The provision of hospital maxillo-facial prosthetic services in Scotland.
Maxillo-facial prosthetics can contribute much to the quality of life of patients with congenital problems or those treated surgically for a head and neck neoplasm. The availability of an adequate service varies internationally. The present study examines the current provision and requirements for such a service in Scotland. A questionnaire survey of 90 oral, plastic and ENT surgeons was carried out. Information was sought on numbers and types of cases seen, prosthetic treatment provided and involvement of Consultants in Restorative Dentistry in their management. The results show that most surgeons only treat a small number of such patients with a consequent dilution of experience, and with a possible need for supra-regional specialist centres. In addition there is a need for improvement of multi-disciplinary planning clinics for such cases.


Symptoms of dry eye and recurrent erosion syndrome after refractive surgery.
To determine the incidence and severity of patient complaints typical of dry eye and recurrent erosion syndrome after excimer laser refractive surgery and to compare the incidence of these symptoms after photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK). Outpatient university practice. A questionnaire was mailed to 1731 patients who had had primary myopic PRK or LASIK at least 6 months previously. Questions were designed to determine the incidence and character of ocular dryness and recurrent erosion symptoms and their impact on patient satisfaction and willingness to have surgery again. Responses from PRK and LASIK patients were compared. Responses from 231 PRK patients and 550 LASIK patients revealed an incidence of dryness symptoms in 43% and 48%, respectively (P >.05). Soreness of the eye to touch was reported by 26.8% and 6.7%, respectively (P <.0001). Sharp pains occurred in 20.4% of PRK patients and 8.0% of LASIK patients (P =.0001). Complaints of the eyelid sticking to the eyeball occurred in 14.7% and 5.6%, respectively (P =.0001). All symptoms occurred predominantly on waking. Frequency of eyelid sticking (P <.0005) and sharp pain (P <.005) symptoms, as well as severity of sharp pain symptoms (P <.0001), were significantly greater in PRK patients than in LASIK patients. On a scale of 0 to 10 (10 high), median overall patient satisfaction with surgery was 9 in both groups. Soreness of the eyelid to touch occurred significantly more frequently among patients with symptoms of sharp pains on waking (P <.001) and the sensation of the eyelid sticking to the eyeball (P <.001). Patients with 1 or more symptoms were twice as likely as asymptomatic patients to have a satisfaction score of less than 8 (P <.001). Ocular dryness symptoms occurred commonly after PRK and LASIK. Symptoms suggestive of mild recurrent erosions included sharp pains, the sensation of the eyelid sticking to the eyeball, and soreness of the eyelid to touch, a previously unrecognized symptom of this condition. These symptoms occurred commonly after excimer laser procedures but were significantly more common, more severe, and more prolonged after PRK. The presence of these symptoms had a significant effect on patient satisfaction.


Association of social vulnerability with receipt of hernia repair in Texas.
The effect of social health determinants on hernia surgery receipt is unclear. We aimed to assess the association of the social vulnerability index with the likelihood of undergoing elective and emergency hernia repair in Texas. This is a retrospective cohort analysis of the Texas Hospital Inpatient Discharge Public Use Data File and Texas Outpatient Surgical and Radiological Procedure Public Use Data File from 2016 to 2019. Patients ≥18 years old with inguinal or umbilical hernia were included. Social vulnerability index and urban/rural status were merged with the database at the county level. Patients were stratified based on social vulnerability index quartiles, with the lowest quartile (Q1) designated as low vulnerability, Q2 and Q3 as average, and Q4 as high vulnerability. Wilcoxon rank sum, t test, and χ2 analysis were used, as appropriate. The relative risk of undergoing surgery was calculated with subgroup sensitivity analysis. Of 234,843 patients assessed, 148,139 (63.1%) underwent surgery. Compared to patients with an average social vulnerability index, the low social vulnerability index group was 36% more likely to receive surgery (relative risk: 1.36, 95% CI 1.34-1.37), whereas the high social vulnerability index group was 14% less likely to receive surgery (relative risk: 0.86, 95% CI 0.85-0.86). This remained significant after stratifying for age, sex, insurance status, ethnicity, and urban/rural status (P < .05). For emergency admissions, there was no difference in receipt of surgery by social vulnerability index. Vulnerable patients are less likely to undergo elective surgical hernia repair, even after adjusting for demographics, insurance, and urbanicity. The social vulnerability index may be a useful indicator of social determinants of health barriers to hernia repair.


A mechanism by which atrial natriuretic factor mediates its glomerular actions.
Differential in vivo glomerular effects of atriopeptin I (AP I) and atriopeptin III (AP III) were studied in parallel with in vitro physiological and biochemical parameters. In anesthetized Sprague-Dawley rats, AP III, but not AP I, significantly increased glomerular filtration rate. Image analysis microscopy was used to assess the effect of AP I and AP III on angiotensin II (ANG II)-induced contraction of cultured rat glomerular mesangial cells. AP III, but not AP I, inhibited ANG II-induced mesangial cell contraction in a concentration-dependent manner. Additional inhibitory agents included exogenous DBcGMP, 8-BrcGMP, Na nitroprusside, and DBcAMP. AP III stimulated mesangial cell cGMP with a lower threshold and greater maximum stimulation than AP I. Neither agent stimulated cAMP accumulation. Since mesangial cell contractility may regulate the glomerular capillary surface area, these results suggest that AP III partially mediates its glomerular effects through inhibition of ANG II-induced mesangial cell contraction. Whereas cGMP is not clearly implicated as the mediator of this effect, it appears that both cGMP and cAMP may regulate the state of mesangial cell contractility.


Sex-related spatial learning differences after prenatal cocaine exposure in the young adult rat.
Prenatal cocaine exposure in humans is associated with a variety of adverse neurobehavioral effects. In the rat, in utero cocaine exposure has been shown to elicit learning impairment during early postnatal development. However, little research has focused on the persistence of these behavioral disruptions. The current study examines the long-term effects of prenatal cocaine exposure on learning performance during young adulthood. Fetal cocaine exposure evoked differential effects in male and female rats on radial-arm maze learning performance. Cocaine-treated females showed significantly impaired choice accuracy during acquisition of radial-arm maze performance when compared to control females. In contrast, cocaine-treated males showed no impairment and in fact showed significantly improved performance on one measure of choice accuracy. For both sexes, this effect was apparent during the final third of acquisition. No evidence was found to suggest altered sensitivity to anticholinergic drugs. While both nicotinic and muscarinic cholinergic antagonists caused significant impairments in memory performance, control and cocaine-exposed rats were effected equally. Single doses of these drugs which caused moderate memory deficits were chosen for use in the current study. The entire dose range should be evaluated to determine the relative sensitivity of cocaine-exposed and control animals to these drugs. The results of this study indicate that there are cognitive effects of prenatal cocaine exposure which persist into adulthood and the sex of the offspring seems to be critical.


Type of RNA Packed in VLPs Impacts IgG Class Switching-Implications for an Influenza Vaccine Design.
Nucleic acid packed within virus-like particles (VLPs) is shown to shape the immune response and to induce stronger B cell responses in different immunisation models. Here, using a VLP displaying the highly conserved extracellular domain of the M2 protein (M2e) from the influenza viruses as an antigen, we demonstrate that the type of RNA packaged into VLPs can alter the quality of the induced humoral response. By comparing prokaryotic RNA (pRNA), eukaryotic RNA (eRNA) and transfer RNA (tRNA), we find that pRNA induces the most protective IgG subclasses using a murine influenza model. We provide evidence that this process is predominantly dependent on endosomal Toll-like receptor (TLR7), and rule out a role for cytoplasmic mitochondrial antiviral signalling protein (MAVS) and its upstream retinoic acid-inducible gene-I-like receptors (RIG-I). Our findings provide considerations for the rational design of VLP-based vaccines and the immunomodulation exerted by TLR7 ligands packaged within the particles. Based on this work, we conclude that VLPs packing prokaryotic RNA must be preferred whenever a response dominated by IgG2 is desired, while eukaryotic RNA should be employed in order to induce a response dominated by IgG1.


Controlled trial of treatment for cerebral concussion.
In a study designed to compare two types of treatment of cerebral concussion, 178 patients were allocated to a routine treatment or to an active treatment group; in the latter a good prognosis was emphasized, the patient was mobilized early and given physiotherapy. In the routine treatment group the average time off work was 32 days compared with 18 days in the active treatment group. Physiotherapy seemed to be particularly valuable in old patients and in those with exaggerated fears about their condition. It is suggested that throughout their illness and follow-up, patients with cerebral concussion should be under the care of one doctor, one who is particularly interested in the subject and that more propaganda is needed


[Effect of membrane modification by PEG on prolongation of circulation time of liposomes in blood in vivo].
PEG-PE (polyethylene glycol-phosphatidyl ethanolamine) of different molecular weight (2000 and 5000) were used to modify the membrane of liposomes. Large unilamellar liposomes containing PEG-PE were prepared by reversed phase evaporation. Fluorescent label-calcein was encapsulated at the internal water phase. To compare the differance between the modified and unmodified membrane, the stability in vitro and distribution in vivo were investigated. The results indicated that the circulation half-life for liposomes unmodified, modified by PEG (2000)-PE and modified by PEG (5000)-PE were 13, 21 and 75 (min) respectively. At 6 h after injection, the ratio b/R (b: distribution in blood, R: distribution in liver and spleen) were 0, 0.8 and 1.4, respectively. The results mean that the stability increased and circulation time was prolonged by the PEG-PE modified membrane. The effect of PEG-PE on membrane was found to be directly proportional to the chain length of the polymer.


