth containing penicillin G (PCG) for enrichment culture and cultured in PCG-4.5% NaCl-BHI agar medium (method 1), while to recover doubly resistant fusants as L-forms and coccal forms, they were grown on reversion medium (R medium) which causes reversion of protoplasts or fusants to parent type cells, and then cultured on assay media, i.e., R medium, BHI agar medium or PCG-4.5% NaCl-BHI agar medium (method 2). Under both experimental conditions, doubly resistant fusants developed as L-form cells by PEG treatment of pairs of protoplasts carrying the chloramphenicol (CP)-resistance plasmid and L-forms having chromosomal resistance to streptomycin (SM). In the reverse combinations, i.e., protoplasts showing chromosomal SM-resistance and L-form cells carrying the CP-resistance plasmid, the first method gave no doubly resistant colonies. By the second method, without enrichment culture on R medium, the latter combination gave doubly resistant fusants as L-form, coccal-type and mixed-type colonial forms, while when the PEG-treated mixture was enriched on R medium, fusants were obtained exclusively as the coccal type on either R medium or BHI agar assay medium. Neither of the methods yielded colonies of doubly resistant fusants on PEG-treatment of pairs of protoplasts and L-forms both of which were chromosomal, but with different drug resistances. These results show that PEG-induced cell fusion between protoplasts and L-forms of S. aureus, unlike the fusion between protoplasts or between L-forms, resulted in transfer of the drug resistance controlled by the plasmid to the fusion products. The fusants obtained were L-forms in method 1, and coccal type in the method 2.


Dual-color fluorescence cross-correlation spectroscopy in a single nanoaperture : towards rapid multicomponent screening at high concentrations.
Single nanometric apertures in a metallic film are used to develop a simple and robust setup for dual-color fluorescence cross-correlation spectroscopy (FCCS) at high concentrations. If the nanoaperture concept has already proven to be useful for single-species analysis, its extension to the dual-color case brings new interesting specificities. The alignment and overlap of the two excitation beams are greatly simplified. No confocal pinhole is used, relaxing the requirement for accurate correction of chromatic aberrations. Compared to two-photon excitation, nanoapertures have the advantage to work with standard fluorophore constructions having high absorption cross-section and well-known absorption/emission spectra. Thanks to the ultra-low volume analysed within one single aperture, fluorescence correlation analysis can be performed with single molecule resolution at micromolar concentrations, resulting in 3 orders of magnitude gain compared to conventional setups. As applications of this technique, we follow the kinetics of an enzymatic cleavage reaction at 2 muM DNA oligonucleotide concentration.We also demonstrate that FCCS in nanoaper-tures can be applied to the fast screening of a sample for dual-labeled species within 1 s acquisition time. This offers new possibilities for rapid screening applications in biotechnology at high concentrations.


Polymorphous ventricular tachyarrhythmias in the absence of structural heart disease.
Polymorphous ventricular tachyarrhythmias (PVTA) in the absence of structural heart disease form a particularly important target for comprehensive research. They occur in young, healthy children and young adults and most probably cover several underlying electrophysiological abnormalities. We individualized two syndromes, namely catecholaminergic ventricular tachyarrhythmias, and torsade de pointes (TDP) with a short coupling interval, but these two entities certainly represent only a part of the problem of idiopathic ventricular fibrillation. Having the implanted defibrillator as a therapeutic umbrella for those patients who were fortunate enough to escape from sudden death is not sufficient. Too often in modern cardiology the therapeutic achievements tend to precede the process of diagnosis and comprehension. At least, the former should not preclude the latter, a situation that can be observed, for instance, when the favorable effect of a drug is evidenced before its mode of action was understood. At best, both progress together, provided we pay attention to adequately exploit the resources of modern technology.


Food restriction increases torpor and improves brown adipose tissue thermogenesis in ob/ob mice.
Restricting the food intake of the genetically obese (ob/ob) mouse is known to ameliorate its cold intolerance. Cold intolerance of the ob/ob mouse is associated with defective thermogenesis in its brown adipose tissue. The objective of the experiments was to find out whether food restriction could increase the thermogenic function of brown adipose tissue of the ob/ob mouse. Obese and lean mice were fed a restricted amount of chow in one meal per day for 3-7 mo. Both lean and ob/ob mice were torpid (rectal temperature of approximately 32 degrees C) in the early morning and aroused spontaneously to a normal body temperature before the anticipated meal time. Obese mice were also torpid during the dark phase, whereas lean mice were active and had a normal body temperature at this time. Brown adipose tissue was in a thermogenically inactive state (low level of mitochondrial GDP binding) in torpid lean and ob/ob mice but became thermogenically active (increase in mitochondrial GDP binding) during stimulated arousal when body temperature increased by 6-7 degrees C in 15-30 min. Ad libitum-fed ob/ob mice had a normal diurnal rhythm in a rectal temperature that was at a lower level than in lean ad libitum-fed mice. They did not raise their rectal temperatures when stimulated and no activation of brown adipose tissue thermogenesis occurred under these conditions. Food restriction increased the capacity of both lean and ob/ob mice to raise their metabolic rate in response to injection of noradrenaline, indicating an increased capacity for thermogenesis in their brown adipose tissue.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative outcomes in intestinal atresia: a clinical outcome and pathophysiology analysis.
To describe the outcomes of 130 intestinal atresias between 1982 and 2007. Records were analyzed for location, demographics, prenatal diagnosis, birth weight, associated anomalies, surgery, establishment of oral intake, re-interventions and mortality. Statistical analyses were performed using Fisher test and ANOVA. There were 59 duodenal (30 male), 63 jejuno-ileal (34 male) and 8 colonic atresias (3 male). Prenatal diagnosis was established in 27 (46%) duodenal (DA), 26 (41%) jejuno-ileal (JIA) and 1 (12.5%) colonic atresias (CA). The mean birth weights, 2,380.5 g (SD 988) DA, 2,814 g (SD 755) JIA and 3,153 g (SD 527) CA were significantly different (p = 0.011). The mean gestational ages were 36, 37 and 37 weeks in DA, JIA and CA, respectively (p-NS). Associated congenital anomalies were seen in 41 (76%) DA, 32 (52%) JIA and 3 (38%) CA (p = 0.08, NS). The median time to full oral feeds after surgery was 18 days in DA, 20 days in JIA and 15.6 days in CA, respectively (p > 0.05). Eight patients with DA and nine patients with JIA underwent repeat surgery for adhesive obstruction. Adhesive bowel obstruction was most common in the first year after surgery in both groups (15/17). Gastroschisis was seen in six (10%) of JIA and three (35%) of CA. Two patients in the JIA group underwent bowel lengthening. Patients with gastroschisis and those with associated anomalies needed prolonged duration of TPN after JIA correction. There was no mortality in the duodenal atresia and colonic atresia groups. Six patients in the JIA group died, three of severe atresias coupled with multiple anomalies and three of cholestasis and sepsis. Distal atresias are difficult to diagnose antenatally. Proximal atresias have a significantly lower birth weight than distal atresias. Associated anomaly screening is important in all atresias.


