Responsive manganese-based nanoplatform amplifying cGAS-STING activation for immunotherapy.
The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has attracted great attention for its ability to up-regulate innate immune response and thus enhance cancer immunotherapy. However, many STING agonists limit the further advancement of immunotherapy due to weak tumor responsiveness or low activation efficiency. The responsive and effective activation of cGAS-STING signaling in tumors is a highly challenging process. In this study, a manganese-based nanoplatform (MPCZ NPs) was constructed that could responsively and efficiently generate more manganese ions (Mn2+) and reactive oxygen species (ROS) to activate cGAS-STING signaling pathway. Briefly, manganese dioxide (MnO2) was loaded with zinc protoporphyrin IX (ZPP) molecule and coated by polydopamine (PDA) embedded with NH4HCO3 to obtain MPCZ NPs. Additionally, MPCZ NPs were evaluated in vitro and in vivo for their antitumor effects by methyl thiazolyl tetrazolium (MTT) assay and TUNEL assays, respectively. In this system, tumor responsiveness was achieved by exogenous (laser irradiation) and endogenous (high levels GSH) stimulation, which triggered the collapse or degradation of PDA and MnO2. Moreover, the release of Mn2+ augmented the cGAS-STING signaling pathway and enhanced the conversion of hydrogen peroxide (H2O2) to hydroxyl radical (·OH) under NIR laser irradiation. Furthermore, the release of ZPP and the elimination of GSH by MPCZ NPs inhibited HO-1 activity and prevented ROS consumption, respectively. This adopted open source and reduce expenditure strategy to effectively generate more ROS and Mn2+ to responsively activate cGAS-STING signaling pathway, providing a new strategy for improving immunotherapy.


N3-methyladenine induces early poly(ADP-ribosylation), reduction of nuclear factor-kappa B DNA binding ability, and nuclear up-regulation of telomerase activity.
Methylation of N3-adenine represents a novel pharmacological strategy for the treatment of resistant tumors. However, little is known about the biochemical pathways involved in cell death induced by N3-methyladenine. In the present study, we show that MeOSO(2) (CH(2))(2)-lexitropsin (Me-Lex), a compound generating almost exclusively N3-methyladenine (>99%), provoked a burst of poly(ADP-ribosylation) and loss of mitochondrial membrane potential in leukemia cells. These events were followed by a marked decrease in nuclear poly(ADP-ribose) polymerase-1 (PARP-1) expression and nuclear factor-kappaB (NF-kappaB) activity. Moreover, DNA damage generated by N3-methyladenine induced a marked decrease in telomerase in the cytosol that was accompanied by a transient up-regulation of activity in the nucleus, as a consequence of nuclear translocation of telomerase in response to genotoxic damage. PARP-1 inhibition blocked ADP-ribose polymer formation, preserved mitochondrial membrane integrity, and counteracted the reduction of NF-kappaB activity, thus preventing the appearance of necrosis. On the other hand, because PARP-1 is a component of the base excision repair (BER), the combination of Me-Lex + PARP-1 inhibitor triggered apoptosis as a result of disruption of BER process. In conclusion, the present study provides new insight into the cellular response to N3-adenine-selective methylating agents that can be exploited for the treatment of tumors unresponsive to classical wide-spectrum methylating agents. Moreover, the results underline the central and paradoxical role of PARP-1 in cell death induced by N3-methyladenine: effector of necrosis and coordinator of methylpurine repair.


Serotonin transporter genotype x construction stress interaction in rats.
A well-known example for gene x environment interactions in psychiatry is the one involving the low activity (s) allelic variant of the serotonin transporter (5-HTT) promoter polymorphism (5-HTTLPR) that in the context of stress increases risk for depression. In analogy, 5-HTT knockout rodents are highly responsive to early life, but also adult external stressors, albeit conflicting data have been obtained. In our study on emotion and cognition using homozygous 5-HTT knockout (5-HTT(-/-)) and wild-type (5-HTT(+/+)) rats we have been confronted with animal facility construction, which were associated with severe lifetime stress (noise and vibrations). To assess the impact of construction stress on well-established 5-HTT(-/-) rat phenotypes we conducted ad hoc analyses of 5-HTT(-/-) and 5-HTT(+/+) rats that grew up before and during the construction. The reproductive capacity of the parents of the experimental 5-HTT(+/-) rats was significantly decreased. Further, 5-HTT(-/-) anxiety-related phenotypes in the elevated plus maze and social interaction tests were abolished after construction noise exposure, due to increased anxiety in 5-HTT(+/+) rats and decreased anxiety in 5-HTT(-/-) rats (social interaction test only). In addition, reversal learning was improved in 5-HTT(+/+) and, to a milder extent, decreased in 5-HTT(-/-) rats. Finally, construction stress genotype-independently increased behavioural despair in the forced swim test. In conclusion, severe construction stress induces 5-HTT genotype-dependent 'for-better-and-for-worse' effects. These data importantly contribute to the understanding of 5-HTT gene x environment interactions and show the risk of losing genotype effects by construction stress.