Cognitive impairment has no impact on hospital-associated dysphagia in aspiration pneumonia patients.
Hospital-associated dysphagia, characterized by deconditioning of swallowing as a result of hospitalization, is sometimes observed in patients with aspiration pneumonia (AP). Cognitive impairment is known as a negative factor in dysphagia rehabilitation. The present study aimed to examine the association between cognitive impairment and hospital-associated dysphagia in patients with AP receiving dysphagia rehabilitation. A retrospective observational study was carried out in an acute geriatric hospital. A total of 249 AP patients receiving multidisciplinary individualized dysphagia rehabilitation were included. Patients were divided into four groups according to their Mini-Mental State Examination scores. The Functional Oral Intake Scale (FOIS) was used to assess swallowing ability, and hospital-associated dysphagia was defined as a FOIS decline of ≥1 or ≥2 levels. Body mass index and Barthel Index were obtained to assess nutritional status and activities of daily living. The mean age was 85.6 ± 7.3 years, and 47% were men. Frequencies of hospital-associated dysphagia observed in lowest to highest Mini-Mental State Examination groups were 43.0%, 36.2%, 47.4% and 27.3% (P = 0.133), and 13.9%, 20.7%, 17.5% and 5.5% (P = 0.117) based on FOIS decline ≥1 or ≥2 levels, respectively. Multivariable regression model showed that the Mini-Mental State Examination score was not an independent determinant of FOIS at discharge (beta = 0.063, P = 0.378) after adjusting for age, sex, body mass index, Barthel Index, pneumonia severity, speech-language pathologist intervention, comorbidities, length of hospital stay and premorbid FOIS. The severity of cognitive impairment has no impact on hospital-associated dysphagia in AP patients receiving dysphagia rehabilitation. A future interventional study will be expected to further validate our findings. Geriatr Gerontol Int 2018; 18: 233-239.


Metagenomics assists in the diagnosis of a refractory, culture-negative pyoderma gangrenosum-like ulcer caused by Helicobacter cinaedi in a patient with primary agammaglobulinemia.
Helicobacter cinaedi is known to cause various infections in immunocompromised hosts ranging from skin lesions to disseminated septicemia. Identification of H. cinaedi is difficult through conventional identification methods due to its fastidious nature. We reported a refractory and culture-negative pyoderma gangrenosum-like ulcer caused by H. cinaedi in a patient with primary agammaglobulinemia. Metagenomic next-generation sequencing (mNGS) was applied for the identification of H. cinaedi and prolonged minocycline and amoxicillin-clavulanate potassium was used to eradicate the infection. Given the difficulties in culturing this organism, it's highly possible that H cinaedi infections have been overlooked. We suggest that early consideration of H. cinaedi infection should be suspected in immunocompromised patients presenting with unexplained skin lesions as the appropriate antibiotic choice plus a prolonged treatment course is essential for the prognosis. Application of mNGS could contribute to the early identification of rare and cryptogenic pathogens.


Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk.
The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10-5). Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.


William Harvey, Aristotle and astrology.
In this paper I argue that William Harvey believed in a form of astrology. It has long been known that Harvey employed a macrocosm-microcosm analogy and used alchemical terminology in describing how the two types of blood change into one another. This paper then seeks to examine a further aspect of Harvey in relation to the magical tradition. There is an important corollary to this line of thought, however. This is that while Harvey does have a belief in astrology, it is strongly related to Aristotle's views in this area and is quite restricted and attenuated relative to some contemporary beliefs in astrology. This suggests a more general thesis. While Harvey was amenable to ideas which we associate with the natural magic tradition, those ideas had a very broad range of formulation and there was a limit to how far he would accept them. This limit was largely determined by Harvey's adherence to Aristotle's natural philosophy and his Christian beliefs. I argue that this is also the case in relation to Harvey's use of the macrocosm-microcosm analogy and of alchemical terminology, and, as far as we can rely on the evidence, this informs his attitudes towards witches as well. Understanding Harvey's influences and motives here is important in placing him properly in the context of early seventeenth-century thought.


Long-term super-resolution inner mitochondrial membrane imaging with a lipid probe.
The inner mitochondrial membrane (IMM) generates power to drive cell function, and its dynamics control mitochondrial health and cellular homeostasis. Here, we describe the cell-permeant, lipid-like small molecule MAO-N3 and use it to assemble high-density environmentally sensitive (HIDE) probes that selectively label and image the IMM in live cells and multiple cell states. MAO-N3 pairs with strain-promoted azide-alkyne click chemistry-reactive fluorophores to support HIDE imaging using confocal, structured illumination, single-molecule localization and stimulated emission depletion microscopy, all with significantly improved resistance to photobleaching. These probes generate images with excellent spatial and temporal resolution, require no genetic manipulations, are non-toxic in model cell lines and primary cardiomyocytes (even under conditions that amplify the effects of mitochondrial toxins) and can visualize mitochondrial dynamics for 12.5 h. This probe will enable comprehensive studies of IMM dynamics with high temporal and spatial resolution.


Changes in psychiatric patients' thoughts about quitting smoking during a smoke-free hospitalization.
Though exempted from national bans of tobacco smoking in hospitals, some psychiatric facilities have voluntarily gone 100% smoke free with little reported difficulty in clinical management. The impact of smoking restrictions on psychiatric patients' thoughts about quitting smoking, however, is not known. This study investigates changes in thoughts about quitting smoking for patients hospitalized in a smoke-free psychiatric inpatient facility. Participants were 100 smokers recruited from a university-based adult inpatient psychiatry unit. The present study focused on participants' reported desire to quit smoking, their expectancy of success and anticipated difficulty with quitting, and their smoking abstinence goal. Assessments were conducted at hospital intake and shortly before hospital discharge. Follow-up assessments were conducted by phone at 1 week, 1 month, and 3 months post-hospitalization to measure smoking behavior. Although no cessation treatment was provided in this observational study, from admission to discharge, participants reported an increased expectancy of success with quitting and a decreased expectancy of difficulty with staying quit. They also were more likely to endorse a smoking-related goal. Psychiatric diagnosis was not related to thoughts about abstinence. Furthermore, participants' thoughts about abstinence at discharge were significantly related to their subsequent smoking behavior. Hospitalization in a smoke-free environment is associated with increases in patients' expectancies about quitting and staying smoke free.


Risk of Malignancy in Thyroid Nodules with Non-Diagnostic Fine-Needle Aspiration: A Retrospective Cohort Study.
Fine-needle aspiration (FNA) of thyroid nodules is commonly performed, and despite the use of ultrasound (US) guidance, the rate of non-diagnostic FNAs is still significant. The risk of malignancy of thyroid nodules with a non-diagnostic FNA is not clearly defined. However, most studies exclude the majority of patients without a repeat biopsy or surgery, thus increasing the likelihood of selection bias. The aims of this study were to determine the malignancy risk in nodules with an initial non-diagnostic FNA, and to identify the factors associated with malignancy. This was a retrospective cohort study of patients with thyroid nodules who underwent US-guided FNA between 2004 and 2010 and had a non-diagnostic result. Patients were followed until confirmatory diagnosis of the nature of the nodule was made. The outcome of malignant or benign disease was based on one of the following: (i) final surgical pathology following thyroidectomy; (ii) repeat biopsy; (iii) clinically, based on repeat ultrasound performed at least three years following biopsy; or (iv) report of thyroid status for patients without follow-up visits contacted by mail. There were 699 nodules from 665 patients included. The mean age was 59 ± 15 years, and 71.7% were women. There was complete follow-up of 495 nodules. After a median follow-up of 2.7 years, thyroid cancer was found in 15 nodules. The prevalence of malignancy was 3% (15/495). The presence of nodular calcifications was the strongest predictor of thyroid malignancy (odds ratio 5.03 [confidence interval 1.8-14.7]). Initial nodule size was inversely associated with malignancy (odds ratio 0.55 [confidence interval 0.28-0.93]). However, the 193 patients without follow-up had smaller nodules compared with those included in the analysis. None of the patients with repeatedly non-diagnostic results were diagnosed with thyroid cancer at follow-up. The prevalence of thyroid cancer in nodules with non-diagnostic results is lower than the malignancy rate in thyroid nodules in general, but not negligible. They should be followed as per guidelines with heightened suspicion for nodules containing calcifications. Nodules with repeatedly non-diagnostic FNA results especially in the absence of calcifications have a low risk of malignancy and may be observed.


Hypothalamic-pituitary control of perinatal prolactin secretion in Macaca mulatta.
Sequential changes in maternal and fetal plasma and amniotic fluid concentrations of prolactin (PRL) and growth hormone (GH) were examined after these intravascular administration of thyrotropin releasing hormone (TRH) or L-dopa alone or combined directly to the near-term Rhesus fetus. The neonatal plasma responses to these same stimuli were also examined. Fetal and neonatal plasma PRL levels increased immediately after TRH injection and remained elevated from baseline levels (102-800%) throughout the 45 min sampling period. Maternal plasma PRL levels also increased markedly. Although amniotic fluid concentrations were more variable, the trend was an increase. After L-dopa injection, fetal and neonatal plasma PRL values declined 26-62% from baseline levels. Maternal plasma PRL concentrations also declined 30-50%, but amniotic fluid PRL concentrations progressively increased. When L-dopa and TRH were administered together, fetal plasma PRL levels declined 14-40% from initial levels, but maternal plasma PRL levels did not change in a consistent manner, and amniotic fluid PRL levels remained stable. There was no change from baseline fetal or neonatal plasma GH concentrations in these experiments. The plasma PRL responses of the primate conceptus to these stimuli are consistent with those found in the adult; the unresponsiveness of plasma GH is not. The direction and magnitude of changes in both maternal plasma and amniotic fluid PRL concentrations provide indirect evidence of placental transfer of TRH and L-dopa in some experiments, and require a biophysical explanation not apparent in others.