Epidemiological & clinical characteristics & early outcome of COVID-19 patients in a tertiary care teaching hospital in India: A preliminary analysis.
In this study we describe the epidemiological data, comorbidities, clinical symptoms, severity of illness and early outcome of patients with coronavirus disease 2019 (COVID-19) from a tertiary care teaching hospital in New Delhi, India. In this preliminary analysis of a prospective observational study, all adult patients admitted to the screening intensive care unit (ICU) of the institute who fulfilled the WHO case definition of COVID-19 and confirmed to have SARS-CoV-2 infection by reverse transcription-polymerase chain reaction were included. Demographics, clinical data and 24 h outcome were assessed. The preliminary analysis of 235 patients revealed that the mean age was 50.7±15.1 yr and 68.1 per cent were male. Fever (68.1%), cough (59.6%) and shortness of breath (71.9%) were the most common presenting symptoms. Hypertension (28.1%) and diabetes mellitus (23.3%) were the most common associated comorbid illnesses. Patients with mild, moderate, severe and critical illness were 18.3, 32.3, 31.1 and 18.3 per cent, respectively, at the time of ICU admission. The proportions (95% confidence interval) of patients requiring any form of oxygen therapy, oxygen therapy by high-flow nasal cannula and invasive mechanical ventilation were 77, 21.7 and 25.5 per cent, respectively, within 24 h of hospital admission. The 24 h ICU mortality was 8.5 per cent, and non-survivors had higher respiratory rate (P <0.01, n=198) and lower baseline oxyhaemoglobin saturation (P <0.001, n=198) at presentation and higher baseline serum lactate (P <0.01, n=122), total leucocyte count (P <0.001, n=186), absolute neutrophil count (P <0.001, n=132), prothrombin time (P <0.05, n=54) and INR (P <0.05, n=54) compared to survivors. Nearly half of the patients presented with severe and critical disease and required high-flow nasal oxygen or invasive mechanical ventilation at admission. Severity of the presenting respiratory illness, haematological parameters and lactate rather than age or presence of comorbidity predicted early death within 24 h.


Cardiorespiratory fitness, LDL cholesterol, and CHD mortality in men.
There are no published data regarding the joint association of cardiorespiratory fitness (CRF) and LDL cholesterol concentration with subsequent CHD mortality in men. A total of 40,718 healthy men received a comprehensive baseline clinical examination between 1971 and 2006. CRF was determined from a maximal treadmill exercise test. Participants were divided into categories of low (quintile 1), moderate (quintiles 2-3), and high (quintiles 4-5) CRF by age group, as well as by Adult Treatment Panel III-defined LDL categories. HRs for CHD mortality were computed with Cox regression analysis. A total of 557 deaths due to CHD occurred during 16.7 ± 9.0 yr (681,731 man-years) of follow-up. After adjustment for age, examination year, smoking status, family history, and body mass index, a significant positive trend in CHD mortality was shown across decreasing categories of CRF. HRs with 95% confidence interval were 1.0 (referent), 1.18 (0.94-1.47), and 2.10 (1.65-2.67) for high, moderate, and low fit groups, P trend <0.0001. Adjusted HRs were significantly higher across increasing LDL categories: 1.0 (referent), 1.30 (0.87-1.95), 1.54 (1.04-2.28), 2.16 (1.45-3.21), and 2.02 (1.31-3.13), P trend <0.0001. When grouped by CRF category as well as by LDL category, there was a significant positive trend (P < 0.02) in adjusted mortality across decreasing categories of CRF within each LDL category. CRF is strongly and inversely associated with CHD mortality in men. Compared with men with low CRF, at a moderate to high level of CRF, the risk of mortality within each LDL category is significantly attenuated. This study suggests that measurement of CRF should be considered for routine cardiovascular risk assessment and risk management.


Impact of Supraphysiological Estradiol Serum Levels on Birth Weight in Singletons Born After Fresh Embryo Transfer.
In assisted reproductive technology, high estradiol (E2) levels at trigger may increase the risk of low birth weight (LBW). Our objective was to investigate the impact of supra-physiological E2 levels at trigger, on the rate of LBW in singleton pregnancies following fresh embryo transfers (ET), in a center that typically employs the 'freeze-all' strategy in case of high E2 levels, to prevent ovarian hyper stimulation syndrome risk. A cohort study was conducted in a university hospital between November 2012 and January 2017. The main inclusion criterion was having a live birth (LB) singleton (≥ 24 weeks of gestation) after a fresh-ET. Four groups were defined according to the E2 level at trigger, as quartiles of the entire patient population. The main measured outcome was the rate of LBW. 497 fresh-ET led to LB. Mean E2 level was 1608.4 ± 945.5 pg/ml. The groups were allocated as follows: 124LB in the Group E2 < 25 percentile(p) (1106.5 pg/ml), 124LB in the Group E2 [25p-50p] (1106.5-1439 pg/ml), 124LB in the Group E2[50p-75p] (1440-1915 pg/ml), and 125LB in the Group E2 > 75p (>1915 pg/ml). There was no significant difference in the rate of LBW (Group E2 < 25p, n = 8/124, (6.5%); Group E2[25p-50p], n = 15/124, (12.1%); Group E2 [50p-75p], n = 13/124, (10.4%); and Group E2 > 75p, n = 10/12, (8.1%); (p = 0.43)). After multivariate analysis, E2 level at trigger was not significantly correlated to the rate of LBW. In our cohort, E2 level on the day of hCG trigger was not associated with increased odds of LBW after fresh embryo transfers.


Altered antibody profiles against common infectious agents in chronic disease.
Despite the important diagnostic value of evaluating antibody responses to individual human pathogens, antibody profiles against multiple infectious agents have not been used to explore health and disease mainly for technical reasons. We hypothesized that the interplay between infection and chronic disease might be revealed by profiling antibodies against multiple agents. Here, the levels of antibodies against a panel of 13 common infectious agents were evaluated with the quantitative Luciferase Immunoprecipitation Systems (LIPS) in patients from three disease cohorts including those with pathogenic anti-interferon-γ autoantibodies (IFN-γ AAB), HIV and Sjögren's syndrome (SjS) to determine if their antibody profiles differed from control subjects. The IFN-γ AAB patients compared to controls demonstrated statistically higher levels of antibodies against VZV (p=0.0003), EBV (p=0.002), CMV (p=0.003), and C. albicans (p=0.03), but lower antibody levels against poliovirus (p=0.04). Comparison of HIV patients with blood donor controls revealed that the patients had higher levels of antibodies against CMV (p=0.0008), HSV-2 (p=0.0008), EBV (p=0.001), and C. albicans (p=0.01), but showed decreased levels of antibodies against coxsackievirus B4 (p=0.0008), poliovirus (p=0.0005), and HHV-6B (p=0.002). Lastly, SjS patients had higher levels of anti-EBV antibodies (p=0.03), but lower antibody levels against several enteroviruses including a newly identified picornavirus, HCoSV-A (p=0.004), coxsackievirus B4 (p=0.04), and poliovirus (p=0.02). For the IFN-γ AAB and HIV cohorts, principal component analysis revealed unique antibody clusters that showed the potential to discriminate patients from controls. The results suggest that antibody profiles against these and likely other common infectious agents may yield insight into the interplay between exposure to infectious agents, dysbiosis, adaptive immunity and disease activity.


