The UpPriority tool supported prioritization processes for updating clinical guideline questions.
We aim to 1) use the UpPriority tool to identify which clinical questions (CQs) within the clinical guidelines (CGs) need to be prioritized for updating and 2) assess the implementation of the tool in a real-world set of CGs. We systematically assessed CQs from a sample of CGs developed in the Spanish National Health System CG program. We applied the UpPriority tool to each CG using a step-by-step process that included: 1) establishment of the UpPriority Implementation Working Group, 2) mapping of the original CG questions and recommendations, 3) development of a survey to prioritize CQs, 4) assessment of CQ's priority according to six items, 5) calculation and ranking of priority scores, 6) decision of prioritized CQs for updating, and 7) development of the priority report. We assessed the tool implementation process (appraisers' experience when using the tool) and the inter-observer reliability of the tool, and we provided suggestions for improvement. We included four CGs with a total of 107 CQs on the following topics: chronic heart failure (10 CQs), inherited retinal dystrophies (39 CQs), menopause (20 CQs), and open-angle glaucoma (38 CQs). We included a total of 30 participants, most of them clinicians that were members of the original CG development groups. CQs were classified in three groups: 1) high priority (CQs prioritized for updating [16/107; 15.0%]), 2) medium priority (CQs that could be prioritized for updating [47/107; 43.9%]), and low priority (CQs that were not prioritized for updating [44/107; 41.1%]). The mean time each appraiser needed to assess the CQs with the tool was 3.8 hours (range 0.5 to 10). Agreement among the appraisers varied among the CGs. Appraisers considered that the tool was useful. We suggest some areas for consideration when using the tool including: 1) identification of key appraisers, 2) customization of training materials, 3) establishment of priority thresholds, and 4) provision of methodological support. The UpPriority is a useful tool to identify which CQs within a CG need to be prioritized for update in a real-world scenario. Recruitment and training of topic experts are the main challenges when using the tool.


Ubiquitin and stromal cell-derived factor-1α in bronchoalveolar lavage fluid after burn and inhalation injury.
The objective of the study was to determine whether the CXC chemokine receptor (CXCR) 4 ligands ubiquitin and stromal cell-derived factor (SDF)-1α are detectable in bronchoalveolar lavage fluid (BALF) after burn and inhalation injury and whether their concentrations in BALF are associated with injury severity, physiological variables, or clinical outcomes. BALF was obtained on hospital admission from 51 patients (48 ± 18 years) with burn (TBSA: 23 ± 24%) and inhalation injury (controls: 10 healthy volunteers, 42 ± 8 years). BALF was analyzed for total protein and for ubiquitin and SDF-1α by enzyme-linked immunosorbent assay. Ubiquitin/SDF-1α levels were normalized to total BALF protein content. The extent of inhalation injury was determined during bronchoscopy using a standardized scoring system. Percent TBSA, Baux scores, revised Baux scores, and clinical variables were documented. Ubiquitin and SDF-1α were detectable in 40% of normal BALF specimens. After injury, ubiquitin was detectable in 90% (P < .01 vs control) and SDF-1α in 10% of the specimens (P < .05 vs control). While SDF-1α levels were reduced in patients (P < .01), ubiquitin levels were increased (P < .01). Ubiquitin concentrations correlated inversely with grade of inhalation injury, revised Baux scores, and resuscitation fluid requirements (Spearman correlation coefficients [r]: -.3, -.33, and -.45, respectively). Ubiquitin levels correlated positively with arterial oxygenation at the time of bronchoscopy (r: .35). BALF levels of CXCR4 agonists are differentially regulated after burn and inhalation injury. Increases in BALF ubiquitin after inhalation injury may maintain CXCR4-mediated lung protection and repair processes. The finding that BALF ubiquitin decreased with higher grades of inhalation injury may provide a biological correlate for an insufficient local inflammatory response after severe inhalation injury.


Ayahuasca and Its DMT- and β-carbolines - Containing Ingredients Block the Expression of Ethanol-Induced Conditioned Place Preference in Mice: Role of the Treatment Environment.
Ayahuasca is a hallucinogenic beverage produced from the decoction of Banisteriopsis caapi (Bc) and Psychotria viridis (Pv), β-carboline- and N,N-dimethyltryptamine(DMT)-containing plants, respectively. Accumulating evidence suggests that ayahuasca may have therapeutic effects on ethanol abuse. It is not known, however, whether its effects are dependent on the presence of DMT or if non-DMT-containing components would have therapeutic effects. The aim of the present study was to investigate the rewarding properties of ayahuasca (30, 100, and 300 mg/kg, orally), Bc (132, 440, and 1320 mg/kg, orally) and Pv (3.75, 12.5 and 37.5 mg/kg, i.p.) extracts and their effects on ethanol (1.8 g/kg, i.p.) reward using the conditioned place preference (CPP) paradigm in male mice. Animals were conditioned with ayahuasca, Bc or Pv extracts during 8 sessions. An intermediate, but not a high, dose of ayahuasca induced CPP in mice. Bc and Pv did not induce CPP. Subsequently, the effects of those extracts were tested on the development of ethanol-induced CPP. Ayahuasca, Bc or Pv were administered before ethanol injections during conditioning sessions. While Bc and Pv exerted no effects on ethanol-induced CPP, pretreatment with ayahuasca blocked the development of CPP to ethanol. Finally, the effects of a post-ethanol-conditioning treatment with ayahuasca, Bc or Pv on the expression of ethanol-induced CPP were tested. Animals were conditioned with ethanol, and subsequently treated with either ayahuasca, Bc or Pv in the CPP environment previously associated with saline or ethanol for 6 days. Animals were then reexposed to ethanol and ethanol-induced CPP was quantified on the following day. Treatment with all compounds in the ethanol-paired environment blocked the expression of ethanol-induced CPP. Administration of an intermediate, but not a high, dose of ayahuasca and Bc, as well as Pv administration, in the saline-paired compartment blocked the expression of ethanol-induced CPP. The present study sheds light into the components underlying the therapeutic effects of ayahuasca on ethanol abuse, indicating that ayahuasca and its plant components can decrease ethanol reward at doses that do not exert abuse liability. Importantly, the treatment environment seems to influence the therapeutic effects of ayahuasca and Bc, providing important insights into clinical practice.


Endometrial stromal sarcoma: An aggressive uterine malignancy.
Endometrial stromal sarcoma (ESS) is an aggressive uterine sarcoma. We report a case of a large endometrial stromal sarcoma in a 42 year nulliparous woman with chronic kidney disease presenting with acute urinary retention and irregular per vaginal bleeding. Ultrasound and Doppler imaging revealed a heterogeneous mass in the endometrial cavity with internal vascularity. Magnetic resonance imaging (MRI) revealed a large lobulated mass in the endometrial cavity extending into the vagina, causing local mass effect. Multiple linear hypointense bands on magnetic resonance T2 weighted (T2wt) images were characteristic of ESS. MRI is a very useful imaging modality in characterizing the lesion and also for the staging. It is necessary to distinguish these tumors from benign as well as other uterine malignancies for better management. We also review relevant literature discussing imaging findings of ESS.