Sleep apnoea in infancy.
Serial polygraphic sleep studies were carried out in 86 index infants (33 'symptomatic', 24 siblings of infants with the sudden infant death syndrome (SIDS), 29 'near-miss' for SIDS) and 11 healthy controls. Brief (greater than or equal to 3 less than 6 sec) or prolonged (greater than or equal to 6 sec) obstructive apnoea was observed only in index caes, and coincided with symptoms due to associated illnesses (usually respiratory). Their prevalence was comparable in 'symptomatic' and 'near-miss' groups--39% and 35% respectively. Prolonged (greater than or equal to 20 sec) central apnoea was seen only in pre-term 'near-miss' infants. Dips in transcutaneous oxygen tension greater than or equal to 15 mmHg occurred during sleep in 17% of 'symptomatic' infants and 19% of 'near-miss' cases, usually in association with obstructive or central apnoea. Diminution or disappearance of these abnormalities following clinical recovery from 'minor' illnesses suggested that they were the result of such illnesses.


Economic aspects of a general vaccination against invasive disease caused by Haemophilus influenzae type b (Hib) via the experience of the Children's Hospital La Fe, Valencia, Spain.
With the aim of studying whether a general vaccination against invasive disease caused by Haemophilus influenzae type b (Hib) is economically profitable bearing in mind the efficacy and safety of the vaccine, its price and the global cost that this disease has in our area, a review is conducted of patients admitted due to invasive disease caused by Hib in the Children's Hospital La Fe, Valencia, born between 1984 and 1993. They total 100, 63 who have meningitis. In the 81 cases (56 with meningitis) born between 1984 and 1990 (years that can be regarded as "closed" since all the patients were younger than 5 years of age) the total cost has been calculated for hospitalization, care during the acute phase, care for the sequelae (6 severe and 7 mild) and death (5 cases). The mean annual cost of care can be calculated at 62 million pesetas, without making an economic valuation of the loss of life, and at 205 million pesetas taking this factor into account. The annual cost of vaccinating the 7000 babies under one year of age and falling within the Hospital's catchment area, on the basis of a vaccination pattern of three doses (at 2, 4 and 6 months) or four doses (at 2, 4, 6 and 15 months) would amount to 63 or 84 million pesetas, normal price to public (not covered by National Health Service), and 40 or 51 million pesetas if acquired by National Health Service. As a conclusion we can state that, even from the economic point of view, without quantifying the cost of the loss of life, a public general anti-Hib vaccination would be profitable in our area since it would mean an administration cost lower than that of the care required by patients. This is without taking into account the fact that emotional, family and social serious disturbances would also be avoided due to hospitalization, sequelae and deaths caused by a disease which is today perfectly preventable.


Prostaglandin formation in bacteria.
We report here that intact Gram positive and Gram negative bacteria, in the presence of exogenous arachidonic acid, produce and release PGE2 and PGF2 alpha into the medium as measured by radioimmunoassay. The seven bacterial strains so far studied release 6.5-50.9 ng PGE2 and less than 0.02-0.51 ng PGF2 alpha per mg bacterial protein during a 1 hour incubation, quantities of the same order of magnitude as those observed in mammalian systems. PGE2 and PGF2 alpha formation in bacteria are inhibited by indomethacin.


Stimulation of duodenal mucosal bicarbonate secretion in the rat by brain peptides.
Bicarbonate secretion by duodenal mucosa free of Brunner's glands was titrated in situ in anesthetized rats. Intracerebroventricular infusion of thyrotropin-releasing hormone (0.01-1 microgram/h), bombesin, gastrin-releasing peptide, or corticotropin-releasing factor increased the bicarbonate secretion and the transmucosal electrical potential difference. The increase in secretion in response to thyrotropin-releasing hormone and bombesin was prevented by cervical vagotomy. Intravenous administration of the alpha-adrenoceptor antagonist phentolamine increased the magnitude and duration of the response, suggesting that these two peptides in addition to eliciting vagal stimulation of the duodenal secretion, by sympathetic activation, inhibit the secretion. Intravenous thyrotropin-releasing hormone (3.6 mg/kg) did not affect the secretion, further indicating that effects were elicited within the central nervous system. Intracerebroventricular infusion of cholecystokinin-octapeptide or beta-endorphin had no effect on duodenal bicarbonate secretion or on the potential difference. The latter peptide was a potent stimulant of the secretion when injected intravenously and probably acts at a peripheral site. The central nervous control of duodenal mucosal bicarbonate secretion is thus influenced by some specific peptides that are known to occur in brain tissue, and duodenal protection against acid might be modulated by agents affecting this control.