Identification of Soil Properties Associated with the Incidence of Banana Wilt Using Supervised Methods.
Over the last few decades, a growing incidence of Banana Wilt (BW) has been detected in the banana-producing areas of the central zone of Venezuela. This disease is thought to be caused by a fungal−bacterial complex, coupled with the influence of specific soil properties. However, until now, there was no consensus on the soil characteristics associated with a high incidence of BW. The objective of this study was to identify the soil properties potentially associated with BW incidence, using supervised methods. The soil samples associated with banana plant lots in Venezuela, showing low (n = 29) and high (n = 49) incidence of BW, were collected during two consecutive years (2016 and 2017). On those soils, sixteen soil variables, including the percentage of sand, silt and clay, pH, electrical conductivity, organic matter, available contents of K, Na, Mg, Ca, Mn, Fe, Zn, Cu, S and P, were determined. The Wilcoxon test identified the occurrence of significant differences in the soil variables between the two groups of BW incidence. In addition, Orthogonal Least Squares Discriminant Analysis (OPLS-DA) and the Random Forest (RF) algorithm was applied to find soil variables capable of distinguishing banana lots showing high or low BW incidence. The OPLS-DA model showed a proper fitting of the data (R2Y: 0.61, p value < 0.01), and exhibited good predictive power (Q2: 0.50, p value < 0.01). The analysis of the Receiver Operating Characteristics (ROC) curves by RF revealed that the combination of Zn, Fe, Ca, K, Mn and Clay was able to accurately differentiate 84.1% of the banana lots with a sensitivity of 89.80% and a specificity of 72.40%. So far, this is the first study that identifies these six soil variables as possible new indicators associated with BW incidence in soils of lacustrine origin in Venezuela.


Private practice occupational therapy in the skilled nursing facility: creative alliance or mutual exploitation?
Occupational therapy private practice appears to play a major role in the provision of rehabilitation services in skilled nursing facilities. A critical look at the meaning of private practice, however, indicates that many of today's private practitioners lack characteristics traditionally associated with that term. Group private practices are well suited to retain the essential qualities of private practice while competing effectively in a corporate environment. They accomplish this difficult task by applying therapeutic principles of growth and change to the complex relationship between the group practice and the skilled nursing facility. Application of these principles allows the occupational therapy group private practice to behave consistently with its professional identity while addressing the competitive demands of the marketplace.


Pushing the bench: A mixed methods study of barriers to and facilitators of identification and referral into depression care by professional nurses in KwaZulu-Natal, South Africa.
Integration of mental health and chronic disease services in primary care could reduce the mental health treatment gap and improve associated health outcomes in low-resource settings. Low rates of nurse identification and referral of patients with depression limit the effectiveness of integrated mental health care; the barriers to and facilitators of identification and referral in South Africa and comparable settings remain undefined. This study explored barriers to and facilitators of nurse identification and referral of patients with depressive symptoms as part of integrated mental health service delivery in KwaZulu-Natal, South Africa. Triangulation mixed methods study incorporating qualitative and quantitative data. Data collection, analysis, and interpretation were guided by the Consolidated Framework for Implementation Research (CFIR). Participants were professional nurses at ten primary health care facilities in Amajuba, KwaZulu-Natal, South Africa. Qualitative data collection involved semi-structured interviews targeting specific CFIR constructs with high- and low-referring nurses. Deductive and inductive coding were used to derive primary themes related to barriers and facilitators. Quantitative data collection involved a structured questionnaire assessing determinants explored in the interviews. Qualitative comparative analysis was used to identify the necessary or sufficient conditions for high and low nurse referral. Twenty-two nurses were interviewed. Primary themes related to insufficient training, supervision, and competency; emotional burden; limited human and physical resources; perceived patient need for integrated services; and intervention acceptability. Sixty-eight nurses completed questionnaires. Quantitative results confirmed and expanded upon the qualitative findings. Low self-assessed competency was a consistent barrier to appropriate service delivery. To promote the success of integrated care in a context of severe staff shortages and over-burdened providers, implementation strategies including direct training, structured supervision, and routine behavioral health screening tools are warranted. Interventions to improve mental health literacy of patients as well as emotional support for nurses are also needed.


Melanoma-induced brain metastases.
Brain metastases are a common site of metastasis from malignant melanoma, and are associated with a poor prognosis. Diagnosis of brain metastasis may also have significant implications for quality of life, and management can be difficult due to rapid progression of disease and resistance to conventional therapies. In this article, we will review the published evidence for treatment modalities for melanoma-induced brain metastases and outline future directions for research. In brief, surgical management of solitary or acutely symptomatic lesions appears to alleviate symptoms and provide the possibility of local control of disease. Stereotactic radiosurgery is an increasingly utilized technique for patients with a limited number of metastases, and presents a less invasive alternative to craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, though combined chemotherapy with external-beam radiation is being investigated. Future directions include combined-modality therapy, the incorporation of novel agents, and careful consideration of the structure of clinical trials for this disease.


Overexpression of hydroperoxide lyase gene in Nicotiana benthamiana using a viral vector system.
13-Lipoxygenase (13-LOX) and 13-hydroperoxide lyases (13-HPL) are the key enzymes for the production of the 'green note' compounds hexanal, (3Z)- and (2E)-hexenal in plant tissues. To produce high levels of 13-LOX and 13-HPL enzymatic activities for a biocatalytic process to generate C(6)-aldehydes on a large scale, soya bean 13-LOX (GmVLXC) and watermelon 13-HPL (ClHPL) genes were expressed in Nicotiana benthamiana using a viral vector system mediated by agroinfiltration. The N. benthamiana leaves produced high activity of watermelon HPL, but not GmVLXC 13-LOX. In addition, all leaves treated with bacterial suspension displayed a high activity of 9-LOX, indicating that the internal tobacco 9-LOX gene was highly induced through agroinfiltration because of wounding. GmVLXC and ClHPL transcripts could be detected in the corresponding transformed tobacco leaves by real-time RT-PCR analysis but the expression level of ClHPL was 24-fold higher than that of GmVLXC. Western blot analysis showed that LOX was present in all tobacco leaves which were treated with bacterial suspensions, but not in the untreated wild-type control. This result confirms that internal 9-LOX was highly induced by agroinfiltration. The highest levels of ClHPL activity under optimal infiltration conditions were 80 times the HPL activity of wild-type plants or plants transformed with control vector. A large amount of hexanal was formed when linoleic acid was incubated with extracts from N. benthamiana leaves over-expressing ClHPL in combination with GmVLXC-expressing yeast extracts. One gram of ClHPL-expressing N. benthamiana leaves (fresh weight) could produce 17 +/- 0.4 mg hexanal from 50 mg linoleic acid after 30 min.


Design decisions to optimize reliability of daytime cortisol slopes in an older population.
The daytime log-cortisol slope appears to be of growing importance in studying the relationship between stress and health. How best to estimate that slope with minimal burden to the participants and the cost of the study is a decision often made without empiric foundation. In 50 older participants, the authors examined cortisol assay comparability across laboratories, assay reliability, test-retest reliability of slopes, and comparability of slope estimates for two, three, and four samples per day. The authors demonstrate in an older sample that 1) assay reliability is a relatively minor issue, that one assay per saliva sample suffices; 2) the use of a sample obtained at wake time for each participant appears to be a preferred anchor for the slope estimate in comparison to a sample 30 minutes postwake time; 3) self-reported times appear preferable to automatic time recording; and 4) test-retest reliability of slopes, however, is not sufficiently high to base a slope estimate on one day; minimally two days and preferably three should be required. Whether these conclusions apply to other populations, or using other protocols, is not assured, but the study itself provides a model that can be used to check research decisions. Unnecessarily imposing a burdensome protocol has both ethical and scientific ramifications and should be carefully avoided.


TNF-alpha gene polymorphism: clinical and biological implications.
TNF-alpha is a proinflammatory cytokine that has been implicated in the severity of different immune-regulated diseases including autoimmune diseases and transplantation. The gene for TNF-alpha is located within the MHC region on chromosome 6p21.3. This is a highly polymorphic region, and the TNF-alpha itself contains a large number of polymorphisms. Some of these polymorphisms form extended haplotypes with the HLA class I and II alleles. TNF polymorphisms have been investigated in different diseases and most often whenever there is an HLA association with the disease (for example IDDM and RA) association(s) with TNF polymorphisms has been described. There are many studies on the function of the TNF polymorphisms showing the influence of the different alleles on the in vitro and in vivo levels of TNF production. However, recent studies in animal models suggest that not only polymorphisms within the TNF cluster are important in the regulation of TNF production but also the receptors as well (TNF R). This suggests that investigating polymorphisms within the TNF cluster and TNF receptors will be important in understanding the role of TNF regulation in a given disease.