The transition to adult income supports for youth that received special education in British Columbia, Canada: A cohort study.
Youth in special education have complex needs that are supported across multiple systems. Our research investigates the use of adult income assistance, as one structure that supports youth as they transition to adulthood. We created a cohort of youth (5-22 years old) using linked administrative data from British Columbia government ministries from 1996 to 2018. Youth were grouped by their special education funding (most to least; Level 1, Level 2, Level 3, Unfunded, and no special education). We investigated (1) youth characteristics and service use patterns, (2) which youth used income supports after the child-to-adult transition (19-22 years old), and what youth characteristics and service use patterns were associated with use, and (3) how much income support they used (CAD$). Of 174,527 youth, 254 (0.1%) were Level 1, 6020 (3.4%) were Level 2, 4409 (2.5%) were Level 3, 21,232 (12.2%) were Unfunded, and 142,612 (81.7%) were not in special education. Youth assigned higher funding levels, compared to lower levels, generally had increased service use, and in the transition to adult services were more likely to use income supports, and received more income support. An important exception was youth with serious behavioural/mental health special education funding (Level 3), who had increased service use for their level of funding, but received less income support due to a reliance on Temporary versus Disability Assistance. Youth that received an accredited diploma were less likely to use income supports. Factors related to the use of income supports are further described. This study highlights differences in access to income support when youth transition to adult services and considerations around equitable access to support.


Leucine metabolism in lactating and dry goats: effect of insulin and substrate availability.
Early lactating goats show insulin resistance with respect to extramammary glucose utilization. However, much less is known about the two major factors, insulin and plasma amino acid concentration, that regulate protein metabolism in lactating goats. To examine this question, the in vivo effect of acute insulin was studied in goats during early lactation (12-31 days postpartum), midlactation (98-143 days postpartum), and the dry period (approximately 1 yr postpartum). Insulin was infused (at 0.36 or 1.79 nmol/min) under euglycemic and eukaliemic clamps. In addition, appropriate amino acid infusion was used to blunt insulin-induced hypoaminoacidemia or to create hyperaminoacidemia and maintain this condition under insulin treatment. Leucine kinetics were assessed using a primed continuous infusion of L-[1-14C]-leucine, which started 2.5 h before insulin. In all animals the insulin treatments failed to stimulate the nonoxidative leucine disposal (an estimate of whole body protein synthesis) under both euaminoacidemic and hyperaminoacidemic conditions. Thus, in goat as well as humans, infusion of insulin fails to stimulate protein synthesis even when combined with a substantially increased provision of amino acids. In contrast, insulin treatments caused a dose-dependent inhibition of the endogenous leucine appearance (an estimate of whole body protein degradation). Under euaminoacidemia the initial slope from the plot of the endogenous leucine appearance as a function of plasma insulin (an insulin sensitivity index) was steeper during early lactation than when compared with the dry period. A similar trend occurred during midlactation but not to any significant degree. These differences were abolished under hyperaminoacidemia. It was concluded that the ability of physiological insulin to inhibit protein degradation was improved during lactation, demonstrating a clear-cut dissociation between the effects of insulin on protein and glucose metabolism. This adaptation no doubt may provide a mechanism to save body protein.


Effect of topical hyaluronic acid on experimental cholesteatoma.
Inflammation and connective tissue hyperplasia are believed to be important etiological factors in cholesteatoma pathogenesis. Previous work has shown that topically applied hyaluronic acid can reduce connective tissue proliferation in healing wounds and accelerate healing of tympanic membrane perforations. This study was undertaken to determine whether the antiproliferative effect of hyaluronic acid may inhibit propylene glycol-induced cholesteatoma in an animal model. A 60% propylene glycol solution was injected bilaterally into the middle ear cavities of 20 adult chinchillas. The control group (N = 10) received propylene glycol alone. In addition to propylene glycol injections, the experimental group (N = 10) received repeated bilateral topical applications of 1.5% hyaluronic acid onto the tympanic membranes. Animals were killed at 4 weeks for gross and light microscopic examination. Seven control and 10 experimental animals survived the full 1-month study period. At the end of that time, cholesteatoma was found in 71% (10/14) of control ears and 70% (14/20) of experimental ears. Tympanic membrane structure did not differ significantly between groups by light microscopy and, in all animals, cholesteatomas originated by migration of hyperplastic epidermis through the tympanic membrane, as has been observed in previous studies using this animal model. Under the conditions of this study, topical hyaluronic acid had no significant effect on cholesteatoma formation.


Nabumetone in the treatment of skin and soft tissue injury.
Nabumetone, a new nonsteroidal anti-inflammatory agent, has been evaluated for the treatment of skin and soft tissue injury, including sports injury, in clinical trials involving nearly 1,000 patients. Its efficacy, safety, and tolerance in these patients is reviewed. The efficacy of nabumetone in the treatment of soft tissue injury has been demonstrated to be similar to that of soluble aspirin, ibuprofen, and naproxen. It was not possible in these studies to demonstrate a definite advantage over placebo, and the reasons for this are discussed along with some suggestions for future studies. There were no serious adverse experiences reported, and nabumetone was well tolerated and compared favorably with the other agents used, including placebo. It caused significantly fewer gastrointestinal side effects than soluble aspirin. Nabumetone is an appropriate choice of nonsteroidal anti-inflammatory drug for the treatment of sports injury.


Regulation of porcine insulin-like growth factor I and growth hormone receptor mRNA expression by energy status.
Regulation of insulin-like growth factor I (IGF-I) and growth hormone (GH) receptor mRNA in liver and muscle by energy status was assessed in 2-mo-old pigs by altering thermoregulatory demand and energy intake over a 5-wk period to produce a range of plasma IGF-I concentrations from 3.5 +/- 0.7 to 28.9 +/- 6.2 nmol/l. These values were related directly to growth rates (0.06 +/- 0.02 to 0.44 +/- 0.01 kg/day) and total hepatic IGF-I mRNA levels. Increased growth rates were accompanied by an increase in hepatic class 1 and class 2 IGF-I mRNA levels and an increase in the ratio of class 2 to class 1 IGF-I mRNA in liver, suggesting a distinct role for class 2 expression in the endocrine growth response. High levels of class 1 transcripts and a virtual absence of class 2 transcripts characterized all muscle tissues examined, and there was no correlation with plasma IGF-I levels. This suggests that growth promotion in response to increased energy status is regulated via endocrine hepatic IGF-I rather than via a paracrine response. The levels of GH receptor mRNA were positively correlated with overall growth rate (P < 0.005) in liver and negatively correlated (P < 0.05) in muscle, indicating distinct tissue-specific effects of energy status.