Morphologic characterization of meniscal root ligaments in the human knee with magnetic resonance microscopy at 11.7 and 3 T.
To determine the feasibility of using MR microscopy to characterize the root ligaments of the human knee at both ultra-high-field (11.7 T) and high-field (3 T) strengths. Seven fresh cadaveric knees were used for this study. Six specimens were imaged at 11.7 T and one specimen at 3 T using isotropic or near-isotropic voxels. Histologic correlation was performed on the posteromedial root ligament of one specimen. Meniscal root ligament shape, signal intensity, and ultrastructure were characterized. High-resolution, high-contrast volumetric images were generated from both MR systems. Meniscal root ligaments were predominantly oval in shape. Increased signal intensity was most evident at the posteromedial and posterolateral root ligaments. On the specimen that underwent histologic preparation, increased signal intensity corresponded to regions of enthesis fibrocartilage. Collagen fascicles were continuous between the menisci and root ligaments. Predominantly horizontal meniscal radial tie fibers continued into the root ligaments as vertical endoligaments. MR microscopy can be used to characterize and delineate the distinct ultrastructure of the root ligaments on both ultra-high-field- and high-field-strength MR systems.


Long-term cost comparison between surgical and medical therapy for benign prostatic hyperplasia: a study using hospital billing data.
To analyse actual long-term medical treatment of benign prostatic hyperplasia (BPH) and compare the incurred cost with that of patients with BPH who underwent early surgery. Patients who were first diagnosed with BPH from 1 January 2008 to 31 December 2010 were identified using the Clinical Data Warehouse. Hospital billing data generated by the electronic hospital management system were collected until December 2015. For outpatient care, only procedures, materials and drugs directly related to the management of BPH were selected for the analysis. For inpatient care, all procedures, materials and drugs ordered on dates with continuity with BPH surgery date were included. The primary endpoint of the study was the total treatment-related direct costs of patients undergoing a long-term curative medical therapy for BPH (Group 1), which was arbitrarily defined as any medical therapy including a 5α-reductase inhibitor with a minimum medication possession ratio of 0.5 during ≥5 consecutive years, or ≥1 year until BPH surgery due to medical therapy failure. In all, 70 patients who underwent BPH surgery at <1 year of initial visit served as controls (Group 2). Amongst 137 patients in the Group 1, four patients underwent BPH surgery at a median of 57.8 months after the initial visit (2.9%). At a median follow-up of 76 months, the mean total treatment cost was significantly higher in Group 1 than in Group 2 ($3987 vs $3036 [USA dollars], P < 0.001). Similarly, the mean 'out-of-pocket' cost was significantly higher in Group 1 than in Group 2 ($1742 vs $1436, P = 0.005). When a linear increment of annual BPH treatment cost is assumed for Group 1 and all costs are assumed to be produced within the first year for Group 2, the total and out-of-pocket costs became equal at the end of the fifth year of medical treatment. For both total and out-of-pocket costs, medication-related costs occupied the largest proportion, exceeding half of the costs. We suggest patient counselling at the beginning of BPH treatment should include the likelihood that the cumulative out-of-pocket cost at 5 years of continuous medication will exceed that of early surgery. Our cost study using hospital billing data extractable from the electronic hospital management system may be a good model for cost studies that could provide valuable information to health providers and payers.


Toxicological assessment of Phormidium sp. derived copper oxide nanoparticles for its biomedical and environmental applications.
Driven by the need to biosynthesized alternate biomedical agents to prevent and treat infection, copper oxide nanoparticles (CuONPs) have surfaced as a promising avenue. Cyanobacteria-derived synthesis of CuONPs is of substantive interest as it offers an eco-friendly, cost-effective, and biocompatible route. In the present study biosynthesized CuONPs were characterized and investigated regarding their toxicity. Morphological analysis using TEM, SEM and AFM showed the spherical particle size of 20.7 nm with 96% copper that confirmed the purity of CuONPs. Biogenic CuONPs with IC50 value of 64.6 µg ml-1 showed 90% scavenging of free radicals in superoxide radical scavenging assay. CuONPs showed enhanced anti-inflammatory activity by 86% of protein denaturation with IC50 value of 89.9 µg ml-1. Biogenic CuONPs exhibited significant toxicity against bacterial strains with lowest MIC value of 62.5 µg ml-1 for B. cereus and fungal strain with a MIC value of 125 µg ml-1 for C. albicans. In addition CuONPs demonstrated a high degree of synergistic interaction when combined with standard drugs. CuONPs exhibited significant cytotoxicity against non-small cell lung cancer with an IC50 value of 100.8 µg ml-1 for A549 and 88.3 µg ml-1 for the H1299 cell line with apoptotic activities. Furthermore, biogenic CuONPs was evaluated for their photocatalytic degradation potential against methylene blue dye and were able to removed 94% dye in 90 min. Free radical scavenging analysis suggested that CuONPs assisted dye degradation was mainly induced by hydroxide radicals. Biogenic CuONPs appears as an eco-friendly and cost effective photocatalyst for the treatment of wastewater contaminated with synthetic dyes that poses threat to aquatic biota and human health. The present study highlighted the blend of biomedical and photocatalytic potential of Phormidium derived CuONPs as an attractive approach for future applications in nanomedicine and bioremediation.