Nurses' experience of providing home-based palliative care in the country setting: An integrated literature review.
The aim of the study is to explore the experiences of nurses providing home-based palliative care for patients who live in country settings. This study is an integrated literature review. Electronic databases, specific journals of interest, and reference lists were searched using key words and Boolean operators. Descriptive thematic analysis was undertaken to identify main themes and subthemes. Critical appraisal of the articles was conducted using the qualitative Critical Appraisal Skills Program guidelines. Primary research articles published in English, in peer-reviewed journals from 1990 to 2017, were included. Twelve articles were included in this review. Two main themes emerged including the nature of nursing in country communities and nurses' emotional responses. The first main theme had the subthemes of community connections, geographical distance and isolation, organizational deficits, lack of education, and resources. The second main theme consisted on five subthemes including feeling rewarded, autonomy and professional isolation, hope and hopelessness, frustration, and fear. Literature is sparse reporting the lived experience of nurses providing palliative care in country areas for patients wanting to die at home. An increase in demand for a home-based palliative nursing service will require additional funding globally to meet this increase in the future.


A practical guide on the use of imiquimod cream to treat lentigo maligna.
Lentigo maligna (LM) is a common in situ melanoma subtype arising on chronically sun-damaged skin and mostly affects the head and neck region. Localisation in cosmetically sensitive areas, difficulty to obtain wide resection margins and advanced patient age/comorbidities have encouraged investigation of less invasive therapeutic strategies than surgery in managing complex cases of LM. Radiotherapy and imiquimod have emerged as alternative treatment options in this context. The treatment of LM with imiquimod cream can be challenging due to the nature of the disease including its often large size, variegated appearance, involvement of adnexal structures, poorly defined peripheral edge and frequent localisation close to sensitive structures such as the eyes and lips, and elderly patients with multiple comorbidities. Prolonged and unpredictable inflammatory reaction and side effects and compliance with a patient-delivered therapy can also be challenging. In the literature to date, studies evaluating the use of imiquimod to treat LM have utilised varying methodologies and provided short follow-up and these limitations have impaired the development of clear guidelines for dosage and management of side effects. Based on our multidisciplinary experience and review of the literature, we propose practical clinical strategies for the use of imiquimod for treating LM, detailing optimal administration procedures in various clinical scenarios and long-term management, with the aim of facilitating optimal patient outcomes.


Yoga as a complementary therapy in neuropathic pain: A systematic review and meta-analysis of randomized controlled trials.
Yoga is an ancient wisdom comprising a multitude of physical and mental practices that are aimed toward a state of optimum physical, mental, social, and spiritual health. Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory nervous system that is often unresponsive to currently available modes of treatment, portending an inferior quality of life for patients. This systematic review and meta-analysis aim to investigate the effect and the potential role of yoga in NP syndromes. PubMed, Scopus, Elton Bryson Stephens Company (EBSCO), and Cochrane Library were screened for randomized controlled trials (RCTs) assessing the effects of yoga in patients on NP. Usual care, no treatment, or any active treatments were acceptable as control interventions. Primary outcome measures were objective or subjective assessment measures of pain intensity. For each outcome, standardized mean differences and 95% confidence intervals (CIs) were calculated. A total of four studies were included for qualitative synthesis. Meta-analysis of three studies revealed an overall effect (Z) in the favor of yoga as an intervention for NP, when compared to controls, although the effect was not statistically significant (three RCTs; Z = 1.10 [P = 0.27]; Heterogeneity: τ2 = 0.37; χ2 = 27.78, df = 2 [P < 0.00001]; I2 = 93%). This review divulged the overall favorable effect of yoga in NP, although it was not statistically significant. It highlights the promising role of yoga on pain intensity and quality of life in NP syndromes while showing that yoga has the advantage of being an inexpensive and easily accessible mode of therapy. Extensive research on the efficiency and safety of yoga must be conducted using robust RCTs with rigorous methodologies.


Viability of competing field theories for the driven lattice gas
It has recently been suggested that the driven lattice gas should be described by an alternate field theory in the limit of infinite drive. We review the original and the alternate field theory, invoking several well-documented key features of the microscopics. Since the alternate field theory fails to reproduce these characteristics, we argue that it cannot serve as a viable description of the driven lattice gas. Recent results, for the critical exponents associated with this theory, are reanalyzed and shown to be incorrect.


Selection bias requires selection: the case of collider stratification bias.
In epidemiology, collider stratification bias, the bias resulting from conditioning on a common effect of two causes, is oftentimes considered a type of selection bias, regardless of the conditioning methods employed. In this commentary, we distinguish between two types of collider stratification bias: collider restriction bias due to restricting to one level of a collider (or a descendant of a collider), and collider adjustment bias through inclusion of a collider (or a descendant of a collider) in a regression model. We argue that categorizing collider adjustment bias as a form of selection bias may lead to semantic confusion, as adjustment for a collider in a regression model does not involve selecting a sample for analysis. Instead, we propose that collider adjustment bias can be better viewed as a type of overadjustment bias. We further provide two distinct causal diagram structures to distinguish collider restriction bias and collider adjustment bias. We hope that such a terminological distinction can facilitate easier and clearer communication.


High burden of malaria following scale-up of control interventions in Nchelenge District, Luapula Province, Zambia.
Malaria control interventions have been scaled-up in Zambia in conjunction with a malaria surveillance system. Although substantial progress has been achieved in reducing morbidity and mortality, national and local information demonstrated marked heterogeneity in the impact of malaria control across the country. This study reports the high burden of malaria in Nchelenge District, Luapula Province, Zambia from 2006 to 2012 after seven years of control measures. Yearly aggregated information on cases of malaria, malaria deaths, use of malaria diagnostics, and malaria control interventions from 2006 to 2012 were obtained from the Nchelenge District Health Office. Trends in the number of malaria cases, methods of diagnosis, malaria positivity rate among pregnant women, and intervention coverage were analysed using descriptive statistics. Malaria prevalence remained high, increasing from 38% in 2006 to 53% in 2012. Increasing numbers of cases of severe malaria were reported until 2010. Intense seasonal malaria transmission was observed with seasonal declines in the number of cases between April and August, although malaria transmission continued throughout the year. Clinical diagnosis without accompanying confirmation declined from 95% in 2006 to 35% in 2012. Intervention coverage with long-lasting insecticide-treated nets and indoor residual spraying increased from 2006 to 2012. Despite high coverage with vector control interventions, the burden of malaria in Nchelenge District, Zambia remained high. The high parasite prevalence could accurately reflect the true burden, perhaps in part as a consequence of population movement, or improved access to care and case reporting. Quality information at fine spatial scales will be critical for targeting effective interventions and measurement of progress.