The preoperative assessment of patients with valvular heart disease as a comorbidity.
In patients with valvular heart disease planned for any type of surgery preoperative evaluation and preparation are especially important for a successfull outcome of the surgery. Preoperative preparation and intraoperative treatment of patients with valvular heart disease are different de-Spending on the type of valvular disease: aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation or mitral valve prolapse. In this paper we have outlined the criteria for evaluating the severity of valvular disease, given that the risk in surgery is proportional to the degree of valvular disease. Also, given that the risk in surgery is also directly proportional to the type and extent of non cardiac surgery, it will be presented recommendations for intraoperative monitoring, with the purpose of evaluating patient's hemodynamic state, as well as recommendations for perioperative treatment of hypotension, tachycardia, and other hemodynamic disturbances. In the paper we will separately discuss bacterial endocarditis profilaxys which can occur after the surgery of patients with valvular disease. Since the patients with valvular disease, and especially the ones with implanted prosthetic valve or heart arrhythmia, are usually on oral anticoagulation therapy, it will be given recommendations for treatment of patients on oral anticoagulation therapy as part of preoperative preparations.


[Gene pool and gene geography of the USSR population].
Gene pool and gene geography are discussed from the point of view of their conceptual history beginning from the original concept of A.S. Serebrovskiĭ (1928). Difference between the present-day gene geography and gene geography of gene pool is accentuated: the former only represents a portion of the latter. Historical and territorial integrity of the USSR population gene pool, in conjunction with its huge diversity, is the main problem being analysed by various means of computerized genetic cartography. Coupled with the gene frequency mapping, following methods were also used: mapping of average heterozygosity, of interpopulation differentiation, of principal component scores and mapping of geographical trend for each mapped genetic parameter. The work is based on 100 allelic genes and haplotypes from 30 independent loci studied on the average in 225 local populations. Statistical analysis of gene geographical maps is based on 3975 nodes of regular cartographic net for the USSR territory. The wind rose of systematic changes in the USSR gene pool has three main geographic orientations: W-E, SW-NE and S-N. At the same time, there are only two main systematic forces of gene pool evolution: the force of social history with predominant W-E orientation and the force of natural history with predominant S-N orientation of their actions. The heterozygosity level of gene pool declines strictly in accordance with the resultant in the SW-NE direction.


Structural characterization of mono- and dihydroxylated metabolites of paclitaxel in rat bile using liquid chromatography/ion spray tandem mass spectrometry.
The capability of high performance liquid chromatography/ion spray mass spectrometry (HPLC/ISP-MS) and HPLC/ISP-tandem mass spectrometry (HPLC/ISP-MS/MS) were investigated to achieve mass separation as well as structural characterization of taxol metabolites directly in rat bile, without their previous isolation. HPLC/ISP-MS yielded information on the molecular weights of several hydroxylated derivatives while HPLC/ISP-MS/MS allowed the on-line structural characterization of all metabolites present in different ratios in rat bile. The approach led to the extraction of nine metabolites and their distinction from the other endogenous contaminants. These metabolites were recognized as three dihydroxytaxols, four monohydroxytaxols, one deacetyltaxol and one containing the taxane ring. Among the derivatives, we were able to identify four new metabolites of paclitaxel belonging to the dihydroxy and monohydroxy series, never previously detected. HPLC/ISP-MS/MS enabled the classification of all di- and monohydroxy isomers. These results demonstrate that the high sensitivity of this method, based on the combined use of tandem mass spectrometry with chromatographic separation, can be considered as offering a valid approach to the detection of new taxol derivatives directly in biological fluids.


Pineal parenchymal tumors. Clinical, pathologic, and therapeutic aspects.
Pineal parenchymal tumors are rare; therefore, only limited clinical data regarding their behavior is available. This study was performed to provide further information regarding the pathologic features, clinical behavior, and response to therapy of these tumors. This study includes data concerning 30 patients (15 male and 15 female patients) with pineal parenchymal tumors (PPT) diagnosed between 1939 and 1991. Based on gross and microscopic features, tumors were divided into four groups: pineocytomas (9); PPT with intermediate differentiation (4); mixed PPT exhibiting elements of both pineocytoma and pineoblastoma (2); and pineoblastomas (15). At the time of diagnosis, four patients had evidence of spinal seeding (two with pineoblastoma, two with PPT with intermediate differentiation). Twenty-two patients received radiation therapy (RT): 6 were treated to local fields, 7 to the whole brain, and 9 to the craniospinal axis. For patients who received RT and had a minimum follow-up of 6 months, local failure occurred in one of four patients with pineocytomas, zero of four patients with PPT with intermediate differentiation, one of two with mixed PPT, and four of nine (44%) with pineoblastomas. In patients receiving > or = 50 Gy to the primary tumor, 0 of 12 had local failure compared with 6 of 7 (86%) patients receiving lesser doses. Leptomeningeal failure occurred in zero of four patients with pineocytomas, zero of four patients with PPT with intermediate differentiation, one of two with mixed PPT, and four of nine with pineoblastomas. All leptomeningeal failures occurred in patients with persistent primary tumor. Of the patients with seeding tumors (PPT other than pineocytomas) one of seven (14%) developed leptomeningeal failure when treated with craniospinal irradiation, compared with four of eight (50%) treated to lesser volumes. The projected 1-year, 3-year, and 5-year survival rates of patients with pineocytomas were 100%, 100%, and 67%, and were 88%, 78%, and 58% for those with the other forms of PPT, respectively. RT recommendations are described in detail and include the use of doses of > or = 50 Gy to areas of gross disease and the administration of craniospinal irradiation in patients with tumors prone to seeding. Surgical, chemotherapeutic, and pathologic considerations are discussed.


Protection of porcine aortic endothelial cells from complement-mediated cell lysis and activation by recombinant human CD59.
Discordant xenogeneic organ transplantation is a potential solution to the critical shortage of suitable donor organs. However, clinical application of xenotransplantation with physiologically suitable organs such as those from the pig, is currently limited by the lack of agents to prevent antibody and complement-mediated hyperacute rejection of the transplanted organ. We have used retrovirus-mediated gene transfer to express the terminal complement inhibitor protein, human CD59, in neonatal porcine aortic endothelial cells (nPAEC). Human CD59 was constitutively expressed in nPAECs at levels similar to that of native CD59 in human umbilical vein endothelial cells. The protein was tethered to the cell surface by a glycosyl-phosphatidylinositol anchor, as demonstrated by its removal following treatment with phosphatidylinositol-specific phospholipase C. In a model of antibody-dependent complement activation, nPAECs expressing human CD59 were protected from membrane pore formation and cell lysis by complement derived from either human or baboon sera. Conversely, nPAECs expressing CD59 were not protected from lysis by rabbit or dog complement, indicating that recombinant CD59 retained its species-restricted inhibitory activity. Additionally, CD59 expressed on nPAECs inhibited the C5b-9-dependent generation of membrane prothrombinase activity. Collectively, these data establish that stable expression of human CD59 on xenotypic (porcine) endothelial cells renders these cells resistant to both the cytolytic and procoagulant effects of human complement. We propose that expression of recombinant human CD59 on porcine donor organs may prevent complement-mediated lysis and activation of endothelial cells that leads to hyperacute rejection.