Projected lifetime cancer risk from cone-beam computed tomography for orthodontic treatment.
To estimate the projected cancer risk attributable to diagnostic cone-beam computed tomography (CBCT) performed under different exposure settings for orthodontic purposes in children and adults. We collected a list of CBCT machines and their specifications from 38 orthodontists. Organ doses were estimated using median and maximum exposure settings of 105 kVp/156.8 mAs and 130 kVp/200 mAs, respectively. The projected cancer risk attributable to CBCT procedures performed 1-3 times within 2 years was calculated for children (aged 5 and 10 years) and adult (aged 20, 30, and 40 years) male and female patients. For maximum exposure settings, the mean lifetime fractional ratio (LFR) was 14.28% for children and 0.91% for adults; this indicated that the risk to children was 16 times the risk to adults. For median exposure settings, the mean LFR was 5.25% and 0.58% for children and adults, respectively. The risk of cancer decreased with increasing age. For both median and maximum exposure settings, females showed a higher risk of cancer than did males in all age groups. Cancer risk increased with an increase in the frequency of CBCT procedures within a given period. The projected dental CBCT-associated cancer risk spans over a wide range depending on the machine parameters and image acquisition settings. Children and female patients are at a higher risk of developing cancer associated with diagnostic CBCT. Therefore, the use of diagnostic CBCT should be justified, and protective measures should be taken to minimize the harmful biological effects of radiation.


Ultrahigh-quality graphene resonators by liquid-based strain-engineering.
Two-dimensional (2D) material-based nanoelectromechanical (NEM) resonators are expected to be enabling components in hybrid qubits that couple mechanical and electromagnetic degrees of freedom. However, challenges in their sensitivity and coherence time have to be overcome to realize such mechanohybrid quantum systems. We here demonstrate the potential of strain engineering to realize 2D material-based resonators with unprecedented performance. A liquid-based tension process was shown to enhance the resonance frequency and quality factor of graphene resonators six-fold. Spectroscopic and microscopic characterization reveals a surface-energy enhanced wall interaction as the origin of this effect. The response of our tensioned resonators is not limited by external loss factors and exhibits near-ideal internal losses, yielding superior resonance frequencies and quality factors to all previously reported 2D material devices. Our approach represents a powerful method of enhancing 2D NEM resonators for future quantum systems.


[Neurocysticercosis in children: clinical and radiological analysis and prognostic factors in 54 patients].
We studied 54 patients younger than 17 years of age with neurocysticercosis to determine the clinical manifestations, neuroimaging findings, and prognostic factors of this condition. Seizures were present in 48 patients, representing the most common clinical manifestation. Forty-eight patients had a normal neurological examination, and only 3 patients had clinical evidence of increased intracranial pressure. CT scan of the brain revealed parenchymal brain cysticerci in 52 patients; one patient had a pure subarachnoid form of the disease and the remaining patient had a mixed (subarachnoid and parenchymal) form. The most common CT finding in patients with parenchymal neurocysticercosis was a single colloidal cyst (19 cases). All patients with seizures were treated with anti-epileptic drugs with an excellent rate of seizure-control. In addition, 23 patients received albendazole that caused resolution of cystic lesions in 19 cases. Anti-epileptic drugs were withdrawn in 13 patients who remained free of seizures during two years. However, 9 (69%) of these patients had recurrent seizures. This evidence is in contrast with the reported benign course of neurocysticercosis in children, since most patients had seizure relapses despite therapy.


Hospital and surgeon volume in relation to long-term survival after oesophagectomy: systematic review and meta-analysis.
Centralisation of healthcare, especially for advanced cancer surgery, has been a matter of debate. Clear short-term mortality benefits have been described for oesophageal cancer surgery conducted at high-volume hospitals and by high-volume surgeons. To clarify the association between hospital volume, surgeon volume and hospital type in relation to long-term survival after oesophagectomy for cancer, by a meta-analysis. The systematic literature search included PubMed, Web of Science, Cochrane library, EMBASE and Science Citation Index, for the period 1990-2013. Eligible articles were those which reported survival (time to death) as HRs after oesophagectomy for cancer by hospital volume, surgeon volume or hospital type. Fully adjusted HRs for the longest follow-up were the main outcomes. Results were pooled by a meta-analysis, and reported as HRs and 95% CIs. Sixteen studies from seven countries met the inclusion criteria. These studies reported hospital volume (N=13), surgeon volume (N=4) or hospital type (N=4). A survival benefit was found for high-volume hospitals (HR=0.82, 95% CI 0.75 to 0.90), and possibly also, for high-volume surgeons (HR=0.87, 95% CI 0.74 to 1.02) compared with their low-volume counterparts. No association with survival remained for hospital volume after adjustment for surgeon volume (HR=1.01, 95% CI 0.97 to 1.06; N=2), while a survival benefit was found in favour of high-volume surgeons after adjustment for hospital volume (HR=0.91, 95% CI 0.85 to 0.98; N=2). This meta-analysis demonstrated better long-term survival (even after excluding early deaths) after oesophagectomy with high-volume surgery, and surgeon volume might be more important than hospital volume. These findings support centralisation with fewer surgeons working at large centres.


Tracking Sleep, Temperature, Heart Rate, and Daily Symptoms Across the Menstrual Cycle with the Oura Ring in Healthy Women.
The ovulatory menstrual cycle is characterized by hormonal fluctuations that influence physiological systems and functioning. Multi-sensor wearable devices can be sensitive tools capturing cycle-related physiological features pertinent to women's health research. This study used the Oura ring to track changes in sleep and related physiological features, and also tracked self-reported daily functioning and symptoms across the regular, healthy menstrual cycle. Twenty-six healthy women (age, mean (SD): 24.4 (1.1 years)) with regular, ovulatory cycles (length, mean (SD): 28.57 (3.8 days)) were monitored across a complete menstrual cycle. Four menstrual cycle phases, reflecting different hormone milieus, were selected for analysis: menses, ovulation, mid-luteal, and late-luteal. Objective measures of sleep, sleep distal skin temperature, heart rate (HR) and vagal-mediated heart rate variability (HRV, rMSSD), derived from the Oura ring, and subjective daily diary measures (eg sleep quality, readiness) were compared across phases. Wearable-based measures of sleep continuity and sleep stages did not vary across the menstrual cycle. Women reported no menstrual cycle-related changes in perceived sleep quality or readiness and only marginally poorer mood in the midluteal phase. However, they reported moderately more physical symptoms during menses (p < 0.001). Distal skin temperature and HR, measured during sleep, showed a biphasic pattern across the menstrual cycle, with increased HR (p < 0.03) and body temperature (p < 0.001) in the mid- and late-luteal phases relative to menses and ovulation. Correspondingly, rMSSD HRV tended to be lower in the luteal phase. Further, distal skin temperature was lower during ovulation relative to menses (p = 0.05). The menstrual cycle was not accompanied by significant fluctuations in objective and perceived measures of sleep or in mood, in healthy women with regular, ovulatory menstrual cycles. However, other physiological changes in skin temperature and HR were evident and may be longitudinally tracked with the Oura ring in women over multiple cycles in a natural setting.


What works? Process evaluation of a school-based fruit and vegetable distribution program in Mississippi.
During the 2004-2005 school year, the Mississippi Department of Education, Office of Child Nutrition, initiated a pilot program to distribute free fruit and vegetable snacks to students during the school day. This article describes the first-year implementation of the Mississippi Fruit and Vegetable Pilot Program. The process evaluation addressed where, when, and how produce was distributed; what was distributed; challenges and successes; and recommended modifications. Five of the 25 program schools were selected to participate in the evaluation; selection was based on grade levels served and demographic characteristics. Data were collected from program staff (N = 11) and administrators (N = 6) via interviews and logs; student (N = 42) and parent (N = 19) focus groups; student questionnaires (N = 660); and school staff questionnaires (N = 207). Distributing fresh fruit and vegetable snacks at school was well received by staff and students. Most schools distributed the fresh fruit and vegetable snacks at morning break in classrooms or a central courtyard. Twenty-two types of fresh fruit, 4 types of dried fruit, and 7 types of vegetables were served to students during the program year. Commonly distributed fruit included apples, oranges, pears, bananas, and tangerines. Carrots were the staple vegetable, followed by celery. Key challenges included getting students to try new foods and receiving the produce in a timely manner without spoiling. Main successes included seeing students try new fruit and vegetable snacks, having the program run smoothly, and teacher support. The program fit well within the school structure and could be an effective component of a multifaceted approach to enhancing child nutrition.


Rhizosphere priming effect on soil organic carbon decomposition under plant species differing in soil acidification and root exudation.
Effects of rhizosphere properties on the rhizosphere priming effect (RPE) are unknown. This study aimed to link species variation in RPE with plant traits and rhizosphere properties. Four C3 species (chickpea, Cicer arietinum; field pea, Pisum sativum; wheat, Triticum aestivum; and white lupin, Lupinus albus) differing in soil acidification and root exudation, were grown in a C4 soil. The CO2 released from soil was trapped using a newly developed NaOH-trapping system. White lupin and wheat showed greater positive RPEs, in contrast to the negative RPE produced by chickpea. The greatest RPE of white lupin was in line with its capacity to release root exudates, whereas the negative RPE of chickpea was attributed to its great ability to acidify rhizosphere soil. The enhanced RPE of field pea at maturity might result from high nitrogen deposition and release of structural root carbon components following root senescence. Root biomass and length played a minor role in the species variation in RPE. Rhizosphere acidification was shown to be an important factor affecting the magnitude and direction of RPE. Future studies on RPE modelling and mechanistic understanding of the processes that regulate RPE should consider the effect of rhizosphere pH.