What is the current role of CT urography and MR urography in the evaluation of the urinary tract?
Technologic advances in both computed tomography (CT) and magnetic resonance (MR) imaging have resulted in the ability to image the urinary tract in ways that surpass the prior mainstay of urinary tract imaging, the intravenous urogram. In adults, for most, if not all, historical indications for intravenous urography, CT urography or MR urography is now the preferred examination. Although a variety of techniques for both examinations have been described, each test provides more diagnostic information than does intravenous urography. With the introduction of multidetector technology, CT urography, to date, has emerged as the initial heir apparent to intravenous urography; many years of experience have now clearly demonstrated that CT is the test of choice for many urologic problems, including urolithiasis, renal masses, urinary tract infection, trauma, and obstructive uropathy. CT urography provides a detailed anatomic depiction of each of the major portions of the urinary tract--the kidneys, intrarenal collecting systems, ureters, and bladder--and thus allows patients with hematuria to be evaluated comprehensively. MR urography can be used also to evaluate the urinary tract and has the advantage of not using ionizing radiation and the potential to provide more functional information than CT. However, MR urography is less established and less reliably results in diagnostic image quality relative to CT urography. Although both tests can be used to evaluate the urinary tract, several issues remain and include reaching a consensus on the optimal protocols and appropriate utilization in an era of cost containment and heightened concerns about radiation exposure.


BolA affects cell growth, and binds to the promoters of penicillin-binding proteins 5 and 6 and regulates their expression.
The gene bolA was discovered in the 80's, but unraveling its function in the cell has proven to be a complex task. The BolA protein has pleiotropic effects over cell physiology, altering growth and morphology, inducing biofilm formation, and regulating the balance of several membrane proteins. Recently, BolA was shown to be a transcription factor by repressing the expression of the mreB gene. The present report shows that BolA is a transcriptional regulator of the dacA and dacC genes, thus regulating both DD-carboxypeptidases PBP5 and PBP6 and thereby demonstrating the versatility of BolA as a cellular regulator. In this work, we also demonstrate that reduction of cell growth and survival can be connected to the overexpression of the bolA gene in different E. coli backgrounds, particularly in the exponential growth phase. The most interesting finding is that overproduction of BolA affects bacterial growth differently depending on whether the cells were inoculated directly from a plate culture or from an overnight batch culture. This strengthens the idea that BolA can be engaged in the coordination of genes that adapt the cell physiology in order to enhance cell adaptation and survival under stress conditions.


[Intracranial arachnoid cyst associated with subdural hygroma: report of a case].
A case of a 10-year-old boy with a congenital arachnoid cyst in the right middle cranial fossa is reported. The symptoms were precipitated by head injury of moderate intensity, occurred some days before the beginning of the clinical picture. The computerized tomography has demonstrated the existence of a simultaneous right fronto-parietal subdural hygroma that was responsible for the intracranial hypertension syndrome. The influence of the cyst in the hygroma formation has been suggested. The mechanisms of growth, the etiology, clinical aspects, the diagnostics and the surgical treatment of the arachnoid cysts are discussed.


Research capacity for childhood obesity prevention in Latin America: an area for growth.
The rise of childhood obesity in Latin America calls for research capacity to understand, monitor and implement strategies, policies and programmes to address it. The objective of the study was to assess current research capacity in Latin America related to childhood obesity, nutrition and physical activity. We conducted a search of peer-reviewed articles on childhood obesity in Latin America with at least one Latin American author from 2010 to May 2015. We coded 484 published articles for author affiliation, study subjects' nationality, research topic and study design and extracted a series of networks per research topic, study design and collaborating country for each of the countries. Obesity is the most frequently explored topic. Nutrition and obesity are somewhat better developed compared with physical activity and sedentary behaviour. There are numerous observational and cross-sectional studies, indicating either a lack of capacity required for more complex research or the extent of the problem and associated factors is still unknown. The low number of intervention studies and the near absence of policy articles suggest a void in research capacity. For childhood obesity, there is a clear need to build research capacity that documents the current state of the problem and design evidence-based prevention and intervention efforts.


Differential regulation of horizontally acquired and core genome genes by the bacterial modulator H-NS.
Horizontal acquisition of DNA by bacteria dramatically increases genetic diversity and hence successful bacterial colonization of several niches, including the human host. A relevant issue is how this newly acquired DNA interacts and integrates in the regulatory networks of the bacterial cell. The global modulator H-NS targets both core genome and HGT genes and silences gene expression in response to external stimuli such as osmolarity and temperature. Here we provide evidence that H-NS discriminates and differentially modulates core and HGT DNA. As an example of this, plasmid R27-encoded H-NS protein has evolved to selectively silence HGT genes and does not interfere with core genome regulation. In turn, differential regulation of both gene lineages by resident chromosomal H-NS requires a helper protein: the Hha protein. Tight silencing of HGT DNA is accomplished by H-NS-Hha complexes. In contrast, core genes are modulated by H-NS homoligomers. Remarkably, the presence of Hha-like proteins is restricted to the Enterobacteriaceae. In addition, conjugative plasmids encoding H-NS variants have hitherto been isolated only from members of the family. Thus, the H-NS system in enteric bacteria presents unique evolutionary features. The capacity to selectively discriminate between core and HGT DNA may help to maintain horizontally transmitted DNA in silent form and may give these bacteria a competitive advantage in adapting to new environments, including host colonization.


[Effect of radioprotectars from various chemical compound classes on dynamic work capacity and carbohydrate metabolism].
The influence of radioprotectors cystamine, mexamine and gammaphos on the physical performance capacity and carbohydrate metabolism was subjected to a comparative study. Cystamine and mexamine were found to lower the capacity of the animals to endure physical loads, this being attended by falling stocks of glycogen in the liver and muscles and a rising level of the blood lactate and pyruvate in comparison with controls. Gammaphos has no effect on the performance capacity of the animals and carbohydrate metabolism.


Matrix metalloproteinase 13 loss associated with impaired extracellular matrix remodeling disrupts chondrocyte differentiation by concerted effects on multiple regulatory factors.
To link matrix metalloproteinase 13 (MMP-13) activity and extracellular matrix (ECM) remodeling to alterations in regulatory factors leading to a disruption in chondrocyte homeostasis. MMP-13 expression was ablated in primary human chondrocytes by stable retrotransduction of short hairpin RNA. The effects of MMP-13 knockdown on key regulators of chondrocyte differentiation (SOX9, runt-related transcription factor 2 [RUNX-2], and beta-catenin) and angiogenesis (vascular endothelial growth factor [VEGF]) were scored at the protein level (by immunohistochemical or Western blot analysis) and RNA level (by real-time polymerase chain reaction) in high-density monolayer and micromass cultures under mineralizing conditions. Effects on cellular viability in conjunction with chondrocyte progression toward a hypertrophic-like state were assessed in micromass cultures. Alterations in SOX9 subcellular distribution were assessed using confocal microscopy in micromass cultures and also in osteoarthritic cartilage. Differentiation of control chondrocyte micromasses progressed up to a terminal phase, with calcium deposition in conjunction with reduced cell viability and scant ECM. MMP-13 knockdown impaired ECM remodeling and suppressed differentiation in conjunction with reduced levels of RUNX-2, beta-catenin, and VEGF. MMP-13 levels in vitro and ECM remodeling in vitro and in vivo were linked to changes in SOX9 subcellular localization. SOX9 was largely excluded from the nuclei of chondrocytes with MMP-13-remodeled or -degraded ECM, and exhibited an intranuclear staining pattern in chondrocytes with impaired MMP-13 activity in vitro or with more intact ECM in vivo. MMP-13 loss leads to a breakdown in primary human articular chondrocyte differentiation by altering the expression of multiple regulatory factors.