Prevalence, clinical characteristics, and impact of active cancer in patients with acute myocardial infarction: data from an all-comer registry.
Although a history of cancer is a poor prognostic factor in patients with acute myocardial infarction (AMI), the clinical importance of coexisting active cancer remains unclear. In this single-center retrospective study, we reviewed an AMI registry and assessed the prevalence and predictors of active cancer, 1-year incidence of cardiac death or major bleeding events (defined as a Bleeding Academy Research Consortium type 3 or 5), and the impact of coexisting active cancer on clinical outcomes. Active cancer was defined as either an already-diagnosed or undiagnosed occult cancer. Between January 2012 and December 2017, 1140 AMI patients (median age, 69 years; male, 76.0%) were enrolled. Active and historical cancers were diagnosed in 63 patients (5.5%) and 50 patients (4.4%), respectively. The most common location was the urinary tract (n=21). In the Kaplan-Meier analysis, the active cancer group had a higher incidence of 1-year cardiac death (17.5% vs. 5.3%, p < 0.001) and major bleeding events (19.0% vs. 5.6%, p < 0.001) than the non-cancer group. In the multivariate Cox proportional hazards regression models, active cancer was an independent predictor of both cardiac death and major bleeding at 1 year. Specifically, gastrointestinal tract and advanced-stage cancers had the poorest outcomes. Compared to the non-cancer group, the 1-year major bleeding rate was higher for all cancer types and stages. In contrast, early-stage cancers had a weaker impact on the 1-year cardiac mortality compared to advanced-stage cancers. Similarly, cardiac death during 1-year also occurred less frequently in occult cancers than in already-known cancers. In patients with AMI, coexisting active cancer was rare, but it significantly impacted cardiac death and major bleeding events.


[Carotid body tumor of a 82-year-old female patient (author's transl)].
A 82-year old female patient with a tumor of the carotid body is presented. With regard to other cases pathogenesis, classification, diagnostics, symptomatology and therapeutics are discussed.


Revealing a hidden problem. An evaluation of a community dementia case-finding program from the Indian 10/66 dementia research network.
Dementia in India is largely a hidden problem with no community awareness and little help seeking from affected families, despite high levels of strain. Cases must therefore be identified before practical help can be offered. After two and a half hours of formal training, local community health workers in rural Kerala were asked to identify possible cases of dementia from the community they served. Diagnoses were then verified by a senior local psychiatrist with clinical and research interests in old age psychiatry. The community health workers identified 51 out of 1979 over 60 year old residents (a prevalence of 2.6%) as suspected cases of dementia. Following the psychiatrist's assessment, 33 met DSM-IV criteria for dementia. The majority of confirmed cases were of the Alzheimer's Disease sub-type. Most "non-cases" were found to be suffering from other major psychiatric disorders, with substantial unmet need. The positive predictive value of the community health workers informal screening was 64.7%. This simple cost-effective case-finding method can be of practical use in the development of community based dementia care services in India and other developing countries with similar health care systems.


Microsurgical Clipping of a Ruptured Wide-Neck Basilar Tip Aneurysm by an Extended Transsylvian Transcavernous Approach: 2-Dimensional Operative Video.
Basilar tip aneurysms are difficult to treat due to their deep location, proximity to cranial nerves and brainstem, and risk of perforator stroke.1-3 A 49-year-old woman presenting to the emergency department with subarachnoid hemorrhage was found to have a wide-neck basilar tip aneurysm measuring 8.6 mm × 5.6 mm × 7.6 mm. The aneurysm had a 4.9-mm wide neck located at the level of the dorsum sellae.4,5 Microsurgical clipping was recommended to the patient due to the complexity of the aneurysm neck, the patient's young age, the expertise of the surgical-anesthetic team, treatment durability, and the low risk of recurrence.2,6-9 We used an extended transsylvian transcavernous approach to expose the aneurysm (Video 1). We preferred this anterolateral approach over the more lateral subtemporal transzygomatic approach because of its versatility in providing better visualization of the bilateral posterior cerebral arteries and superior cerebellar arteries.10 The surgical exposure to the proximal basilar artery was gained by drilling the posterior clinoid process and dorsum sellae. Two titanium clips were applied across the aneurysm neck, and indocyanine green angiography confirmed complete aneurysm obliteration. Protection of critical brainstem perforators was ensured using the rubber-dam technique. The patient tolerated the procedure well with no deficits at the 12-month follow-up. We review the microsurgical nuances of treating complex wide-neck basilar tip aneurysms that are not good candidates for endovascular treatment. Although endovascular tools are favored as the first-line treatment choice for most cerebral aneurysms, microsurgical clipping techniques remain an important tool in the contemporary cerebrovascular neurosurgeon's toolkit.2,6,11-15.