Expression of ricin B chain in Spodoptera frugiperda.
DNA encoding ricin B chain was derived from preproricin genomic DNA and ligated into the baculovirus transfer vector, pAcGP67A. Co-transfection of Spodoptera frugiperda Sf9 cells with BaculoGold DNA was followed by limiting dilution purification of recombinant baculovirus. Infection of SF9 cells at a multiplicity of infection of 1 in the presence of 25 mM lactose produced 3 mg/l of soluble, glycosylated, 34 kDa protein immunoreactive with monoclonal and polyclonal antibodies to ricin B chain. The recombinant ricin B chain had similar lectin-binding activity to plant ricin B chain. The recombinant protein reassociated with ricin toxin A chain similarly to ricin toxin B chain and the recombinant heterodimers had similar cell cytotoxicity to ricin.


Metabolic fate of phenobarbital. A quantitative study of p-hydroxyphenobarbital elimination in man.
Biotransformation of phenobarbital (PB) to p-hydroxyphenobarbital (PHPB) was studied quantitatively by gas-liquid chromatography in 8 epileptic patients who were receiving an established regimen of antiepileptic drugs including PB. PB and both conjugated and unconjugated PHPB were present in each patient's urine; m-hydroxyphenobarbital (MHPB) was not detected despite an assay sensitivity of 0.25 mug/ml. Incubation of the urine with beta-glucuronidase, but not with arylsulfatase, liberated PHPB which was, therefore, presumed to be conjugated with glucuronic acid. In general, the patients' urine contained more PB than total PHPB. Recovery of the patients' total daily dose of PB ranged from 24 to 77% (mean, 42%). After receiving a single iv dose of PB, PB and both conjugated and unconjugated PHPB were found in a normal volunteer's urine throughout a 16-day collection period; 30% of the dose was recovered. PB excretion was proportional to urine volume in the volunteer and in two additional patients who were made to vary their daily fluid intake. PHPB was not detected in the cerebrospinal fluid of 10 patients receiving PB. Neither PB, PHPB, nor MHPB were detected in the feces of four patients. These results suggest that metabolites other than PHPB or MHPB may be important in the elimination of PB in man.


High-frequency ultrasound as a useful device in the preliminary differentiation of lichen sclerosus et atrophicus from morphea.
High-frequency ultrasound diagnostic equipment (HFUS) using probes with frequencies above 15-MHz has been utilized conventionally in preoperative assessments and postoperative follow-up of skin tumors. The advent of probes with even higher frequencies (up to 30-MHz) has widened the clinical applications of HFUS to inflammatory dermatoses which are histologically confined to the epidermis and upper dermis, such as psoriasis and atopic dermatitis. Ultrasound imaging has the advantage of being a noninvasive and relatively inexpensive technology that is quick and easy to perform. In addition, information obtained from HFUS is unique and useful for clinical diagnosis and evaluation for various skin disorders. We believe that HFUS has the potential to become a powerful tool for either clinical or investigative dermatology. Herein, we present a case of lichen sclerosus et atrophicus (LSA) to which we applied HFUS before skin biopsy and obtained substantial information for the differential diagnosis from morphea, and we reemphasize the usefulness of HFUS in studying the inflammatory skin disorders.


Biological inferences from a mathematical model of comedo ductal carcinoma in situ of the breast.
The growth of a tumour in a duct is examined in order to model ductal carcinoma in situ (DCIS) of the breast, the earliest known stage of breast cancer. Interactions between the expansive forces created by tumour cell proliferation and the stresses that develop in the compliant basement membrane are studied using numerical and analytical techniques. Particular attention focuses on the impact that proteolytic enzymes have on the tumour's progression. As the tumour expands and the duct wall deforms, the tumour cells are subjected to mechanical and nutritional stresses caused by high pressures and oxygen deprivation. Such stresses may stimulate the cells to produce proteolytic enzymes that degrade the duct wall, making it more compliant and prone to penetration by the tumour cells. We use our model to compare these two hypotheses for enzyme production and find that mechanical stress is likely the dominant mechanism, with the wall deforming most at the centre of the duct. We then discuss the biological implications of our theoretical results and suggest possible directions for future work.


Virtual-reality balance training with a video-game system improves dynamic balance in chronic stroke patients.
Stroke is one of the most serious healthcare problems and a major cause of impairment of cognition and physical functions. Virtual rehabilitation approaches to postural control have been used for enhancing functional recovery that may lead to a decrease in the risk of falling. In the present study, we investigated the effects of virtual reality balance training (VRBT) with a balance board game system on balance of chronic stroke patients. Participants were randomly assigned to 2 groups: VRBT group (11 subjects including 3 women, 65.26 years old) and control group (11 subjects including 5 women, 63.13 years old). Both groups participated in a standard rehabilitation program (physical and occupational therapy) for 60 min a day, 5 times a week for 6 weeks. In addition, the VRBT group participated in VRBT for 30 min a day, 3 times a week for 6 weeks. Static balance (postural sway velocity with eyes open or closed) was evaluated with the posturography. Dynamic balance was evaluated with the Berg Balance Scale (BBS) and Timed Up and Go test (TUG) that measures balance and mobility in dynamic balance. There was greater improvement on BBS (4.00 vs. 2.81 scores) and TUG (-1.33 vs. -0.52 sec) in the VRBT group compared with the control group (P < 0.05), but not on static balance in both groups. In conclusion, we demonstrate a significant improvement in dynamic balance in chronic stroke patients with VRBT. VRBT is feasible and suitable for chronic stroke patients with balance deficit in clinical settings.


Assessment of the relationship between aortic pulse wave velocity and aortic arch calcification.
We aimed to assess arterial stiffness parameters and to investigate the relationship between these parameters and aortic calcification in patients with aortic arch calcification and without symptomatic atherosclerotic disease. The population of this study consisted of 41 patients with aortic arch calcification verified by chest X-ray (group I, 17 males, mean age 70±5 years) and individuals without aortic arch calcification (group II, 17 males, mean age 68±6 years). Subjects with symptomatic or known vascular disease were excluded from the study. The arterial stiffness parameters of all subjects were measured non-invasively with a SphygmoCor device. Aortic pulse wave velocity (PWV), augmentation pressure (AP), augmentation index (AIx) and heart rate normalized augmentation index (AIx@75) were used as parameters of arterial stiffness. The two groups were compared according to demographic characteristics, medications currently being taken, and levels of serum lipids. There was no significant difference between the groups. AP in group I was significantly higher than that of group II (p=0.002). AIx and AIx@75 were similar in both groups. Aortic PWV of group I was significantly higher than that of group II (p<0.0001). According to the results of this study, the presence of aortic calcification, verified by chest radiography, was associated with increased aortic PWV.