Prolonged ethanol treatment enhances lipopolysaccharide/phorbol myristate acetate-induced tumor necrosis factor-alpha production in human monocytic cells.
Ethanol (EtOH) is known to alter host immune responses and cytokine production. Acute EtOH exposure can suppress tumor necrosis factor (TNF)-alpha production, which attenuates pulmonary defense against infection. Previous studies in our laboratory show that acute EtOH inhibited TNF-alpha production by a posttranscriptional process, namely suppression of TNF-alpha-converting, enzyme-mediated, ectodomain shedding. However, chronic EtOH has been shown to augment TNF-alpha production, and this has been associated with EtOH-induced liver injury. To further characterize this paradoxical effect of EtOH on TNF-alpha production, we developed an in vitro model by using Mono Mac 6 cells, a human monocytic cell line. Mono Mac 6 cells were treated with EtOH (0-75 mM) for 1 to 7 days. TNF-alpha production was induced by lipopolysaccharide and phorbol myristate acetate and quantitated by enzyme-linked immunosorbent assay. Generation of reactive oxygen species (ROS) was assayed by using a specific fluorogenic reagent. Acute EtOH initially inhibited lipopolysaccharide/phorbol myristate acetate-induced TNF-alpha production in Mono Mac 6 cells. However, during chronic EtOH exposure, this inhibition was reversed gradually over time. By day 6 after EtOH treatment, Mono Mac 6 cells demonstrated significant up-regulation of TNF-alpha production. Moreover, chronic EtOH induced the generation of ROS in these Mono Mac 6 cells. Scavenging ROS by Mn(III)tetrakis(1-methyl-4pyridyl)porphyrin pentachloride and N-acetyl-L-cysteine attenuated chronic EtOH-enhanced TNF-alpha production. These results suggest that ROS induction is involved in EtOH-enhanced TNF-alpha production by monocytes. This study also provides insight into the mechanisms of alteration of TNF-alpha production in different EtOH exposure settings.


Progenitor cells of the testosterone-producing Leydig cells revealed.
The cells responsible for production of the male sex hormone testosterone, the Leydig cells of the testis, are post-mitotic cells with neuroendocrine characteristics. Their origin during ontogeny and regeneration processes is still a matter of debate. Here, we show that cells of testicular blood vessels, namely vascular smooth muscle cells and pericytes, are the progenitors of Leydig cells. Resembling stem cells of the nervous system, the Leydig cell progenitors are characterized by the expression of nestin. Using an in vivo model to induce and monitor the synchronized generation of a completely new Leydig cell population in adult rats, we demonstrate specific proliferation of vascular progenitors and their subsequent transdifferentiation into steroidogenic Leydig cells which, in addition, rapidly acquire neuronal and glial properties. These findings, shown to be representative also for ontogenetic Leydig cell formation and for the human testis, provide further evidence that cellular components of blood vessels can act as progenitor cells for organogenesis and repair.


Regional variations in prevalence and severity of autosomal dominant polycystic kidney disease in the United States.
To evaluate geographic variation in the prevalence of autosomal dominant polycystic kidney disease (ADPKD) in the US, including ADPKD at risk of rapid progression. Claims data from the IBM MarketScan Commercial and Medicare Supplemental databases (01/16/2016-12/31/2017) were used to estimate the 2017 annual and 2016-2017 two-year prevalence of diagnosed ADPKD and ADPKD at risk of rapid progression in the US overall, and stratified by census regions and states. Risk of rapid progression was identified based on either: hypertension <35 years, hematuria <30 years, albuminuria, stage 2 chronic kidney disease (CKD) <30 years, stage 3 CKD <50 years, and stage 4/5 CKD or kidney transplant <55 years. Annual prevalence was estimated at 2.34 and two-year prevalence at 3.61 per 10,000 in the US. Across census regions, two-year prevalence per 10,000 was highest in the Northeast (4.14) and lowest in the West (3.35). Prevalence was significantly correlated with the proportion of individuals in urban areas (r = .34, one-sided p = .026). In 2017, 37.5% of patients were identified as being at risk for rapid progression, and this proportion was larger among patients in the South (42.1%, p < .001). This estimate for ADPKD prevalence is consistent with previously reported national estimates, with regional variation suggesting that ADPKD might be under-diagnosed in rural areas with more limited access to care. More than one-third of ADPKD patients presented risk factors associated with rapid progression, highlighting the need for timely identification, as disease-modifying therapy may delay progression to end-stage renal disease.


Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions.
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a distinct phenotype of severe drug eruptions characterized by sequential reactivations of herpesviruses. Although a progressive loss of suppressive function in regulatory T cells (Tregs) occurred during the course of DiHS/DRESS, but not in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), no previous studies investigated the mechanism. Given the recent finding that Treg development could be differentially regulated by CD16+ patrolling monocytes (pMOs) and CD14+ classical monocytes (cMOs), we can hypothesize that a differential fine-tuned interaction between Tregs and monocytes is the driving force behind the possible shift from Tregs to Th17 cells over a prolonged period of time in DiHS/DRESS. To investigate whether the shift from Treg to Th17 could specifically occur during the course of DiHS/DRESS and to elucidate which subsets of monocytes could be involved in the shift. We performed a prospective longitudinal study on the frequencies of Tregs, Th17 cells and monocyte subsets after onset of DiHS/DRESS and SJS/TEN, and long after their clinical resolutions. We next examined whether pMOs and cMOs could have a strong impact on the Th17/Treg differentiation and which cytokines could be crucial for the interaction between Th17/Tregs and MO subsets, by in vitro cocultures. Selective depletion of pMOs occurring at the acute stage of DiHS/DRESS was associated with the relative increase in the frequencies of cMOs producing IL-10 and it did drive Treg expansions. After clinical resolution, pMOs producing IL-6 were alternatively recruited and contributed to the eventual shift from a Treg to Th17 responses. The gradual shift from Treg to Th17 cell development observed during the clinical course of DiHS/DRESS is mediated by the predominance of cMOs at the acute stage and alternatively recruited pMOs at the resolution stage, respectively.


Baseline cluster membership demonstrates positive associations with first occurrence of multiple gerontologic outcomes over 10 years.
BACKGROUND/STUDY CONTEXT: The potential of cluster analysis (CA) as a baseline predictor of multivariate gerontologic outcomes over a long period of time has not been previously demonstrated. Restricting candidate variables to a small group of established predictors of deleterious gerontologic outcomes, various CA methods were applied to baseline values from 754 nondisabled, community-living persons, aged 70 years or older. The best cluster solution yielded at baseline was subsequently used as a fixed explanatory variable in time-to-event models of the first occurrence of the following outcomes: any disability in four activities of daily living, any disability in four mobility measures, and death. Each outcome was recorded through a maximum of 129 months or death. Associations between baseline ordinal cluster level and first occurrence of all three outcomes were modeled over a 10-year period with proportional hazards regression and compared with the associations yielded by the analogous latent class analysis (LCA) solution. The final cluster-defining variables were continuous measures of cognitive status and depressive symptoms, and dichotomous indicators of slow gait and exhaustion. The best solution yielded by baseline values of these variables was obtained with a K-means algorithm and cosine similarity and consisted of three clusters representing increasing levels of impairment. After adjustment for age, sex, ethnic group, and number of chronic conditions, baseline ordinal cluster level demonstrated significantly positive associations with all three outcomes over a 10-year period that were equivalent to those from the corresponding LCA solution. These findings suggest that baseline clusters based on previously established explanatory variables have potential to predict multivariate gerontologic outcomes over a long period of time.