Sauna Yoga Superiorly Improves Flexibility, Strength, and Balance: A Two-Armed Randomized Controlled Trial in Healthy Older Adults.
Besides strength and balance, flexibility is an important indicator of health-related physical fitness. Thus, the aim of this two-armed randomized controlled pilot trial was to investigate whether sauna yoga at a moderate temperature (50 °C) beneficially affects flexibility, strength, balance, and quality of life (QOL) in healthy elderly community dwellers. Participants were randomly assigned to an intervention group (INT, n = 11, age: 68.7 ± 5.9) or control group (CON, n = 12, age: 69.3 ± 4.9), using the minimization method. Age, physical activity, gender, and the primary outcome flexibility were used as strata for group allocation. Both groups completed similar exercises in the sauna over eight weeks. Only the INT group was exposed to moderate temperatures of 50 °C. Large and statistically significant improvement in favor of the sauna group (INT) was observed for the chair sit-and-reach test (INT: +83%, CON +3%, p = 0.028, nр² = 0.24). The shoulder and lateral spine flexibility were not relevantly affected. Strength in the lower extremities merely showed a tendency to significant changes (INT: 16%, CON: 3%, p = 0.061, nр² = 0.181). Additionally, balance abilities, with eyes closed, improved (INT: 187%, CON +58%, p = 0.056, nр² = 0.189) in favor of the INT group. QOL only improved in favor of the INT for environmental dimension (INT: +7%, CON: 0%, p = 0.034, nр² = 0.227). These first but preliminary findings indicate that sauna yoga may serve as a promising and feasible means to improve flexibility in elderly people. Strength and balance do not meaningfully benefit from a sauna environment, although strength improved to a slightly higher extent in the sauna group. Future large-scale research is needed to elucidate underlying mechanisms and corroborate these findings.


Disentangling two QTL on porcine chromosome 12 for backfat fatty acid composition.
A previous study allowed the identification of two QTL regions at positions 11-34 cM (QTL1) and 68-76 cM (QTL2) on porcine chromosome SSC12 affecting several backfat fatty acids in an Iberian x Landrace F2 intercross. In the current study, different approaches were performed in order to better delimit the quoted QTL regions and analyze candidate genes. A new chromosome scan, using 81 SNPs selected from the Porcine 60KBeadChip and six previously genotyped microsatellites have refined the QTL positions. Three new functional candidate genes (ACOX1, ACLY, and SREBF1) have been characterized. Moreover, two putative promoters of porcine ACACA gene have also been investigated. New isoforms and 24 SNPs were detected in the four candidate genes, 19 of which were genotyped in the population. ACOX1 and ACLY SNPs failed to explain the effects of QTL1 on palmitic and gadoleic fatty acids. QTL2, affecting palmitoleic, stearic, and vaccenic fatty acids, maps close to the ACACA gene location. The most significant associations have been detected between one intronic (g.53840T > C) and one synonymous (c.5634T > C) ACACA SNPs and these fatty acids. Complementary analyses including ACACA gene expression quantification and association studies in other porcine genetic types do not support the expected causal effect of ACACA SNPs.


In vitro antiproliferative effect of trastuzumab (Herceptin(®)) combined with cetuximab (Erbitux(®)) in a model of human non-small cell lung cancer expressing EGFR and HER2.
Lung cancer is the leading cause of cancer death. For this reason, new therapies are needed for the treatment of this devastating disease. In this study, we investigated the effects of combining cetuximab and the trastuzumab on the growth of a model of human non-small cell lung carcinoma cell line (A549). The results were compared with those obtained from a human lung squamous carcinoma cell line (NCI-H226). Both cell lines were treated with cetuximab and trastuzumab, alone or in combination, at various concentrations, for 24, 48 and 72 h. Cell proliferation was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. EGFR and HER-2 mRNA expression was detected by reverse transcription polymerase chain reaction, and the gene amplification status of receptors was evaluated by fluorescence in situ hybridisation. The colorimetric proliferation assay showed that trastuzumab combined with cetuximab significantly inhibited A549 cells at a dose of 40 μg/ml after 72 h of treatment (p < 0.05), while no time-dose dependent inhibition was observed in NCI-H226 cells. The combined treatment influenced both levels of EGFR and HER-2 mRNA in A549 cells and only EGFR mRNA levels in NCI-H226 cells. Fluorescence in situ hybridisation showed that both cell lines were aneuploid for the two genes with equally increased EGFR and CEN7 signals, as well as HER-2 and CEN17 signals, indicating a condition of polysomy without amplification. The preliminary results of this study encourage further investigations to elucidate the downstream events involved and to understand how these mechanisms influence non-small cell lung cancers growth.


RITA (Reactivating p53 and Inducing Tumor Apoptosis) is efficient against TP53abnormal myeloma cells independently of the p53 pathway.
The aim of this study was to evaluate the efficacy of the p53-reactivating drugs RITA and nutlin3a in killing myeloma cells. A large cohort of myeloma cell lines (n = 32) and primary cells (n = 21) was used for this study. This cohort contained cell lines with various TP53 statuses and primary cells with various incidences of deletion of chromosome 17. Apoptosis was evaluated using flow cytometry with Apo2.7 staining of the cell lines or via the loss of the myeloma-specific marker CD138 in primary cells. Apoptosis was further confirmed by the appearance of a subG1 peak and the activation of caspases 3 and 9. Activation of the p53 pathway was monitored using immunoblotting via the expression of the p53 target genes p21, Noxa, Bax and DR5. The involvement of p53 was further studied in 4 different p53-silenced cell lines. Both drugs induced the apoptosis of myeloma cells. The apoptosis that was induced by RITA was not related to the TP53 status of the cell lines or the del17p status of the primary samples (p = 0.52 and p = 0.80, respectively), and RITA did not commonly increase the expression level of p53 or p53 targets (Noxa, p21, Bax or DR5) in sensitive cells. Moreover, silencing of p53 in two TP53(mutated) cell lines failed to inhibit apoptosis that was induced by RITA, which confirmed that RITA-induced apoptosis in myeloma cells was p53 independent. In contrast, apoptosis induced by nutlin3a was directly linked to the TP53 status of the cell lines and primary samples (p < 0.001 and p = 0.034, respectively) and nutlin3a increased the level of p53 and p53 targets in a p53-dependent manner. Finally, we showed that a nutlin3a-induced DR5 increase (≥ 1.2-fold increase) was a specific and sensitive marker (p < 0.001) for a weak incidence of 17p deletion within the samples (≤ 19%). These data show that RITA, in contrast to nutlin3a, effectively induced apoptosis in a subset of MM cells independently of p53. The findings and could be of interest for patients with a 17p deletion, who are resistant to current therapies.


Vascular endothelial growth factor: an angiogenic factor reflecting airway inflammation in healthy smokers and in patients with bronchitis type of chronic obstructive pulmonary disease?
Patients with bronchitis type of chronic obstructive pulmonary disease (COPD) have raised vascular endothelial growth factor (VEGF) levels in induced sputum. This has been associated with the pathogenesis of COPD through apoptotic and oxidative stress mechanisms. Since, chronic airway inflammation is an important pathological feature of COPD mainly initiated by cigarette smoking, aim of this study was to assess smoking as a potential cause of raised airway VEGF levels in bronchitis type COPD and to test the association between VEGF levels in induced sputum and airway inflammation in these patients. 14 current smokers with bronchitis type COPD, 17 asymptomatic current smokers with normal spirometry and 16 non-smokers were included in the study. VEGF, IL-8, and TNF-alpha levels in induced sputum were measured and the correlations between these markers, as well as between VEGF levels and pulmonary function were assessed. The median concentrations of VEGF, IL-8, and TNF-alpha were significantly higher in induced sputum of COPD patients (1,070 pg/ml, 5.6 ng/ml and 50 pg/ml, respectively) compared to nonsmokers (260 pg/ml, 0.73 ng/ml, and 15.4 pg/ml, respectively, p < 0.05) and asymptomatic smokers (421 pg/ml, 1.27 ng/ml, p < 0.05, and 18.6 pg/ml, p > 0.05, respectively). Significant correlations were found between VEGF levels and pack years (r = 0.56, p = 0.046), IL-8 (r = 0.64, p = 0.026) and TNF-alpha (r = 0.62, p = 0.031) levels both in asymptomatic and COPD smokers (r = 0.66, p = 0.027, r = 0.67, p = 0.023, and r = 0.82, p = 0.002, respectively). No correlation was found between VEGF levels in sputum and pulmonary function parameters. VEGF levels are raised in the airways of both asymptomatic and COPD smokers. The close correlation observed between VEGF levels in the airways and markers of airway inflammation in healthy smokers and in smokers with bronchitis type of COPD is suggestive of VEGF as a marker reflecting the inflammatory process that occurs in smoking subjects without alveolar destruction.


Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma.
A prospective randomized phase III clinical trial was conducted to assess whether the addition of tamoxifen (TAM) to the three-agent regimen of cisplatin (CDDP), dacarbazine (DTIC), and carmustine (BCNU) significantly increased the progression-free survival and overall survival of patients with advanced malignant melanoma. Patients with advanced malignant melanoma were treated with CDDP + DTIC + BCNU (CDB) with or without TAM. The dose schedule was CDDP 25 mg/m(2) given intravenously (IV) for 30 to 45 minutes in 500 mL of dextrose and (1/2) normal saline (NS) on days 1 to 3 of a 3-week cycle; DTIC 220 mg/m(2) IV for 1 hour in 500 mL of dextrose and (1/2) NaCl on days 1 to 3 of a 3-week cycle; BCNU 150 mg/m(2) IV for 2 to 3 hours in 750 to 1,000 mL of dextrose and 5% water on day 1 of every odd 3-week cycle; and TAM 20 mg taken orally every morning. There were 184 eligible patients enrolled. These patients were observed until death or for a minimum of 1.3 years. At last contact, 12 were still alive. The median time to progression was 3.4 months on the CDB arm and 3.1 months on the CDB + TAM arm. The median survival time was 6.8 months with CDB and 6.9 months with CDB + TAM. Progression-free survival (P =.429) and overall survival (P =.545) were not found to differ by treatment. The addition of TAM to this three-agent regimen of CDB was not found to provide a meaningful clinical advantage in the treatment of patients with advanced malignant melanoma.