Synovial Fluid Biomarkers for the Diagnosis of Periprosthetic Joint Infection: A Systematic Review and Meta-Analysis.
The search for a single standard reference test for determining periprosthetic joint infection (PJI) through analysis of synovial fluid has yielded numerous biomarkers as potential candidates. The purpose of the present systematic review and meta-analysis was to evaluate the diagnostic accuracy of synovial fluid biomarkers and to determine which test has the highest diagnostic odds ratio (DOR) for the diagnosis of PJI. An online literature search of the MEDLINE, Embase, and Cochrane databases identified 33 articles reporting a total of 13 major parameters for diagnosing PJI through analysis of synovial fluid. Each of the included articles was independently analyzed for risk of bias and for concerns regarding applicability utilizing the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool. The mada (meta-analysis of diagnostic accuracy) tool was used to generate forest plots for sensitivity, specificity, and the log of the DOR, as well as summary statistics. In this analysis, 13 index tests (leukocyte count; measurement of the percentage of polymorphonucleocytes [PMN%] and the levels of C-reactive protein [CRP], α-defensin, leukocyte esterase [LE], interleukin [IL]-6, IL-8, IL-10, IL-1β, vascular endothelial growth factor [VEGF], and granulocyte-colony stimulating factor [G-CSF]; culture; and polymerase chain reaction [PCR] analysis) were evaluated on the basis of ≥2 articles. Of these tests, 8 (leukocyte count, PMN%, CRP, α-defensin, LE, IL-6, IL-8, and culture) were appropriate for pooled analysis. The overall sensitivity of these 8 markers was 0.85, and all but culture showed a sensitivity of ≥0.8. All markers showed a specificity of ≥0.9. Of the 8 tests, measurement of the α-defensin level showed the highest log DOR. Synovial fluid leukocyte count, PMN%, CRP, α-defensin, LE, IL-6, and IL-8 all demonstrated high sensitivity for diagnosing PJI, with α-defensin being the best synovial marker based on the highest log DOR. However, other synovial fluid tests that demonstrate good diagnostic performance can also be used in combination for the diagnosis of PJI. Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Gaps in Team Communication About Service Statistics Among Health Extension Workers in Ethiopia: Secondary Data Analysis.
In Ethiopia, health extension workers (HEWs) are deployed across the country by the government to meet public health needs. Team communication is important for effective teamwork, but community health workers in low-resource settings like Ethiopia may face challenges in carrying out team meetings to compile service statistics. This is due to the nature of their outreach activities, which requires extensive travel. This study aimed to identify gaps in team communication about service statistics among HEWs in Ethiopia. Considering mobile communication and data collection as tools for bridging these gaps, we examined disparities in access to electricity, which has been identified as one of the major barriers to this approach. Data from the most recent Performance Monitoring and Accountability 2020 service delivery point survey were used for our analysis. Logistic regression analysis was performed to identify disparities in team communication on service statistics for family planning, which is a major component of the HEW's job. Disparities were examined across health facilities with different levels of HEW integration in their staffing structure (ie, no HEWs, at least one HEW, or only HEWs). Additionally, a chi-square test was conducted to examine disparities in access to electricity to explore the potential of mobile communication and data collection integration. In total, 427 health facilities of four different types (ie, hospitals, health centers, health posts, and health clinics) were included in our analysis. At most health posts (84/95, 88%), only HEWs were employed; none of the health clinics integrated the HEW model into their staffing structure. Among the 84 health posts, the odds of having team meetings on family planning service statistics in the past 12 months were 0.48 times the odds of those without HEWs (P=.02). No statistically significant differences were found between HEW-only facilities and facilities with at least one HEW. Most health facilities (69/83, 83.13%) with HEWs as the only staff had no electricity at the time of the survey while 71.25% (57/80) had intermittent access (ie, service disruption lasting 2 or more hours that day). There were statistically significant differences in electricity access among health facilities with different levels of HEW integration (P<.001). Facilities employing only HEWs were less likely to have regular team meetings to discuss service statistics. Since their responsibilities involve extensive outreach activities, travel, and paper-based recordkeeping, empowering HEWs with mobile communication and data collection can be a workable solution. The empirical evidence regarding disparities in electricity access also supports the need for and the feasibility of this approach.


Richmond Instructive Nurse's Visiting Association: A Glimpse into the Care of Older Adults: 1900 to 1929
1. In the beginning of the 20th century, the provision of nursing services to older adults took a lesser role behind the focus on communicable diseases and maternal and infant care. 2. The Instructive Visiting Nurse's Association records in Richmond, Virginia provide a snapshot into the delivery of home-based care to older adults from 1900 to 1929. 3. Financing care of the U.S. elderly population has been an ongoing issue for more than 100 years.


Autonomy and audit--striking the balance.
The Data Protection Act 1998 purports to implement European legislation which aims to protect the privacy of individuals. There were such concerns about the implications of the Act for certain research and audit that it became necessary to enact further legislation to enable such essential activities to continue. Although this empowers the Secretary of State for Health to approve proposals for these purposes, there should still be a requirement that the use of identifiable personal information without consent must be justified on compelling public interest grounds. It is this that can confound those seeking to rely on such justification. There can either be too cavalier an approach to the issue, and/or there is little sense of what considerations should come into play. This paper attempts to highlight some of the difficulties that are theoretically raised by some audit activities and set out the legal framework within which they must operate. However, the key focus is on how ethical considerations might inform the public interest argument.


Workplace violence: prevalence and risk factors in the safe at work study.
Nurses face one of the highest rates of reported workplace violence (WPV). This research examined the prevalence of WPV and demographic, work-related, and adult and childhood abuse histories as risk factors for WPV among 2166 nurses/nursing personnel across four health care institutions in one US metropolitan area. Using data from an online cross-sectional survey, multivariate logistic regression was utilized to determine risk factors for physical and psychological WPV. Almost one-third (30%) of nurses/nursing personnel experienced WPV (19.4% physical, 19.9% psychological). Risk factors included being a nurse, white, male, working in the emergency department, older age, longer employment, childhood abuse, and intimate partner violence. Adult and childhood abuse histories have not been considered in previous large-scale investigations, but were significant risk factors along with other previously identified risk factors for WPV.


Exploitation of the nutritional and functional characteristics of traditional Italian legumes: the potential of sourdough fermentation.
This study aimed at evaluating the composition of nineteen traditional Italian legumes and at investigating the potential of the sourdough fermentation with selected lactic acid bacteria to improve the nutritional and functional features. Traditional Italian legumes, all with product certifications and belonging to Phaseolus vulgaris, Cicer arietinum, Lathyrus sativus, Lens culinaris and Pisum sativum species, were used in this study. Seeds were milled, and flours were analyzed for proximate composition and subjected to sourdough fermentation at 30°C for 24h. Lactobacillus plantarum C48 and Lactobacillus brevis AM7 were used as selected starters. Compared to control doughs, without bacterial inoculum, the concentrations of free amino acids (FAA), soluble fibres, and total phenols increased for all legume sourdoughs. Raffinose decreased of up to ca. 64%. During sourdough fermentation, the level of GABA markedly increased and reached values up to 624mg/kg. Condensed tannins decreased. At the same time, almost all legume sourdoughs showed increases of the antioxidant and phytase activities. As shown by PCA analysis based on data of total FAA, GABA, raffinose, soluble/insoluble dietary fibre, condensed tannins and antioxidant and phytase activities, all legume sourdoughs were clearly differentiated from control doughs. The traditional Italian legumes are bio-diverse, and all showed high levels of nutritional elements and suitability for optimal sourdough fermentation. Legume flours subjected to sourdough fermentation would be suitable to be used alone or better in mixture with cereals, and as gluten-free ingredients for making novel and healthy foods.