Including climate change in pest risk assessment: the peach fruit fly, Bactrocera zonata (Diptera: Tephritidae).
Bactrocera zonata (Saunders) is one of the most harmful species of Tephritidae. It causes extensive damage in Asia and threatens many countries located along or near the Mediterranean Sea. The climate mapping program, CLIMEX 3.0, and the GIS software, ArcGIS 9.3, were used to model the current and future potential geographical distribution of B. zonata. The model predicts that, under current climatic conditions, B. zonata will be able to establish itself throughout much of the tropics and subtropics, including some parts of the USA, southern China, southeastern Australia and northern New Zealand. Climate change scenarios for the 2070s indicate that the potential distribution of B. zonata will expand poleward into areas which are currently too cold. The main factors limiting the pest's range expansion are cold, hot and dry stress. The model's predictions of the numbers of generations produced annually by B. zonata were consistent with values previously recorded for the pest's occurrence in Egypt. The ROC curve and the AUC (an AUC of 0.912) were obtained to evaluate the performance of the CLIMEX model in this study. The analysis of this information indicated a high degree of accuracy for the CLIMEX model. The significant increases in the potential distribution of B. zonata projected under the climate change scenarios considered in this study suggest that biosecurity authorities should consider the effects of climate change when undertaking pest risk assessments. To prevent the introduction and spread of B. zonata, enhanced quarantine and monitoring measures should be implemented in areas that are projected to be suitable for the establishment of the pest under current and future climatic conditions.


Physician-Assisted Death and Severe, Treatment-Resistant Depression.
Should people suffering from untreatable psychiatric conditions be eligible for physician-assisted death? This is possible in Belgium and the Netherlands, where PAD for psychiatric conditions is permitted, though rare, so long as the criteria of due care are met. Those opposed to all instances of PAD point to Belgium and the Netherlands as a dark warning that once PAD is legalized, restricting it will prove impossible because safeguards, such as the requirement that a patient be terminally ill, will inevitably be eroded or discarded. However, some supporters respond that limiting PAD to those suffering from terminal illness, or physical illnesses generally, is arbitrary and illogical. In addition, precisely because such patients are not terminally ill, their suffering may last for years, even the rest of their lives. Finally, severe depression may not be treatable. If PAD is justifiable under some conditions-as I shall assume in this article-then why wouldn't it be justifiable for these patients? Why shouldn't psychiatrists who have nothing else to offer their suffering patients be able to help them to die, if that is what they want?


Same-day combined percutaneous coronary intervention and coronary artery surgery.
Either percutaneous coronary intervention (PCI) or coronary artery bypass grafting can be chosen for the treatment of multiple-vessel coronary artery disease. We report the results of a hybrid procedure performed on the same day, combining PCI of the right coronary artery and internal mammary artery bypass grafting of the left coronary artery, for the treatment of diffuse extensive lesions. Since January 2000, 70 patients (53 male, mean age 68.5 +/- 10 years) underwent this hybrid revascularization combining primary right coronary artery PCI and, within the next 16 h, left coronary artery grafting with left and/or right internal mammary artery. Thirty-one patients (98%) were treated on the same day. At a mean follow-up of 33 months (range: 2-70 months), 68 patients (97%) were asymptomatic at the time of writing. Three adverse events were reported: 2 were PCI-related, due to failure to take ticlopidine, and 1 was surgery-related, resulting in the patient's death during hospitalization. These preliminary results for a same-day combined procedure in patients with diffuse multivessel coronary artery disease are encouraging. This strategy optimizes revascularization when patients are unstable or present very severe coronary lesions, which requiring rapid treatment and are not ideally suitable for PCI management alone.


A web tool for age-period-cohort analysis of cancer incidence and mortality rates.
Age-period-cohort (APC) analysis can inform registry-based studies of cancer incidence and mortality, but concerns about statistical identifiability and interpretability, as well as the learning curves of statistical software packages, have limited its uptake. We implemented a panel of easy-to-interpret estimable APC functions and corresponding Wald tests in R code that can be accessed through a user-friendly Web tool. Input data for the Web tool consist of age-specific numbers of events and person-years over time, in the form of a rate matrix of paired columns. Output functions include model-based estimators of cross-sectional and longitudinal age-specific rates, period and cohort rate ratios that incorporate the overall annual percentage change (net drift), and estimators of the age-specific annual percentage change (local drifts). The Web tool includes built-in examples for teaching and demonstration. User data can be input from a Microsoft Excel worksheet or by uploading a comma-separated-value file. Model outputs can be saved in a variety of formats, including R and Excel. APC methodology can now be carried out through a freely available user-friendly Web tool. The tool can be accessed at http://analysistools.nci.nih.gov/apc/. The Web tool can help cancer surveillance researchers make important discoveries about emerging cancer trends and patterns.


Labelling fashion magazine advertisements: Effectiveness of different label formats on social comparison and body dissatisfaction.
The experiment investigated the impact on women's body dissatisfaction of different forms of label added to fashion magazine advertisements. Participants were 340 female undergraduate students who viewed 15 fashion advertisements containing a thin and attractive model. They were randomly allocated to one of five label conditions: no label, generic disclaimer label (indicating image had been digitally altered), consequence label (indicating that viewing images might make women feel bad about themselves), informational label (indicating the model in the advertisement was underweight), or a graphic label (picture of a paint brush). Although exposure to the fashion advertisements resulted in increased body dissatisfaction, there was no significant effect of label type on body dissatisfaction; no form of label demonstrated any ameliorating effect. In addition, the consequence and informational labels resulted in increased perceived realism and state appearance comparison. Yet more extensive research is required before the effective implementation of any form of label.


[The Antioxidant and Geroprotective Properties of an Extract of Mountain Ash (Sorbus aucuparia L.) Fruits].
Plant polyphenols are characterized by a wide range of biological activities, including antioxidant properties, and have a high geroprotective potential. The purpose of this work was to investigate the effect of the extract of rowan berries (Sorbus aucuparia L.) on the lifespan and stress resistance of Drosophila melanogaster with the identification of possible mechanisms of its biological activity. It has been established that an ethanol extract of S. aucuparia berries, the main components of which are rutin and cyanidin-3-rutinoside, has a pronounced antioxidant activity in vitro. At the same time, treatment with rowan berry extract increased the resistance of D. melanogaster males to starvation, but reduced resistance to hyperthermia. In females, the extract reduced resistance to oxidative stress but increased resistance to hyperthermia. The effects of rowan berry extract on longevity depended both on its concentration and on the sex of fruit flies. In response to treatment with rowan berry extract, D. melanogaster males and females showed slight differences in the background level of expression of cellular stress response genes, including heat shock genes (hsp27, hsp68, and hsp83), oxidative stress resistance genes (hif1, nrf2, and sod1), circadian rhythm genes (clk and per), and the longevity gene sirt1, which may explain the differences in the observed effects.


Assessment of short reports using a human rights-based approach to tobacco control to the Commitee on Economics, Cultural and Social Rights.
The health impact of tobacco use remains a major global public health concern and a human rights issue. The Human Rights and Tobacco Control Network (HRTCN) was established to increase the visibility of tobacco as a human rights issue. HRTCN submitted short reports to the UN Committee on Economic Social and Cultural Rights evaluating individual nations' tobacco control policies and offering recommendations. HRTCN reviewed Concluding Observations documents for nations for which the HRTCN submitted reports. If tobacco was mentioned in the Concluding Observations through acknowledging the Framework Convention on Tobacco Control ratification, policy changes or discussing tobacco in the recommendations, this was scored as a positive finding. HRTCN also reviewed Concluding Observations for nations for which HRTCN did not submit reports as a comparison. Thirty-eight HRTCN reports were submitted and tobacco was mentioned in Concluding Observations for 11 nations for a rate of 28.9%. In a comparison set of Concluding Observations (n=59), 7% had comments or recommendations relative to tobacco. This was not a controlled study and the 28.9% 'success rate' for impacting the Concluding Observations, although encouraging, is less than optimal-and leaves room for improvement. The higher rate of tobacco mentions for the cases where the HRTCN short reports were submitted provides preliminary indications that the short reports may have potential to increase the state focus on tobacco control. Future work will seek to improve the design and scope of the reports, and the specificity of the background information and recommendations offered.