Parental perceptions and childhood dietary quality.
The early years represent a critical period of growth and development of health behaviours. While optimal child growth is associated with a complex set of factors, the importance of diet quality is undeniable. The objective of this narrative review is to examine contributors to child diet quality and parental perception and how such perceptions might affect child diet quality. An extensive literature search was conducted, generating a variety of sources including research trials (randomized and non-randomized), lab-based studies, cohort studies, topical reviews, government or NGO reports and grey literature. In addition, reflection and opinion, accrued through regular interaction with families, regarding some of the potential links has also been included. Parental perception of diet quality is influenced by many different social, biological economical and psychological factors. Research suggests that diet quality of today's children is sub-optimal and a parent's perception of their child's diet may not accurately reflect this reality. Various parental attitudes and perceptions/misperceptions are important to address as knowledge awareness and beliefs can impact diet quality as can parental practices, and family structure. Issues related to socioeconomics and convenience, and a child's preferences and their peer and/or social environment are also potential factors impacting child diet quality. Knowing that parents play such an integral role in the development and maintenance of their child's health behaviours, addressing misconceptions and unhealthy parental beliefs about diet quality may be an important area for early intervention and prevention work in childhood obesity.


Comparison of Transfer Learning and Conventional Machine Learning Applied to Structural Brain MRI for the Early Diagnosis and Prognosis of Alzheimer's Disease.
Alzheimer's Disease (AD) is the most common neurodegenerative disease, with 10% prevalence in the elder population. Conventional Machine Learning (ML) was proven effective in supporting the diagnosis of AD, while very few studies investigated the performance of deep learning and transfer learning in this complex task. In this paper, we evaluated the potential of ensemble transfer-learning techniques, pretrained on generic images and then transferred to structural brain MRI, for the early diagnosis and prognosis of AD, with respect to a fusion of conventional-ML approaches based on Support Vector Machine directly applied to structural brain MRI. Specifically, more than 600 subjects were obtained from the ADNI repository, including AD, Mild Cognitive Impaired converting to AD (MCIc), Mild Cognitive Impaired not converting to AD (MCInc), and cognitively-normal (CN) subjects. We used T1-weighted cerebral-MRI studies to train: (1) an ensemble of five transfer-learning architectures pretrained on generic images; (2) a 3D Convolutional Neutral Network (CNN) trained from scratch on MRI volumes; and (3) a fusion of two conventional-ML classifiers derived from different feature extraction/selection techniques coupled to SVM. The AD-vs-CN, MCIc-vs-CN, MCIc-vs-MCInc comparisons were investigated. The ensemble transfer-learning approach was able to effectively discriminate AD from CN with 90.2% AUC, MCIc from CN with 83.2% AUC, and MCIc from MCInc with 70.6% AUC, showing comparable or slightly lower results with the fusion of conventional-ML systems (AD from CN with 93.1% AUC, MCIc from CN with 89.6% AUC, and MCIc from MCInc with AUC in the range of 69.1-73.3%). The deep-learning network trained from scratch obtained lower performance than either the fusion of conventional-ML systems and the ensemble transfer-learning, due to the limited sample of images used for training. These results open new prospective on the use of transfer learning combined with neuroimages for the automatic early diagnosis and prognosis of AD, even if pretrained on generic images.


The use of DNA microarrays for the developmental expression analysis of cDNAs from the oesophageal gland cell region of Heterodera glycines.
Summary A microarray was printed containing cDNAs from a library made from cytoplasm microaspirated from the oesophageal gland cell region of parasitic stages of the soybean cyst nematode, Heterodera glycines. The array contained both previously described clones (Wang et al. Mol. Plant-Microbe Interact. 2001, 14, 536-544) and uncharacterized cDNAs. Fluorescent probes for array hybridization were prepared using RNA polymerase amplification of nematode mRNA. Developmental expression profiles of the arrayed cDNAs were determined by hybridizing the microarray with probes from parasitic and non-parasitic H. glycines life stages. Distinct patterns of developmental expression were ascertained for the previously described gland expressed genes. In addition, four H. glycines cDNAs (SCN1018, SCN1020, SCN1028 and SCN1167) were identified that showed up-regulation in one or more parasitic life stages. Clone SCN1018 encodes a C-type lectin domain and is expressed in the hypodermis of females. Clone SCN1020 encodes a probable S-adenosylmethionine synthetase. Clone SCN1028 encodes a piwi protein with high similarity to the germ-line-specific protein R06C7.1 of Caenorhabditis elegans. The sequence of SCN1167 had no similarity to known genes. This paper describes the first use of cDNA microarrays to analyse genes of a plant-parasitic nematode and establishes a functional method to mine nematode cDNA libraries.


Interleukin-6 secretion in mice is associated with reduced glucose-6-phosphatase and liver glycogen levels.
Mice bearing interleukin-6 (IL-6)-secreting tumor were used to study the chronic effect of IL-6 on carbohydrate metabolism. Mice were injected with allogeneic tumor cells transduced with the murine IL-6 gene. Serum IL-6 levels were correlated exponentially with tumor weight. Secretion of IL-6 from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Insulin levels did not change, and 2-deoxyglucose uptake was not affected in most tissues examined. A significant increase of 2-deoxyglucose uptake was measured in the liver. Glycogen content in the liver determined 0, 6, 12, and 18 days after tumor inoculation was 42, 23, 12, and 3 mg/g, respectively. The activity of phosphoenolpyruvate carboxykinase was not affected. The activity of glucose-6-phosphatase (G-6-Phase) determined 6, 12, and 18 days after tumor injection was 84, 70, and 50% of G-6-Pase activity in pair-fed mice bearing nonsecreting tumors, respectively. G-6-Pase mRNA levels were markedly reduced due to inhibition of G-6-Pase gene transcriptional rate.


Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex.
MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia [Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969-76.]. Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) [Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010;53:839-47.]. We investigated the expression levels of miR-137 and three candidate target genes (ZNF804A, CACNA1C, TCF4) in the DLPFC of postmortem brain tissue from 2 independent cohorts: (1) 26 subjects (10 control (CTR), 7 schizophrenia (SZ), 9 bipolar disorder (BD)) collected at the UCI brain bank; and (2) 99 subjects (33 CTR, 35 SZ, 31 BD) obtained from the Stanley Medical Research Institute (SMRI). MiR-137 expression in the DLPFC did not differ between diagnoses. We also explored the relationship between rs1625579 genotypes and miR-137 expression. Significantly lower miR-137 expression levels were observed in the homozygous TT subjects compared to TG and GG subjects in the control group (30% decrease, p-value = 0.03). Moreover, reduced miR-137 levels in TT subjects corresponded to increased levels of the miR-137 target gene TCF4. The miR-137 expression pattern in 9 brain regions was significant for regional effect (ANOVA p-value = 1.83E-12), with amygdala and hippocampus having the highest miR-137 expression level. In conclusion, decreased miR-137 expression is associated with the SZ risk allele of rs1625579, and potential regulation of TCF4, another SZ candidate gene. This study offers additional support for involvement of miR-137 and downstream targets as mechanisms of risk for psychiatric disorders.


Academic health systems management: the rationale behind capitated contracts.
To determine why hospitals enter into "capitated" contracts, which often generate accounting losses. The authors' hypothesis is that hospitals coordinate contracts to keep beds full and that in principal, capitated contracts reflect sound capacity management. In high-overhead industries, different consumers pay different prices for similar services (e.g., full-fare vs. advanced-purchase plane tickets, full tuition vs. financial aid). Some consumers gain access by paying less than total cost. Hospitals, like other high-overhead business enterprises, must optimize the use of their capacity, amortizing overhead over as many patients as possible. This necessity for enhanced throughput forces hospitals and health systems to discount empty beds, sometimes to the point where they incur accounting losses serving some payors. The authors analyzed the cost accounting system at their university teaching hospital to compare hospital and intensive care unit (ICU) lengths of stay (LOS), variable direct costs (VDC), overhead of capitated patients, and reimbursement versus other payors for all hospital discharges (n = 29,036) in fiscal year 1998. The data were analyzed by diagnosis-related groups (DRGs), length of stay (LOS), insurance carrier, proximity to hospital, and discharge disposition. Patients were then distinguished across payor categories based on their resource utilization, proximity to the hospital, DRG, LOS, and discharge status. The mean cost for capitated patients was $4,887, less than half of the mean cost of $10,394 for the entire hospitalized population. The mean capitated reimbursement was $928/day, exceeding the mean daily VDC of $616 but not the total cost of $1,445/day. Moreover, the mean total cost per patient day of treating a capitated patient was $400 less than the mean total cost per day for noncapitated patients. The hospital's capitated health maintenance organization (HMO) patients made up 16. 0% of the total admissions but only 9.4% of the total patient days. Both the mean LOS of 3.4 days and the mean ICU LOS of 0.3 days were significantly different from the overall values of 5.8 days and 1 day, respectively, for the noncapitated population. For patients classified with a DRG with complication who traveled from more than 60 miles away, the mean LOS was 10.7 days and the mean total cost was $21,658. This is in contrast to all patients who traveled greater than 60 miles, who had an LOS of 7.2 days and a mean total cost of $12,569. The capitated payor directed the bulk of its subscribers to one hospital (other payors transferred their sicker patients). This was reflected in the capitated group's lower costs and LOS. This stable stream of relatively low-acuity patients enhanced capacity utilization. For capitated patients, the hospital still benefits by recovering the incremental cost (VDC) of treating these patients, and only a portion of the assigned overhead. Thus, in the short run, capitated patients provide a positive economic benefit. Other payors' higher-acuity patients arrive more randomly, place greater strains on capacity, and generate higher overhead costs. This results in differential reimbursement to cover this incremental overhead. Having a portfolio of contracts allows the hospital to optimize capacity both in terms of patient flows and acuity. One risk of operating near capacity is that capitated patients could displace other higher-paying patients.