[Quality management in patients with heart failure inside an Internal Medicine Department].
To evaluate the quality management of Heart failure within an Internal Medicine Department, based in quality criteria settled in ACOVE study. Retrospective study reporting 267 patients admitted to our Internal Medicine Department with a diagnosis of heart failure (from January 2001 to January 2001). We applied ACOVE protocol to evaluate quality of management assigning a positive numerical score to every accomplished section and a negative score to those sections that were not carried out. Two hundred and sixty seven patients and their clinical records were evaluated (Mean age 76 +/- 9 years, male 50%). They had a mean score of 6.72 +/- 1.33 points. Heart failure etiology was determined in 82% (33% ischemic heart failure, 30% hypertensive heart disease, 12% valvulopathy and 7% others). ACE-Inhibitors/ARA II were used in 66% of patients, with poor utilization of beta-blockers (16%), calcium channel blockers (7%) and class I antiarrhythmic drugs (1%). 94% of patients had written instructions about manage of their disease. Only 36% of patients had an echocardiography study. In patients with atrial fibrillation, 19% were treated with oral anticoagulants and 26% with anti-platelet drugs. In-hospital mortality rate was 4%. We could not meet differences among different physicians and their gender in department of Internal Medicine treating for heart failure, however the score of patients older 70 years was 6.5 +/- 1.38 points while score in younger to years was 7.15 +/- 1.17 points (p = 0.011). Management of heart failure in our department of Internal Medicine is acceptable. However, there are several points in which improvement could be reached, much as to increase the utilization of ACE inhibitors and beta-blockers in handling of heart failure and to rise the are of echocardiography in the evaluation of these patients. Moreover, older patients showed a lower quality level that could be improved.


Egocentric Projection is a Rational Strategy for Accurate Emotion Prediction.
People need to accurately understand and predict others' emotions in order to build and maintain meaningful social connections. However, when they encounter new social partners, people often do not have enough information about them to make accurate inferences. Rather, they often resort to an egocentric heuristic, and make predictions about a target by using their own self-knowledge as a proxy. Is this egocentric heuristic a form of cognitive bias, or is it a rational strategy for real-world social prediction? If egocentrism provides a rational and effective solution to the challenging task of social prediction in naturalistic contexts, we should expect that a) egocentric predictions tend to be more accurate, and b) people rely on self-knowledge to a greater extent when it's more likely to be a good proxy. Using an emotion prediction task and personality measures, we assessed similarity and predictive accuracy between first-year college students and their new acquaintance roommate. Results demonstrated that, when people need to predict an unfamiliar target's emotions, self-knowledge can often effectively approximate knowledge about others, and thus support accurate predictions. Moreover, participants that were typical of the sample, whose self-knowledge can better approximate information about the target, relied more on self-knowledge in their predictions, and thus achieved higher accuracy. These findings suggest that people rationally tune their use of egocentrism based on whether it is likely to pay off. Overall, these findings demonstrate a rational side to a cognitive phenomenon usually framed as a cognitive pitfall, namely egocentric projection, when its natural decision context is taken into consideration.


Total shoulder arthroplasty: complications and revision surgery.
Fortunately, revision surgery after prosthetic shoulder arthroplasty is rarely required. However, various complications or combinations of complications can lead to the need for revision surgery. For many of these, several treatment options are possible. Recognizing all the problems that contributed to failure in an individual patient may be difficult before revision surgery. Understanding the abnormality present at the time of surgery requires considerable experience. For example, glenoid loosening, in addition to being accompanied by scapular bone loss, may be associated with rotator-cuff tearing, instability, or joint contracture. In addition to the component loosening, all of these must also be treated if the revision procedure is to be successful. When addressing glenoid loosening, it seems to be best to revise the component, if possible. If there is extreme bone loss, one may have to bone graft the deficiencies and not replace the glenoid component. Fortunately, clinically significant humeral loosening is rare. When it occurs, revision of the component is justified and almost always possible. In hemiarthroplasties with pain, conversion to a total shoulder arthroplasty by placing a glenoid component is highly effective. In instability after shoulder arthroplasty, soft-tissue repair does not always create stability. Unfortunately, for most patients, component revision is a necessary part of the revision surgery. When rotator-cuff tearing is acute, repair is indicated; for chronic rotator-cuff tearing, repair depends on the severity of the symptoms. When infection develops after shoulder arthroplasty, implant removal is almost always necessary, but occasionally, in low-grade infections, a primary or secondary exchange procedure may be possible.


Process analysis of microplastic degradation using activated PMS and Fenton reagents.
The environmental degradation and physical aging of microplastics (MP) caused by oxidative stress have not been thoroughly elucidated. In this study, we used different oxidative agents (Fe2+-activated peroxymonosulfate and Fenton reagents) that can form free radicals to study the degradation mechanisms of nylon 6 (PA6) and polystyrene (PS) MPs. After 4 cycles of treatment, mass losses of 25.6% and 22.1% were obtained with PA6 and PS MPs, respectively. Scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS) were employed to confirm the MP oxidation, and polymer chain scissions. FTIR data indicated the existence of oxygen-containing chemical groups resulting from MPs oxidation, and chain scissions, such as CO, C-O, and O-CO. Raman spectroscopy suggested the presence of exposed aromatic groups, and weakening of the relative intensity of C-H related to the oxidation, and chain scission of the MPs. SEM imaging revealed visible morphological changes on the surface of MPs as a result of degradation. XPS indicated that the O/C ratio could be used as an indicator for the degree of MPs oxidation. By analyzing the degradation products with surface-enhanced Raman scattering (SERS) and gas chromatography-mass spectrometry, low-molecular-weight alkanes, alcohols, aldehydes, carboxylic acids derived from the derivatization of alcohols, were detected. These findings confirmed the advantage of using multiple analytic methods in tandem to evaluate the degradation of environmental MPs.


Application of gravitational clustering analysis to liquid gastric emptying.
A gravitational clustering analysis was applied to principal component weighting factors and t1/2 values from 100 liquid gastric emptying studies. Using principal components, groups of patients with clinical features in common were identified, whereas the analysis of the t1/2 values failed to differentiate them.