Associations of relative income deprivation with perceived happiness and self-rated health among the Hong Kong Chinese population.
To investigate the association of relative income deprivation (RID) with perceived happiness and self-rated health in Hong Kong. We measured RID on Yitzhaki indices constructed using multiple reference groups and used multilevel ordinal logistic regression models to assess its linkages with the two outcomes, using data from 6272 respondents from a large-scale representative household survey. Among the overall population, increased RID was found to be consistently associated with reduced perceived happiness, even after adjusting for respondents' level of absolute income and other socio-demographic covariates; however, there were no consistent associations between RID and self-rated health. In subgroup analysis, we observed significant linkages between RID and self-rated health only among men, the middle and older age ranges, and among those with less education and those not engaged in economic activities. Our findings suggest that RID is adversely associated with perceived happiness. However, its negative linkage with self-rated health is less clear. The weak tie between RID and self-rated health may relate to the Hong Kong context, where the public health system is relatively equitable and has multiple pro-poor health policies.


Association of Bulimia Nervosa With Long-term Risk of Cardiovascular Disease and Mortality Among Women.
Bulimia nervosa is associated with short-term cardiovascular complications in women, but its long-term consequences on cardiovascular health are unknown. To study the association of bulimia nervosa with the long-term risk of cardiovascular disease and mortality in women. In this longitudinal cohort study, 416 709 women hospitalized in Quebec, Canada, including women hospitalized for bulimia nervosa and those for pregnancy-related events as a comparison group, were followed up for 12 years from 2006 to 2018 to identify incidences of cardiovascular disease and death. At least 1 hospitalization for bulimia nervosa. The study participants were followed up to identify future incidences of cardiovascular disease and deaths. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs to assess the association of bulimia nervosa with future outcomes after adjustment for patient characteristics. The study population comprised 818 women who were hospitalized for bulimia nervosa (mean [SD] age, 28.3 [13.4] years) and 415 891 hospitalized for pregnancy-related events (mean [SD] age, 28.3 [5.4] years). Patients were followed up for a total of 2 957 677 person-years. The women hospitalized for bulimia nervosa had a greater incidence of cardiovascular disease compared with those hospitalized for pregnancy-related events (10.34 [95% CI, 7.77-13.76] vs 1.02 [95% CI, 0.99-1.06] per 1000 person-years). Incidence of future cardiovascular disease was even higher for women with 3 or more bulimia admissions (25.13 [95% CI, 13.52-46.70] per 1000 person-years). Women hospitalized for bulimia nervosa had 4.25 (95% CI, 2.98-6.07) times the risk of any cardiovascular disease and 4.72 (95% CI, 2.05-10.84) times the risk of death compared with women hospitalized for pregnancy-related events. Bulimia nervosa was found to be associated with ischemic heart disease (HR, 6.63; 95% CI, 3.34-13.13), atherosclerosis (HR, 6.94; 95% CI, 3.08-15.66), and cardiac conduction defects (HR, 2.99; 95% CI, 1.57-5.71). Bulimia was also associated with 21.93 (95% CI, 9.29-51.74) times the risk of myocardial infarction at 2 years of follow-up and 14.13 (95% CI, 6.02-33.18) times the risk at 5 years of follow-up. This study's findings suggest that bulimia nervosa may be associated with the long-term risk of any cardiovascular disease, such as ischemic cardiac events and conduction disorders, as well as with death among women. The findings also suggest that women with a history of bulimia nervosa should be screened regularly for ischemic cardiovascular disease and may benefit from prevention of and treatment for cardiovascular risk factors.