Design and characterisation of a novel in vitro skin diffusion cell system for assessing mass casualty decontamination systems.
The efficient removal of contaminants from the outer surfaces of the body can provide an effective means of reducing adverse health effects associated with incidents involving the accidental or deliberate release of hazardous materials. Showering with water is frequently used by first responders as a rapid method of mass casualty decontamination (MCD). However, there is a paucity of data on the generic effectiveness and safety of aqueous decontamination systems. To address these issues, we have developed a new in vitro skin diffusion cell system to model the conditions of a common MCD procedure ("ladder pipe system"). The new diffusion cell design incorporates a showering nozzle, an air sampling port for measurement of vapour loss and/aerosolisation, adjustable (horizontal to vertical) skin orientation and a circulating manifold system (to maintain a specified flow rate, temperature and pressure of shower water). The dermal absorption characteristics of several simulants (Invisible Red S, curcumin and methyl salicylate) measured with the new in vitro model were in good agreement with previous in vitro and in vivo studies. Moreover, these initial studies have indicated that whilst flow rate and water temperature are important factors for MCD, the presence of clothing during showering may (under certain circumstances) cause transfer and spreading of contaminants to the skin surface.


Almond consumption decreases android fat mass percentage in adults with high android subcutaneous adiposity but does not change HbA1c in a randomised controlled trial.
The purpose of this study was to determine if the mixed evidence of almond consumption on HbA1c stems from testing people with different body fat distributions (BFD) associated with different risks of glucose intolerance. A 6-month randomised controlled trial in 134 adults was conducted. Participants were randomly assigned to the almond (A) or control (C) group based on their BFD. Those in the almond group consumed 1·5 oz of almonds with their breakfast and as their afternoon snack daily. Those in the control group continued their habitual breakfast and afternoon snack routines. Body weight and composition were measured and blood samples were collected for determination of HbA1c, glycaemia and lipaemia at 0 and 6 months. Appetite ratings, energy intake and diet quality were collected at 0, 2, 4 and 6 months. Participants consuming almonds ingested 816 (sem 364) kJ/d more than participants in the control group (P = 0·03), but this did not result in any differences in body weight (A: -0·3 (sem 0·4), C: -0·4 (sem 0·4); P > 0·3). Participants in the almond, high android subcutaneous adipose tissue (SAT) group had a greater reduction in android fat mass percentage (A: -1·0 (sem 0·6), C: 1·1 (sem 0·6); P = 0·04), preserved android lean mass percentage (A: 0·9 (sem 0·6), C: -1 (sem 0·6); P = 0·04) and tended to decrease android visceral adipose tissue mass (A: -13 (sem 53) g, C: 127 (sem 53) g; P = 0·08) compared with those in the control, high SAT group. There were no differences in HbA1c between groups (A: 5·4 (sem 0·04), C: 5·5 (sem 0·04); P > 0·05). Thus, BFD may not explain the mixed evidence on almond consumption and HbA1c. Long-term almond consumption has limited ability to improve cardiometabolic health in those who are overweight and obese but otherwise healthy.


Effect of high-intensity ultrasound on the structural and functional properties of proteins in housefly larvae (Musca demestica).
Insect protein has gradually attracted wide attention from the international research community as a promising source of high-quality protein that can replace traditional protein sources. The larvae of the housefly, a prevalent and widespread species, contain high levels of protein with beneficial properties, namely, anti-fatigue, anti-radiation, and anti-aging functions, as well as liver protection and immunity enhancement. This work thoroughly examined the impact of high-intensity ultrasound (HIUS) on the structural and functional characteristics of housefly larval concentrate protein (HLCP). HLCP samples were sonicated for 20 min at a frequency of 20 kHz with varying energies (0, 100, 200, 300, 400, and 500 W). The findings demonstrated that sonication considerably altered the secondary and tertiary structures of HLCP but had no effect on molecular weight. With an increase in ultrasonic power, HLCP's particle size shrank, more hydrophobic groups were exposed, more free sulfhydryl groups were present, the solution's stability improved, and HLCP's solubility rose. In addition, HLCP's emulsification and foaming abilities were improved by HIUS treatment. It is anticipated that this study's findings will offer fresh insights into the implementation of HLCP in the food sector.


A modifier of Huntington's disease onset at the MLH1 locus.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets.


Benzodiazepines: a major problem. Introduction.
Benzodiazepine use is prevalent. Moreover, benzodiazepine abuse, addiction, tolerance, and dependence occur commonly with benzodiazepine use. Confusion arises in assessing the nature and magnitude of benzodiazepine use and its consequences. Abuse, addiction, tolerance, and dependence occur in medical and nonmedical populations, but the studies do not clearly differentiate the benzodiazepine use between these two populations. The nonmedical use in medical populations is underestimated and underdiagnosed. The nonmedical use is also misdiagnosed in nonmedical populations as medical use. Clearer definitions and usage of the terms of abuse, addiction, tolerance, and dependence would result in accurate diagnosis and proper treatment of the disorders associated with benzodiazepine use, that is, anxiety and depressive disorders, alcoholism, and other drug addictions.


Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial.
The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone vs sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100 × 109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% confidence interval, 10.0-44.7). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment of KHE with KMP. This trial was registered at www.clinicaltrials.gov as #NCT03188068.


Effect of topical administration of propolis in chronic periodontitis.
To investigate the effect of topical administration of propolis (a honeybee product) or curry leaf (an herbal product) into the periodontal pockets of periodontitis patients, a double-blind controlled clinical trial was conducted with 24 subjects including one drop-out diagnosed with moderate-to-advanced chronic periodontitis who completed initial periodontal therapy. They were randomly allocated to the following treatments: placebo, propolis, curry leaf, and minocycline. Gingival crevicular fluid (GCF) samples collected before and after the intervention were analyzed to quantify the number of total bacteria and number of six major periodontopathic bacteria by real-time PCR. Periodontitis-related clinical parameters were also analyzed. Among the six propolis-treated patients whose GCF samples were P. gingivalis-positive, three patients converted to be P. gingivalis-negative after the intervention. The minocycline-treated group exhibited a decrease in probing pocket depth (PPD) with statistically significant improvement, but not gain of clinical attachment level (CAL). Both PPD and CAL have been improved in the propolis-treated group at a statistically significant level, but not the curry leaf-treated group. In conclusion, treatment with propolis significantly improved both PPD and CAL, together with a tendency towards reduced P. gingivalis burden in GCF. It is likely that a propolis-based therapy becomes an alternative treatment option for chronic periodontitis during supportive periodontal therapy.


Pelagia benovici sp. nov. (Cnidaria, Scyphozoa): a new jellyfish in the Mediterranean Sea.
A bloom of an unknown semaestome jellyfish species was recorded in the North Adriatic Sea from September 2013 to early 2014. Morphological analysis of several specimens showed distinct differences from other known semaestome species in the Mediterranean Sea and unquestionably identified them as belonging to a new pelagiid species within genus Pelagia. The new species is morphologically distinct from P. noctiluca, currently the only recognized valid species in the genus, and from other doubtful Pelagia species recorded from other areas of the world. Molecular analyses of mitochondrial cytochrome c oxidase subunit I (COI) and nuclear 28S ribosomal DNA genes corroborate its specific distinction from P. noctiluca and other pelagiid taxa, supporting the monophyly of Pelagiidae. Thus, we describe Pelagia benovici sp. nov. Piraino, Aglieri, Scorrano & Boero.


Monoclonal and polyclonal antibodies against acetaldehyde-containing epitopes in acetaldehyde-protein adducts.
Immunization of mice with acetaldehyde conjugated to human plasma proteins resulted in the production of polyclonal antibodies that reacted with erythrocyte protein-acetaldehyde conjugates, but not with control erythrocyte proteins. Such antibodies recognized erythrocyte protein-acetaldehyde conjugates prepared with 20-100 microM acetaldehyde, concentrations that exist in the blood of alcoholics. The antibodies also recognized acetaldehyde condensation products with synthetic poly-(L-lysine). Immunization with keyhole limpet hemocyanin-acetaldehyde conjugates resulted in antibodies against both plasma protein-acetaldehyde and erythrocyte protein-acetaldehyde conjugates, which did not cross-react with the respective unmodified carrier proteins. Immunization with human erythrocyte protein-acetaldehyde condensates led to the production of antibodies against both the protein moiety as well as the condensate. Monoclonal antibodies with affinities 50 times greater for the condensate than for the carrier protein were produced by hybridization of spleen cells from the immunized mice. Chronic alcohol administration to mice for 45-50 days led to the generation of antibodies that reacted against protein-acetaldehyde conjugates, suggesting that such adducts are formed in vivo and can act as neoantigens. Antibodies against acetaldehyde adducts should be of value in the identification of alcohol consumption and in the study of the biology of the adducts in relation to organ pathology.


Dietary gamma-linolenate attenuates tumor growth in a rodent model of prostatic adenocarcinoma via suppression of elevated generation of PGE(2) and 5S-HETE.
Prostate cancer poses considerable threat to the aging male population as it has become a leading cause of cancer death to this group. Due to the complexity of this age-related disease, the mechanism(s) and factors resulting in prostate cancer remain unclear. Reports showing an increase risk in prostatic cancer with increasing dietary fat are contrasted by other studies suggesting the beneficial effects of certain polyunsaturated fatty acid (PUFA) in the modulation of tumor development. The n-6 PUFA, gamma-linolenic acid (GLA), has been shown to suppress tumor growth in vitro. Therefore, using the Lobund-Wistar (L-W) rat model of prostate cancer, we tested the hypothesis whether dietary supplementation of GLA could suppress tumor growth and development in vivo. Prostatic adenocarcinomas were induced in two groups of L-W rats, the experimental group (N-nitroso-N-methylurea, NMU/testosterone propionate, TP) and the GLA group (NMU/TP/GLA fed) undergoing similar treatment but fed a purified diet supplemented with GLA. Our findings revealed a decrease in prostate growth in the NMU/TP/GLA-fed group as determined by weight, tissue size, DNA content and prostate-specific antigen (tumor marker of prostate cancer). Comparison between the two groups showed a significant increase in 5S-hydroxyeicosatetraenoic acid and prostaglandin E(2) in the NMU/TP group. These increases paralleled the increased protein expression and activity of cyclooxygenase-2 as well as increased activity of 5-lipoxygenase. Taken together, the findings showed that intake of GLA-enriched diet does reduce prostatic cancer development in L-W rats and could serve as a non-toxic adjunct in management of human prostatic cancer.