Chemosensitization of androgen-independent prostate cancer with neutral endopeptidase.
We investigated whether neutral endopeptidase (NEP) could augment chemosensitivity to anticancer drugs by promoting protein kinase C (PKC)delta-mediated mitochondrial apoptosis in prostate cancer (PC) cells. Human PC cell lines LNCaP and PC-3, and a normal prostate epithelial cell line (PrEC) were used. The protein expression was detected by Western blot analysis, and the protein turnover was determined by pulse-chase assay. Apoptotic ratio was measured by annexin V staining. Western blot analyses and pulse-chase assays showed that the specific NEP inhibitor CGS24592 decreased PKCdelta protein expression by promoting PKCdelta protein degradation in NEP-expressing LNCaP cells. Conversely, recombinant NEP (rNEP) increased PKCdelta protein expression by delaying PKCdelta protein degradation in NEP-negative PC-3 cells. Apoptosis assays showed that rNEP promoted anticancer drug-induced apoptosis in PC-3 cells specifically through PKCdelta activity that mediated anticancer drug-induced mitochondrial change such as cytochrome-c release and caspase-9 activation. Of note, rNEP was able to increase PKCdelta protein expression predominantly in PC-3 cells rather than in PrEC cells. Treatment with rNEP before subtoxic concentrations of etoposide (0.1 micro M) significantly promoted mitochondrial apoptosis compared with only etoposide in PC-3 cells (P < 0.01) but not in PrEC cells. These results suggest that NEP enzyme activity contributes to anticancer drug-induced PC cell apoptosis dependent on PKCdelta-mediated mitochondrial events. More importantly, the combination of NEP with anticancer drugs may be a promising therapeutic modality because rNEP is able to augment chemosensitivity in androgen-independent PC with minimal toxicity in normal tissues.


Diabetes Insipidus: An Update.
The differential diagnosis of diabetes insipidus involves the distinction between central or nephrogenic diabetes insipidus and primary polydipsia. Differentiation is important because treatment strategies vary; the wrong treatment can be dangerous. Reliable differentiation is difficult especially in patients with primary polydipsia or partial forms of diabetes insipidus. New diagnostic algorithms are based on the measurement of copeptin after osmotic stimulation by hypertonic saline infusion or after nonosmotic stimulation by arginine and have a higher diagnostic accuracy than the water deprivation test. Treatment involves correcting preexisting water deficits, but is different for central diabetes insipidus, nephrogenic diabetes insipidus, and primary polydipsia.


Properties of alpha- and beta-adrenoceptors in circulating blood cells of patients with essential hypertension.
The properties of platelet alpha 2-adrenoceptors and of lymphocyte beta 2-adrenoceptors were determined in 40 male patients with established essential hypertension and compared with those in 40 male normotensives. The densities of platelet alpha 2-adrenoceptors (assessed by 3H-yohimbine binding) and of lymphocyte beta 2-adrenoceptors [determined by (+/-)-125iodocyanopindolol binding] were in patients with essential hypertension significantly higher than in controls; there were significant positive correlations between the mean arterial blood pressure of the subjects and alpha 2- and beta 2-adrenoceptor density, respectively. Concomitantly with receptor densities, functional responses to adrenergic stimulation were exaggerated in essential hypertension: in platelets, the aggregatory response to (-)-adrenaline (via alpha 2-adrenoceptor stimulation) was enhanced; in lymphocytes, the cyclic AMP response to (-)-isoprenaline (via beta 2-adrenoceptor stimulation) was elevated. It is concluded that the increased adrenoceptor density and responsiveness in circulating blood cells of patients with essential hypertension may reflect increased sympathetic activity, which might contribute to the elevation of blood pressure.


Outer Retinal Layer Thickness Changes in White Matter Hyperintensity and Parkinson's Disease.
Purpose: To investigate the thickness changes of outer retinal layers in subjects with white matter hyperintensities (WMH) and Parkinson's Disease (PD). Methods: 56 eyes from 31 patients with WMH, 11 eyes from 6 PD patients, and 58 eyes from 32 healthy controls (HC) were enrolled in this study. A macular-centered scan was conducted on each participant using a spectral-domain optical coherence tomography (SD-OCT) device. After speckle noise reduction, a state-of-the-art deep learning method (i.e., a context encoder network) was employed to segment the outer retinal layers from OCT B-scans. Thickness quantification of the outer retinal layers was conducted on the basis of the segmentation results. Results: WMH patients had significantly thinner Henle fiber layers, outer nuclear layers (HFL+ONL) and photoreceptor outer segments (OS) than HC (p = 0.031, and p = 0.005), while PD patients showed a significant increase of mean thickness in the interdigitation zone and the retinal pigment epithelium/Bruch complex (IZ+RPE) (19.619 ± 4.626) compared to HC (17.434 ± 1.664). There were no significant differences in the thickness of the outer plexiform layer (OPL), the myoid and ellipsoid zone (MEZ), and the IZ+RPE layer between WMH and HC subjects. Similarly, there were also no obvious differences in the thickness of the OPL, HFL+ONL, MEZ and the OS layer between PD and HC subjects. Conclusion: Thickness changes in HFL+ONL, OS, and IZ+RPE layers may correlate with brain-related diseases such as WMH and PD. Further longitudinal study is needed to confirm HFL+ONL/OS/IZ+RPE layer thickness as potential biomarkers for detecting certain brain-related diseases.


Epidemiological mechanisms of genetic resistance to kuru.
Transmissible spongiform encephalopathies (TSEs), such as kuru, are invariably fatal neurodegenerative conditions caused by a malformation of the prion protein. Heterozygosity of codon 129 of the prion protein gene has been associated with increased host resistance to TSEs, although the mechanism by which this resistance is achieved has not been determined. To evaluate the epidemiological mechanism of human resistance to kuru, we developed a model that combines the dynamics of kuru transmission and the population genetics of human resistance. We fitted our model to kuru data from the epidemic that occurred in Papua New Guinea over the last hundred years. To elucidate the epidemiological mechanism of human resistance, we estimated the incubation period and transmission rate of kuru for codon 129 heterozygotes and homozygotes using kuru incidence data and human genotype frequency data from 1957 to 2004. Our results indicate that human resistance arises from a combination of both a longer incubation period and reduced susceptibility to infection. This work provides evidence for balancing selection acting on a human population and the mechanistic basis for the heterozygote resistance to kuru.


Structure of a monoclonal kappa chain of the V kappa IV subgroup in the kidney and plasma cells in light chain deposition disease.
That structural abnormalities may be responsible for nonamyloid immunoglobulin (Ig) light chain deposition disease (LCDD) is suggested by previous results of Ig biosynthesis studies, but this hypothesis was not documented at the molecular level. We report on the first complete primary sequence deduced from cDNA analysis of a kappa light chain responsible for LCDD associated with an apparently nonsecretory myeloma. Bone marrow myeloma cells contained intracellular kappa chains and no heavy chains by immunofluorescence. Kidney biopsy showed typical nonamyloid PAS-positive kappa chain deposits. SDS-PAGE analysis of material extracted from a kidney biopsy specimen and of Ig produced by the myeloma cells revealed kappa chains of abnormally high apparent molecular mass (30,000). Comparison of the NH2-terminal aminoacid sequence of the kappa chain deposited in the kidney and of the complete sequence of several identical kappa cDNA clones from bone marrow cells showed the identity of the tissue deposited and plasma cell kappa chain. The kappa mRNA had an overall normal structure and corresponded to the V kappa IV gene rearranged to J kappa 1 and followed by a normal constant exon of the Km(3) allotype. The variable sequence differed from the V kappa IV germline gene by nine point mutations, including an Asp----Asn substitution at position +70 resulting in a potential N-glycosylation site. In vitro biosynthesis experiments and treatment with N-glycosidase provided evidence for the intracellular glycosylation of the monoclonal kappa chain. The peculiar sequence and the glycosylation of a kappa chain of the rare V kappa IV subgroup might be responsible for structural abnormalities leading to tissue deposition.