The functional and structural connectomes associated with geriatric depression and anxiety symptoms in mild cognitive impairment: Cross-syndrome overlap and generalization.
Geriatric depression and anxiety disorders often manifest as neuropsychiatric symptoms among those with mild cognitive impairment. Both tend to co-occur, and overlap in symptomology and etiology. Such commonalities are likely to be reflected in the brain as common neural correlates. Using connectome-based predictive modeling (CPM), we examined the functional and structural connectomes predicting depression and anxiety symptoms, and subsequently the overlap and cross-syndrome generalization of the connectomes associated with either disorder. Ninety-one older adults completed self-reported measures of depression and anxiety, and underwent diffusion tensor imaging and resting-state functional magnetic resonance imaging. Functional connectivity (FC) and structural connectivity (SC) matrices were derived from these scans and, in various combinations, entered into CPM models to predict either type of symptoms. Leave-one-out cross-validation was performed. Predictive accuracy was assessed via the correlation between predicted and observed scores (ρpredicted-observed). While FC or SC features alone significantly predicted either type of symptoms, these symptoms were best predicted by models that consisted of both FC and SC features (depression: ρpredicted-observed = 0.497; anxiety: ρpredicted-observed = 0.455). The features common to depression and anxiety were identified and entered into another model which was similarly accurate in predicting either type of symptoms. Moreover, cross-syndrome generalization was observed- the depression-associated features significantly predicted anxiety symptoms (ρpredicted-observed = 0.403) and vice-versa (ρpredicted-observed = 0.378). These FC and SC features are complementary biomarkers of geriatric depression and anxiety symptoms. Both types of symptoms are largely underpinned by common patterns of altered FC and SC, alluding to the transdiagnostic neurobiological susceptibility in both disorders.


Forecasting in foodservice: model development, testing, and evaluation.
This study was designed to develop, test, and evaluate mathematical models appropriate for forecasting menu-item production demand in foodservice. Data were collected from residence and dining hall foodservices at Ohio State University. Objectives of the study were to collect, code, and analyze the data; develop and test models using actual operation data; and compare forecasting results with current methods in use. Customer count was forecast using deseasonalized simple exponential smoothing. Menu-item demand was forecast by multiplying the count forecast by a predicted preference statistic. Forecasting models were evaluated using mean squared error, mean absolute deviation, and mean absolute percentage error techniques. All models were more accurate than current methods. A broad spectrum of forecasting techniques could be used by foodservice managers with access to a personal computer and spread-sheet and database-management software. The findings indicate that mathematical forecasting techniques may be effective in foodservice operations to control costs, increase productivity, and maximize profits.


Right ventricle injury in RCA occlusion: Exploration using precordial bipolar leads and surrogate vectorcardiograms.
Precordial Bipolar Leads (PBL) provide new electrocardiographic information derived from standard 12‑lead ECG recordings. To explore the usefulness of PBL in patients with acute right coronary artery (RCA) occlusion. Sixteen patients undergoing elective percutaneous transluminal coronary angioplasty (PTCA) were studied before and after RCA occlusion and their data were processed with new methods based on PBL. The findings were: 1. In PBL V2-V1, strong systolic currents of injury moving in the left to right direction coexist with those directed towards leads II, III and aVF. 2. Changes in the time of the peaks of the QRS waves do not alter the duration of the QRS. 3. The QRS loops of the surrogate VCG generated show that, during ischemia, the time changes in the peak of the QRS waves displayed in one axis are the consequence of an increase in the amplitude of the waves observed in the perpendicular axis. 4. The use of two simultaneous dimensions (transverse and frontal planes) facilitates the location of the J-point. 5. In the surrogate VCGs of this group of patients, J-point and ST segment shifts produced an image that reminded the Greek letter omega (Ω). 6. The QRS wave changes, in time and amplitude, explained the rotational changes and the ischemic distortions of the surrogate VCG loops. Computerized processing of ECG data appears to provide new and valuable diagnostic data in patients with acute RCA occlusion. The loops revealed important information related to systolic currents of injury. Because these methods use routine 12‑lead ECG data, the procedure is based only in software applications.


Pharmacists as immunizers in Lebanon: a national survey of community pharmacists' willingness and readiness to administer adult immunization.
Since the focus of healthcare has shifted toward prevention, pharmacists were highly encouraged to expand their practice to include immunization services. Our study aimed to assess the knowledge, attitudes and beliefs of community-based Lebanese pharmacists, in addition to their willingness to expand their practice scope to include vaccine administration. A cross-sectional study was conducted during the phase preceding the arrival of the COVID-19 vaccine in Lebanon between 1 and 31st December 2020. Using a stratified random sampling method, data were collected from Lebanese community pharmacists (CPs) through an online survey that included information on socio-demographic characteristics, clinical experience, willingness to administer vaccines, knowledge about vaccination, attitudes towards immunization, reasons supporting utilizing pharmacists as immunizers and the requested elements to incorporate immunization in pharmacists' practice scope. Multivariable analyses were performed to identify the factors associated with knowledge. A total of 412 community pharmacists participated in this survey. Of the total, 66.5% of the surveyed CPs are willing to administer vaccines. The majority of them (89.8%) had an overall good level. Out of all, 92.7% showed a positive overall attitude score toward immunization, 95.4% agreed that community pharmacists can play an important role in advertising and promoting vaccination. The main needed elements for implementing immunization services in pharmacies listed by participants were: support of health authorities (99.3%), statutory allowance (82.8%), patient demand (95.4%), pharmacist's interest (96.1%) and continuous education and training workshops on immunization. Older CPs (50 years and above) [aOR = 0.703, CI 95% (0.598-0.812)] and those working in Bekaa and North have lower knowledge score than their counterparts. High educational level [aOR = 1.891, CI 95% (1.598-2.019)], previous experience in immunization [aOR = 3.123, CI 95% (2.652-4.161)] and working in urban areas [aOR = 3.640, CI 95% (2.544-4.717)] were positively associated with a good knowledge level. Most of Lebanese community pharmacists are willing to offer immunizations. The expansion of the pharmacists practice scope to include provision of immunizations required a national plan that encompasses strengthening knowledge, training, certification for eligibility to administer vaccines, enhancing pharmacovigilance and statutory reform.