Phenotypic expression of oxacillin resistance in Staphylococcus epidermidis: roles of mecA transcriptional regulation and resistant-subpopulation selection.
The MICs for many oxacillin-resistant (OR) Staphylococcus epidermidis (ORSE) strains are below the Staphylococcus aureus methicillin or oxacillin resistance breakpoint. The difficulty detecting the OR phenotype in S. epidermidis may be due to extreme heterotypy in resistance expression and/or transcriptional repression of mecA, the OR gene, by MecI. To determine the role of these factors in the phenotypic expression of ORSE, 17 geographically diverse mecI(+) ORSE isolates representing 14 distinct pulsed-field gel electrophoresis pulse types (>3 band differences) were investigated. Thirteen of the 14 types contained mecI and mecA promoter-operator sequences known to be associated with maximal mecA repression, and in all isolates, mecA transcription was repressed. All 17 were heterotypic in their resistance expression. Oxacillin MICs ranged from 1 to 128 microg/ml and increased for 16 of 17 isolates after beta-lactam induction. Allelic replacement inactivation of mecI in three isolates similarly resulted in a four- to sevenfold increase in MIC. In the two of these three isolates producing beta-lactamase, mecA transcription was regulated by both mecI and beta-lactamase regulatory sequences. Heterotypic expression of resistance in these three isolates was unaffected by either beta-lactam induction or mecI inactivation. However, prolonged incubation in concentrations of oxacillin just sufficient to produce a lag in growth (0.5 to 1.0 microg/ml) converted the population resistance expression from heterotypic to homotypic. Homotypic conversion could also be demonstrated in microtiter wells during MIC determinations in one isolate for which the MIC was high. We conclude that the phenotypic expression of S. epidermidis OR in broth can be affected both by mecA transcriptional regulation and by subpopulation resistance expression.


Bone strain index as a predictor of further vertebral fracture in osteoporotic women: An artificial intelligence-based analysis.
Osteoporosis is an asymptomatic disease of high prevalence and incidence, leading to bone fractures burdened by high mortality and disability, mainly when several subsequent fractures occur. A fragility fracture predictive model, Artificial Intelligence-based, to identify dual X-ray absorptiometry (DXA) variables able to characterise those patients who are prone to further fractures called Bone Strain Index, was evaluated in this study. In a prospective, longitudinal, multicentric study 172 female outpatients with at least one vertebral fracture at the first observation were enrolled. They performed a spine X-ray to calculate spine deformity index (SDI) and a lumbar and femoral DXA scan to assess bone mineral density (BMD) and bone strain index (BSI) at baseline and after a follow-up period of 3 years in average. At the end of the follow-up, 93 women developed a further vertebral fracture. The further vertebral fracture was considered as one unit increase of SDI. We assessed the predictive capacity of supervised Artificial Neural Networks (ANNs) to distinguish women who developed a further fracture from those without it, and to detect those variables providing the maximal amount of relevant information to discriminate the two groups. ANNs choose appropriate input data automatically (TWIST-system, Training With Input Selection and Testing). Moreover, we built a semantic connectivity map usingthe Auto Contractive Map to provide further insights about the convoluted connections between the osteoporotic variables under consideration and the two scenarios (further fracture vs no further fracture). TWIST system selected 5 out of 13 available variables: age, menopause age, BMI, FTot BMC, FTot BSI. With training testing procedure, ANNs reached predictive accuracy of 79.36%, with a sensitivity of 75% and a specificity of 83.72%. The semantic connectivity map highlighted the role of BSI in predicting the risk of a further fracture. Artificial Intelligence is a useful method to analyse a complex system like that regarding osteoporosis, able to identify patients prone to a further fragility fracture. BSI appears to be a useful DXA index in identifying those patients who are at risk of further vertebral fractures.


Endothelium-dependent vasodilation by melittin: are lipoxygenase products involved?
Vascular relaxation in response to acetylcholine and other vasodilator compounds has been shown to depend on intact endothelial cells. These dilator compounds obviously induce the formation of an unstable endothelium-derived relaxing factor or factors (EDRF) from the intima which relax the subjacent smooth muscle cells. The chemical identity of this factor (these factors) is still unclear. In the present study we demonstrate that endothelium-dependent relaxation of rabbit aorta was induced by melittin, a polypeptide toxin that activates phospholipase A2 to liberate polyunsaturated fatty acids (especially arachidonic acid) from membrane phospholipids. The relaxation induced by melittin had several properties similar to the acetylcholine relaxation. It was inhibited by potential inhibitors of phospholipase (mepacrine and p-bromophenacylbromide), by inhibitors of lipoxygenase (nordi-hydroguaiaretic acid, compound BW 755C, and 5,8,11,14-eicosatetraynoic acid) but not by the cyclooxygenase inhibitor indomethacin. An exogenous preparation of phospholipase C also induced endothelium-dependent relaxations. These findings support the hypothesis that oxidized metabolites of polyunsaturated fatty acids (e.g., arachidonic acid) may be involved directly (as mediators) or indirectly in the process of endothelium-dependent relaxation. On the other hand, exogenous arachidonic acid was a comparatively weak endothelium-dependent relaxant. However, this does not exclude an important role of endogenous arachidonic acid since the exogenous acid may not sufficiently reach its site of metabolism.


Solution structure and dynamics of the central CCP module pair of a poxvirus complement control protein.
The complement control protein (CCP) module (also known as SCR, CCP or sushi domain) is prevalent amongst proteins that regulate complement activation. Functional and mutagenesis studies have shown that in most cases two or more neighbouring CCP modules form specific binding sites for other molecules. Hence the orientation in space of a CCP module with respect to its neighbours and the flexibility of the intermodular junction are likely to be critical for function. Vaccinia virus complement control protein (VCP) is a complement regulatory protein composed of four tandemly arranged CCP modules. The solution structure of the carboxy-terminal half of this protein (CCP modules 3 and 4) has been solved previously. The structure of the central portion (modules 2 and 3, VCP approximately 2,3) has now also been solved using NMR spectroscopy at 37 degrees C. In addition, the backbone dynamics of VCP approximately 2,3 have been characterised by analysis of its (15)N relaxation parameters. Module 2 has a typical CCP module structure while module 3 in the context of VCP approximately 2,3 has some modest but significant differences in structure and dynamics to module 3 within the 3,4 pair. Modules 2 and 3 do not share an extensive interface, unlike modules 3 and 4. Only two possible NOEs were identified between the bodies of the modules, but a total of 40 NOEs between the short intermodular linker of VCP approximately 2,3 and the bodies of the two modules determines a preferred, elongated, orientation of the two modules in the calculated structures. The anisotropy of rotational diffusion has been characterised from (15)N relaxation data, and this indicates that the time-averaged structure is more compact than suggested by (1)H-(1)H NOEs. The data are consistent with the presence of many intermodular orientations, some of which are kinked, undergoing interconversion on a 10(-8)-10(-6) second time-scale. A reconstructed representation of modules 2-4 allows visualisation of the spatial arrangement of the 11 substitutions that occur in the more potent complement inhibitor from Variola (small pox) virus.


Comparison of satisfaction after direct browplasty in Asian patients with and without brow tattoo.
To determine patient-based scar assessment after direct browplasty for correction of brow ptosis between Asian female patients with and without brow tattoos. A retrospective study with questionnaire via telephone interview. A total of 30 female Asian patients underwent direct browplasty from January 2008 to December 2011. The Patient Scar Assessment Questionnaire (PSAQ) with 5 subscales including appearance, symptoms, consciousness, satisfaction with appearance, and satisfaction with symptoms was used at least 6 months after surgery in patients who underwent direct browplasty. PSAQ scores were compared between Group A (15 cases with brow tattoo lines) and Group B (15 cases without brow tattoo). A lower score indicates a favourable cosmetic outcome. Of the subscales of PSAQ, only "satisfaction with appearance" was significantly lower in Group A (1.4 ± 0.5) than in Group B (2.0 ± 1.0; p = 0.039). Mean scores of appearance, symptoms, satisfaction with symptoms, and overall scores were not different between 2 groups. According to the PSAQ, mean scores of appearance, symptoms, and consciousness regarding surgical scar after direct browplasty were relatively low. Asian patients who underwent direct browplasty were generally satisfied with overall appearance and comfort of their scar regardless of brow tattoo lines, despite the statistical difference in their satisfaction with appearance.


Associations Between Online Pornography Consumption and Sexual Dysfunction in Young Men: Multivariate Analysis Based on an International Web-Based Survey.
Expanding access to the internet has resulted in more and earlier consumption of online pornography. At the same time, a higher prevalence of erectile dysfunction (ED) among young men is seen. Increased pornography consumption has been suggested as a possible explanation for this rise. The aim of this study was to better understand associations between problematic pornography consumption (PPC) and ED. A 118-item survey was published online, and data collection took place between April 2019 and May 2020. Of the 5770 men who responded, the responses from 3419 men between 18 years old and 35 years old were analyzed. The survey used validated questionnaires such as the Cyber Pornography Addiction Test (CYPAT), International Index of Erectile Function (IIEF-5), and Alcohol Use Disorders Identification Test-Concise (AUDIT-C). The estimated amount of porn watching was calculated. Univariable and multivariable analyses were performed. For the multivariable analysis, a logistic regression model using a directed acyclic graph was used. According to their IIEF-5 scores, 21.48% (444/2067) of our sexually active participants (ie, those who attempted penetrative sex in the previous 4 weeks) had some degree of ED. Higher CYPAT scores indicating problematic online pornography consumption resulted in a higher probability of ED, while controlling for covariates. Masturbation frequency seemed not to be a significant factor when assessing ED. This prevalence of ED in young men is alarmingly high, and the results of this study suggest a significant association with PPC. Research Registry researchregistry5111; https://tinyurl.com/m45mcaa2.