Revisiting the rules for freehand ventriculostomy: a virtual reality analysis.
OBJECTIVE Frontal ventriculostomy is one of the most frequent and standardized procedures in neurosurgery. However, many first and subsequent punctures miss the target, and suboptimal placement or misplacement of the catheter is common. The authors therefore reexamined the landmarks and rules to determine the entry point and trajectory with the best hit rate (HtR). METHODS The authors randomly selected CT scans from their institution's DICOM pool that had been obtained in 50 patients with normal ventricular and skull anatomy and without ventricular puncture. Using a 5 × 5-cm frontal grid with 25 entry points referenced to the bregma, the authors examined trajectories 1) perpendicular to the skull, 2) toward classic facial landmarks in the coronal and sagittal planes, and 3) toward an idealized target in the middle of the ipsilateral anterior horn (ILAH). Three-dimensional virtual reality ventriculostomies were simulated for these entry points; trajectories and the HtRs were recorded, resulting in an investigation of 8000 different virtual procedures. RESULTS The best HtR for the ILAH was 86% for an ideal trajectory, 84% for a landmark trajectory, and 83% for a 90° trajectory, but only at specific entry points. The highest HtRs were found for entry points 3 or 4 cm lateral to the midline, but only in combination with a trajectory toward the contralateral canthus; and 1 or 2 cm lateral to the midline, but only paired with a trajectory toward the nasion. The same "pairing" exists for entry points and trajectories in the sagittal plane. For perpendicular (90°) trajectories, the best entry points were at 3-5 cm lateral to the midline and 3 cm anterior to the bregma, or 4 cm lateral to the midline and 2 cm anterior to the bregma. CONCLUSIONS Only a few entry points offer a chance of a greater than 80% rate of hitting the ILAH, and then only in combination with a specific trajectory. This "pairing" between entry point and trajectory was found both for landmark targeting and for perpendicular trajectories, with very limited variability. Surprisingly, the ipsilateral medial canthus, a commonly reported landmark, had low HtRs, and should not be recommended as a trajectory target.


Injectable and adhesive hydrogels for dealing with wounds.
The development of wound dressing materials that combine healing properties, ability to self-repair the material damages, skin-friendly adhesive nature, and competent mechanical properties have surpassing functional importance in healthcare. Due to their specificity, hydrogels have been recognized as a new gateway in biological materials to treat dysfunctional tissues. The design and creation of injectable hydrogel-based scaffolds have extensively progressed in recent years to improve their therapeutic efficacy and to pave the way for their easy minimally invasive administration. Hence, injectable hydrogel biomaterials have been prepared to eventually translate into minimally invasive therapy and pose a lasting effect on regenerative medicine. This review highlights the recent development of adhesive and injectable hydrogels that have applications in wound healing and wound dressing. Such hydrogel materials are not only expected to improve therapeutic outcomes but also to facilitate the easy surgical process in both wound healing and dressing. Wound healing seems to be an appealing approach for treating countless life-threatening disorders. With the average increase of life expectancy in human societies, an increase in demand for injectable skin replacements and drug delivery carriers for chronic wound healing is expected.


De Novo Discovery of Cysteine Frameworks for Developing Multicyclic Peptide Libraries for Ligand Discovery.
Conserved cysteine frameworks are essential components of disulfide-rich peptides (DRPs), which dominantly define the structural diversity of both naturally occurring and de novo-designed DRPs. However, there are only very limited numbers of conserved cysteine frameworks, and general methods enabling de novo discovery of cysteine frameworks with robust foldability are still not available. Here, we devised a "touchstone"-based strategy that relies on chasing oxidative foldability between two individual disulfide-rich folds on the phage surface to discover new cysteine frameworks from random sequences. Unique cysteine frameworks with a high degree of compatibility with phage display systems and broad sequence tolerance were successfully identified, which were subsequently exploited for the development of multicyclic DRP libraries, enabling the rapid discovery of new peptide ligands with low-nanomolar and picomolar binding affinity. This study provides an unprecedented method for exploring and exploiting the sequence and structure space of DRPs that is not readily accessible by existing strategies, holding the potential to revolutionize the study of DRPs and significantly advance the design and discovery of multicyclic peptide ligands and drugs.


Keratins turn over by ubiquitination in a phosphorylation-modulated fashion.
Keratin polypeptides 8 and 18 (K8/18) are intermediate filament (IF) proteins that are expressed in glandular epithelia. Although the mechanism of keratin turnover is poorly understood, caspase-mediated degradation of type I keratins occurs during apoptosis and the proteasome pathway has been indirectly implicated in keratin turnover based on colocalization of keratin-ubiquitin antibody staining. Here we show that K8 and K18 are ubiquitinated based on cotransfection of His-tagged ubiquitin and human K8 and/or K18 cDNAs, followed by purification of ubiquitinated proteins and immunoblotting with keratin antibodies. Transfection of K8 or K18 alone yields higher levels of keratin ubiquitination as compared with cotransfection of K8/18, likely due to stabilization of the keratin heteropolymer. Most of the ubiquitinated species partition with the noncytosolic keratin fraction. Proteasome inhibition stabilizes K8 and K18 turnover, and is associated with accumulation of phosphorylated keratins, which indicates that although keratins are stable they still turnover. Analysis of K8 and K18 ubiquitination and degradation showed that K8 phosphorylation contributes to its stabilization. Our results provide direct evidence for K8 and K18 ubiquitination, in a phosphorylation modulated fashion, as a mechanism for regulating their turnover and suggest that other IF proteins could undergo similar regulation. These and other data offer a model that links keratin ubiquitination and hyperphosphorylation that, in turn, are associated with Mallory body deposits in a variety of liver diseases.


Gallium-68-labelled NOTA-oligonucleotides: an optimized method for their preparation.
One of the most essential aspects to the success of radiopharmaceuticals is an easy and reliable radiolabelling protocol to obtain pure and stable products. In this study, we optimized the bioconjugation and gallium-68 ((68) Ga) radiolabelling conditions for a single-stranded 40-mer DNA oligonucleotide, in order to obtain highly pure and stable radiolabelled oligonucleotides. Quantitative bioconjugation was obtained for a disulfide-functionalized oligonucleotide conjugated to the macrocylic bifunctional chelator MMA-NOTA (maleimido-mono-amide (1,4,7-triazanonane-1,4,7-triyl)triacetic acid). Next, this NOTA-oligonucleotide bioconjugate was radiolabelled at room temperature with purified and pre-concentrated (68) Ga with quantitative levels of radioactive incorporation and high radiochemical and chemical purity. In addition, high chelate stability was observed in physiological-like conditions (37 °C, PBS and serum), in the presence of a transchelator (EDTA) and transferrin. A specific activity of 51.1 MBq/nmol was reached using a 1470-fold molar excess bioconjugate over (68) Ga. This study presents a fast, straightforward and reliable protocol for the preparation of (68) Ga-radiolabelled DNA oligonucleotides under mild reaction conditions and without the use of organic solvents. The methodology herein developed will be applied to the preparation of oligonucleotidic sequences (aptamers) targeting the human epidermal growth factor receptor 2 (HER2) for cancer imaging.