Origins of language delay in abused infants.
This paper presents a reanalysis of data collected in a study of abusing mother-infant pairs, emphasizing the failure of infants with a history of physical abuse to develop appropriate language skills. Bayley Mental Development indices of abused infants decreased with age. This decrease was attributable largely to the failure of abused infants to pass verbal items. None of the abused children had any verbal communication skills. Results are discussed in relation to patterns of maternal ignoring and lack of verbal stimulation.


Four Distinct Subtypes of Alzheimer's Disease Based on Resting-State Connectivity Biomarkers.
Alzheimer's disease (AD) is a neurodegenerative disorder with significant heterogeneity. Different AD phenotypes may be associated with specific brain network changes. Uncovering disease heterogeneity by using functional networks could provide insights into precise diagnoses. We investigated the subtypes of AD using nonnegative matrix factorization clustering on the previously identified 216 resting-state functional connectivities that differed between AD and normal control subjects. We conducted the analysis using a discovery dataset (n = 809) and a validated dataset (n = 291). Next, we grouped individuals with mild cognitive impairment according to the model obtained in the AD groups. Finally, the clinical measures and brain structural characteristics were compared among the subtypes to assess their relationship with differences in the functional network. Individuals with AD were clustered into 4 subtypes reproducibly, which included those with 1) diffuse and mild functional connectivity disruption (subtype 1), 2) predominantly decreased connectivity in the default mode network accompanied by an increase in the prefrontal circuit (subtype 2), 3) predominantly decreased connectivity in the anterior cingulate cortex accompanied by an increase in prefrontal cortex connectivity (subtype 3), and 4) predominantly decreased connectivity in the basal ganglia accompanied by an increase in prefrontal cortex connectivity (subtype 4). In addition to these differences in functional connectivity, differences between the AD subtypes were found in cognition, structural measures, and cognitive decline patterns. These comprehensive results offer new insights that may advance precision medicine for AD and facilitate strategies for future clinical trials.


Imaging of Acute and Chronic Skull Base Infection.
Skull base infections are uncommon but can be life threatening without timely recognition. Imaging plays a crucial role because symptoms can be vague and nonlocalizing. Necrotizing otitis externa in diabetic or immunocompromised patients is the commonest cause of skull base osteomyelitis (SBO), followed by sinogenic infections and idiopathic central SBO. Multiparametric magnetic resonance (MR) and high-resolution CT are the mainstays for establishing a diagnosis and estimating disease extent, with MR being superior in ascertaining marrow and soft tissue involvement. Monitoring treatment response, of which imaging is a fundamental part, is challenging, with emerging promising imaging tools.


Psychologists' Perspectives on the Psychological Suffering of Refugee Patients in Brazil.
Worldwide there are 79.5 million displaced people, many of which face war, violence, tragic flights and struggles in host countries. Research shows augmented prevalence rates of mental disorders among refugees internationally, but little is known about refugee mental health in Latin American countries. Furthermore, only a few studies have taken into consideration the knowledge of clinical psychologists who treat refugee patients. The present study examines the experiences of 32 psychologists in Brazil regarding their refugee patients' psychological suffering and mental disorders. Semi-structured interviews were conducted in various locations in Brazil and analysed following a consensual qualitative research approach. Four clusters of refugee patients' suffering were synthesised: post-migration stressors, traumatic experiences, flight as life rupture, and the current situation in the country of origin. The most frequently described conditions in patients were anxiety and depression. However, the results also show that the use of manuals for the classification of mental disorders is contested among psychologists in Brazil. Most psychologists stressed patients' socio-political suffering and saw patients' symptoms as normal reactions to their experiences. There is a need to acknowledge the socio-political suffering of refugees in Brazil and foster their mental health by tackling current post-migration stressors such as discrimination.