2B-Alert Web 2.0, an Open-Access Tool for Predicting Alertness and Optimizing the Benefits of Caffeine: Utility Study.
One-third of the US population experiences sleep loss, with the potential to impair physical and cognitive performance, reduce productivity, and imperil safety during work and daily activities. Computer-based fatigue-management systems with the ability to predict the effects of sleep schedules on alertness and identify safe and effective caffeine interventions that maximize its stimulating benefits could help mitigate cognitive impairment due to limited sleep. To provide these capabilities to broad communities, we previously released 2B-Alert Web, a publicly available tool for predicting the average alertness level of a group of individuals as a function of time of day, sleep history, and caffeine consumption. In this study, we aim to enhance the capability of the 2B-Alert Web tool by providing the means for it to automatically recommend safe and effective caffeine interventions (time and dose) that lead to optimal alertness levels at user-specified times under any sleep-loss condition. We incorporated a recently developed caffeine-optimization algorithm into the predictive models of the original 2B-Alert Web tool, allowing the system to search for and identify viable caffeine interventions that result in user-specified alertness levels at desired times of the day. To assess the potential benefits of this new capability, we simulated four sleep-deprivation conditions (sustained operations, restricted sleep with morning or evening shift, and night shift with daytime sleep) and compared the alertness levels resulting from the algorithm's recommendations with those based on the US Army caffeine-countermeasure guidelines. In addition, we enhanced the usability of the tool by adopting a drag-and-drop graphical interface for the creation of sleep and caffeine schedules. For the 4 simulated conditions, the 2B-Alert Web-proposed interventions increased mean alertness by 36% to 94% and decreased peak alertness impairment by 31% to 71% while using equivalent or smaller doses of caffeine as the corresponding US Army guidelines. The enhanced capability of this evidence-based, publicly available tool increases the efficiency by which diverse communities of users can identify safe and effective caffeine interventions to mitigate the effects of sleep loss in the design of research studies and work and rest schedules.


MicroRNA-376a regulates cell proliferation and apoptosis by targeting forkhead box protein P2 in lymphoma.
The present study aimed to investigate microRNA-376a (miR-376a) expression in lymphoma, and to investigate the effect of miR-376a on cell proliferation and apoptosis at cytological and molecular levels. The expression of miR-376a in lymphoma issue and cells was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR), the expression of forkhead box protein P2 (FOXP2) was detected by RT-qPCR and western blot analysis, and the effect of miR-376a on cell proliferation and apoptosis were studied by an MTT assay and flow cytometry, respectively. Additionally, the expression levels of cyclin D2, cyclin A, cyclin B, apoptosis-associated proteins B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blot analysis. Furthermore, the target of miR-376a was predicted and clarified using a dual-luciferase reporter assay. The expression of miR-376a was downregulated and FOXP2 was upregulated in lymphoma tissues and cells. miR-376a overexpression inhibited lymphoma cell proliferation and induced apoptosis by regulating the expression levels of cyclin D2, cyclin A, Bax and Bcl-2. The dual-luciferase reporter assay demonstrated that FOXP2 was a target of miR-376a. miR-376a overexpression induced apoptosis by targeting FOXP2. Overexpression of miR-376a inhibited cell proliferation and induced apoptosis by targeting FOXP2 in lymphoma. Therefore, miR-376a and FOXP2 have the potential for use as biomarkers of lymphoma.


Complement Activation Products and Cytokines in Pachychoroid Neovasculopathy and Neovascular Age-Related Macular Degeneration.
To investigate the characteristics of complement activation products and angiogenic cytokines in the aqueous humor in eyes with pachychoroid neovasculopathy (PNV) and neovascular age-related macular degeneration (nAMD). This was a prospective, comparative, observational study. All patients with choroidal neovascularization were classified as PNV without polyps, PNV with polyps (polypoidal choroidal vasculopathy [PCV]), or drusen-associated nAMD according to the presence or absence of pachychoroid features and soft drusen. This study included a total of 105 eyes. Aqueous humor samples were collected from 25 eyes with PNV without polyps, 23 eyes with PCV, and 24 eyes with drusen-associated nAMD before intravitreal anti-vascular endothelial growth factor (VEGF) injection and cataract surgery in 33 control eyes. Clinical samples were measured for complement component 3a (C3a), C4a, C5a, VEGF, and macrophage chemoattractant protein 1 (MCP-1) using a bead-based immunoassay. C3a and MCP-1 levels were significantly higher in PCV (P = 0.032 and P = 0.039, respectively) and drusen-associated nAMD (P = 0.01 for both comparisons) than in controls, and no difference was seen in C3a and MCP-1 levels between PNV and controls (P = 0.747 and P = 0.294, respectively). VEGF levels were significantly higher in PNV (P = 0.016), PCV (P = 0.009), and drusen-associated nAMD (P = 0.043) than in controls. In PNV, the VEGF levels elevated without elevated C3a and MCP-1. PNV, PCV, and drusen-associated nAMD had significantly distinct profiles of complement activation products and cytokines in the aqueous humor.


Understanding the transition from water to land: Insights from multi-omic analyses of the perivitelline fluid of apple snail eggs.
Unlike most of the freshwater gastropod families, the family Ampullariidae includes members that exhibit both underwater and aerial oviposition, making it an ideal model for understanding mechanisms underlying the evolutionary transition from water to land. We applied SDS-PAGE and LC-MS/MS to analyse the proteome of the egg perivitelline fluid (PVF) of Marisa cornuarietis - an aquatic ovipositing ampullariid. Comparison with the reported PVF proteomes of two aerial ovipositing ampullariids (Pomacea canaliculata and P. maculata) showed that the three species all contain several major perivitellins that nourish the embryos. However, M. cornuarietis invests more heavily on immune-related proteins, which might be due to exposure to aquatic pathogens. Interestingly, only the PVF of out-of-water egg laying species have PV2 - a neurotoxin lethal to mice, and a calcium-binding protein which might be involved in the formation of calcareous eggshell. Integrated phylogenetic, evolutionary and gene expressional analyses detected the involvement of gene duplication, positive selection and neofunctionalisation in the formation of several major PVF proteins. Overall, our study provides multiple lines of evidence of adaptive evolution in the PVF proteins, and contributes to a better understanding of how aquatic gastropod ancestors invaded terrestrial habitats. SIGNIFICANCE: Aerial egg deposition has evolved in several groups of animals, but except for Vertebrata little is known about the mechanisms underlying this critical evolution process. We compared aquatic and aerial egg laying apple snails to understand the molecular mechanisms enabling such a transition in egg laying habitat. We found that the composition of perivitelline fluid proteomes of underwater and aerial egg depositors was remarkably different, and then gene duplication and positive selection were responsible for the formation of such novel proteins than enabled the evolutionary transition.


Clenbuterol, a beta 2-receptor agonist, reduces net bone loss in denervated hindlimbs.
Clenbuterol treatment for several weeks prevented up to one-third of the reduction in mineralization of femurs and tibias caused by sectioning of the sciatic nerve in young rats. The normalizing effect of clenbuterol on bone mineral content was directly proportional to similar alterations in muscle mass, which in turn could be abolished by ablation of the triceps surae or hindlimb unweighting and reduced by hypophysectomy. In contrast to the effects of inactivity, ovariectomy caused small reductions (2-4%) in bone density that were not affected by clenbuterol and were not accompanied by changes in ash weight. Together, our results suggest that the ability of beta 2-agonists to retard the loss in net muscle mass and enhance contractile tension can oppose net bone loss caused by denervation. Increases in contractile tension caused by beta 2-agonists may enhance the utility of exercise or electrical stimulation as countermeasures for the effects of scoliosis, prolonged bed rest, spinal cord injury, or weightlessness in space on bone mass.


Opioid gene expression in the developing and adult rat heart.
Opioid peptides are known to play a role in the function and growth of the mammalian heart. Although some information about gene expression of opioids in the heart is available, there is no data on the cellular location of opioid gene expression during development or in the adult. Using in situ hybridization and rat heart ranging from embryonic day 14 (E14) to adulthood, we have evaluated the distribution of gene expression for proenkephalin, proopiomelanocortin, and prodynorphin. With respect to preproenkephalin mRNA (PPE mRNA), message in the ventricle was abundant from E14 (the first time point examined) until shortly after birth, with a marked reduction noted on postnatal days 5, 10, and 21. Adults displayed considerable message, though less than in preparations of embryonic and neonatal heart. PPE mRNA was detected in epicardial, myocardial, and endocardial cells, as well as the walls of blood vessels, capillaries, and fibroblasts. Preproopiomelanocortin (POMC) mRNA was only found in adults, and was localized to the myocardium. Message for preprodynorphin could not be observed in the ventricles of developing or adult rats. These results are the first to define the temporal and spatial ontogeny of opioid gene expression with regard to the emergence of cardiac architecture. The data suggest that gene expression for proenkephalin is especially prevalent in embryonic and neonatal rats and may be related to the modulatory activity of the opioid growth factor, [Met5]-enkephalin, on cell proliferation and differentiation. The role of PPE and POMC mRNA in adult rat heart requires elucidation.


A Protocol for the Safe Use of Hazardous Drugs in the OR.
Hazardous drug (HD) use in the perioperative environment poses unique challenges and risks for exposure that can have adverse consequences for perioperative personnel. The United States Pharmacopeial Convention has implemented new standards to address the safe handling and administration of HDs by health care workers. To comply with these standards and minimize perioperative personnel's occupational exposure to HDs, a multidisciplinary team at an academic medical center in Boston that was performing an increased number and variety of operative and other invasive procedures using antineoplastic agents updated their protocol for the safe use of HDs in the OR. This article discusses HDs and the risks they pose to health care workers and outlines the new HD safety protocol for the OR that was part of a performance improvement plan to ensure compliance with new standards and staff member safety in the perioperative setting.