A structural study towards the understanding of the interactions of SoxY, SoxZ, and SoxB, leading to the oxidation of sulfur anions via the novel global sulfur oxidizing (sox) operon.
Microbial redox reactions of inorganic sulfur compounds, mainly the sulfur anions, are one of the vital reactions responsible for the environmental sulfur balance. These reactions are mediated by phylogenetically diverse prokaryotes, which also take part in the extraction of metal ions from their sulfur containing ores. The sulfur oxidizing gene cluster (sox) of alpha-Proteobacteria comprises of at least 16 genes, forming two transcriptional units, viz., soxSRT and soxVWXYZABCDEFGH. SoxY is known to be a sulfur covalently binding protein, which binds sulfur anions (such as sulfate) to form SoxY-thiocysteine-S-sulfate, the first covalently bound sulfur adduct in the novel global sulfur anion oxidation cycle. SoxZ, a sulfur compound chelating protein, binds to SoxY forming a complex to which SoxB, a sulfate thiol-esterase, binds and ultimately cleaves the sulfur adduct. We employed homology modeling to construct the three-dimensional structures of the SoxY, SoxZ, and SoxB from Paracoccus pantotrophus. With the help of docking and molecular dynamics studies we have identified the residues of SoxY, SoxZ, and SoxB involved in the interaction. The probable mechanisms of the binding of SoxY with sulfate as well as the removal of sulfate from the SoxYZ complex are also established. Our study provides a rational basis to illustrate the molecular mechanism of the biochemistry of sulfur anion oxidation reactions by these industrially important organisms.


High-throughput sequencing of the transcriptome and chromatin accessibility in the same cell.
Single-cell RNA sequencing can reveal the transcriptional state of cells, yet provides little insight into the upstream regulatory landscape associated with open or accessible chromatin regions. Joint profiling of accessible chromatin and RNA within the same cells would permit direct matching of transcriptional regulation to its outputs. Here, we describe droplet-based single-nucleus chromatin accessibility and mRNA expression sequencing (SNARE-seq), a method that can link a cell's transcriptome with its accessible chromatin for sequencing at scale. Specifically, accessible sites are captured by Tn5 transposase in permeabilized nuclei to permit, within many droplets in parallel, DNA barcode tagging together with the mRNA molecules from the same cells. To demonstrate the utility of SNARE-seq, we generated joint profiles of 5,081 and 10,309 cells from neonatal and adult mouse cerebral cortices, respectively. We reconstructed the transcriptome and epigenetic landscapes of major and rare cell types, uncovered lineage-specific accessible sites, especially for low-abundance cells, and connected the dynamics of promoter accessibility with transcription level during neurogenesis.


Folate levels determine effect of antioxidant supplementation on micronuclei in subjects with cardiovascular risk.
We have investigated the effect of modest supplementation with alpha-tocopherol (100 mg/day), beta-carotene (6 mg/day), vitamin C (100 mg/day) and selenium (50 microg/day) on oxidative stress and chromosomal damage, and the influence of methylenetetrahydrofolate reductase (MTHFR) genotype on these end-points. Subjects were two groups of middle-aged men differing in cardiovascular risk; 46 survivors of myocardial infarction before age 50 and 60 healthy controls. They were randomly divided into equal groups to receive antioxidants or placebo for 12 weeks. Twenty-eight patients and 58 controls completed the intervention. Micronucleus levels in peripheral lymphocytes and changes seen after intervention were studied in relation to the MTHFR C677T genotype, basal homocysteine and plasma folate levels. Ferric reducing ability of plasma and concentration of malondialdehyde were measured to assess the antioxidant effect of supplementation. There was no association of micronuclei with folate, homocysteine or malondialdehyde levels before supplementation. Micronucleus frequencies and plasma folate levels did not vary significantly with MTHFR genotype. Homocysteine levels in subjects with the TT variant genotype were significantly higher compared with CT or CC (P = 0.001), especially in subjects with low folate (P = 0.012). In the placebo control group an increase in micronuclei (P = 0.04) was detected at the end of the intervention period. This effect was not seen in the supplemented group. In antioxidant-supplemented myocardial infarction survivors we found an increase in the ferric reducing ability of plasma (P < 0.001) and a decrease in malondialdehyde (P = 0.001). Micronucleus frequency showed a decrease, strongest in subjects with normal folate levels (P = 0.015). In subjects with low folate levels, a high correlation was found between micronuclei after supplementation and homocysteine, both before (r = 0.979, P = 0.002) and after supplementation (r = 0.922, P = 0.009). Thus, folate deficiency may amplify the effect of other risk factors such as elevated homocysteine levels or variant MTHFR genotype, as well as influencing the ability of antioxidant supplementation to protect against genetic damage.