The effect of working memory load on semantic illusions: what the phonological loop and central executive have to contribute.
When asked how many animals of each kind Moses took on the Ark, most people respond with "two" despite the substituted name (Moses for Noah) in the question. Possible explanations for semantic illusions appear to be related to processing limitations such as those of working memory. Indeed, individual working memory capacity has an impact upon how sentences containing substitutions are processed. This experiment examined further the role of working memory in the occurrence of semantic illusions using a dual-task working memory load approach. Participants verified statements while engaging in either articulatory suppression or random number generation. Secondary task type had a significant effect on semantic illusion rate, but only when comparing the control condition to the two dual-task conditions. Furthermore, secondary task performance in the random number generation condition declined, suggesting a tradeoff between tasks. Response time analyses also showed a different pattern of processing across the conditions. The findings suggest that the phonological loop plays a role in representing semantic illusion sentences coherently and in monitoring for details, while the role of the central executive is to assist gist-processing of sentences. This usually efficient strategy leads to error in the case of semantic illusions.


Survey aimed at public giving.
While many donation policy issues were not answered by a survey of the membership of the American College of Physician Executives, the results did permit some policy determinations for handling requests to health care organizations for donations to community agencies and organizations.


Assessing patients with epiphora who are patent to syringing: clinical predictors of response to dacryocystorhinostomy.
To assess the value of an abnormal fluorescein dye disappearance test (FDDT), lacrimal syringing, and Jones test for patients with epiphora who are clinically patent to syringing. Prospective cohort study of 68 consecutive patients with epiphora who were clinically patent to syringing and otherwise normal to examination. Patients were assessed using FDDT and lacrimal syringing, as well as the Jones test comparing either single- or multiple-drop technique. FDDT and canalicular reflux on lacrimal syringing were subjectively graded. Success was defined as nil or only mild epiphora after surgery. Surgery was performed on 68 patients with a successful result in 64 (94%). The majority of these patients had severely delayed FDDT (90%), > or = 50% reflux on lacrimal syringing (78%), or were Jones I negative (81%). There was no significant difference between outcomes of the single- and multiple-drop tests. In patients examined with the single-drop Jones test, patients with a Jones I negative result had a statistically significant better surgical outcome (p = 0.04). This comparison was highly significant when the subgroup of patients with severely delayed/nonclearing FDDT and > or = 50% reflux was examined (p = 0.005). The results were not significant for the multiple-drop group. These findings show that a negative single-drop Jones I test is predictive of symptomatic improvement after dacryocystorhinostomy surgery in patients with epiphora who are clinically patent to syringing. Lacrimal syringing and the FDDT, on their own, were not predictive of surgical outcome. Jones testing was of significant value in patients, but only when the traditional single-drop test was used.


Circadian transcription contributes to core period determination in Drosophila.
The Clock-Cycle (CLK-CYC) heterodimer constitutes a key circadian transcription complex in Drosophila. CYC has a DNA-binding domain but lacks an activation domain. Previous experiments also indicate that most of the transcriptional activity of CLK-CYC derives from the glutamine-rich region of its partner CLK. To address the role of transcription in core circadian timekeeping, we have analyzed the effects of a CYC-viral protein 16 (VP16) fusion protein in the Drosophila system. The addition of this potent and well-studied viral transcriptional activator (VP16) to CYC imparts to the CLK-CYC-VP16 complex strongly enhanced transcriptional activity relative to that of CLK-CYC. This increase is manifested in flies expressing CYC-VP16 as well as in S2 cells. These flies also have increased levels of CLK-CYC direct target gene mRNAs as well as a short period, implicating circadian transcription in period determination. A more detailed examination of reporter gene expression in CYC-VP16-expressing flies suggests that the short period is due at least in part to a more rapid transcriptional phase. Importantly, the behavioral effects require a period (per) promoter and are therefore unlikely to be merely a consequence of generally higher PER levels. This indicates that the CLK-CYC-VP16 behavioral effects are a consequence of increased per transcription. All of this also suggests that the timing of transcriptional activation and not the activation itself is the key event responsible for the behavioral effects observed in CYC-VP16-expressing flies. The results taken together indicate that circadian transcription contributes to core circadian function in Drosophila.


DO PROXIMAL AND DISTAL GASTRIC TUMOURS BEHAVE DIFFERENTLY?
Although the incidence of gastric (adenocarcinoma) cancer has been decreasing over time, it is still one of the most common malignancies worldwide, and proximal tumours tend to have a worse prognosis. To compare surgical outcomes and prognosis between proximal - excluding tumours of the cardia - and distal gastric cancer. Out of 293 cases reviewed - 209 with distal and 69 with proximal gastric cancer - were compared for clinical and pathological features, stage, surgical outcome, mortality and survival. Statistically, there was no significant difference between patients in both groups regarding mortality (p=0.661), adjuvant chemotherapy (p 0.661), and radiation (p=1.000). However, there was significant difference in the degree of lymph node dissection employed (p=0.002) and the number of positive lymph nodes resected (p=0.038) between the two groups. The odds of death at five years for patients who had a D0 dissection was three times greater (odds ratio 2.78; (95%CI 1.33-5.82) than that for patients who had a D2 dissection, while for patients who had a D1 dissection the odds ratio was only 1.41 (95%CI 0.71-2.83) compared to D2-dissected patients. Although no significant differences were found between proximal and distal gastric cancer, the increased risk of death in D0- and D1-dissected patients clearly suggests an important role of radical D2 lymph node dissection in survival.


Key nutritional factors and interactions during larval development of pikeperch (Sander lucioperca).
The effects of 8 nutritional variables (Ca/P, Eicosapentaenoic acid (20:5n-3) + Docosahexaenoic acid (22:6n - 3) (EPA + DHA), Arachidonic acid (20:4n - 6) (ARA), Se, vitamins E, C, D and A) were investigated to identify their respective importance and interactions in pikeperch larval development. In this respect, two modalities (low and high levels) of each variable were tested through a fractional factorial experimental design allowing a reduction from 256 (28) to 16 (28 - 4) experimental units. Survival was significantly higher in larvae fed a high Ca/P diet while larval growth was significantly lower in larvae fed the same diet variant, associated with a higher incidence of kyphosis and pectoral anomalies in these larvae. Lordosis and scoliosis seemed to be mostly affected by dietary long chain polyunsaturated fatty acids (LC-PUFAs). A significant interaction was shown between n-3 LC-PUFA and vitamin C on jaw anomalies, while myocyte-specific enhancer factor 2C (mef2c) gene expression correlated positively with dietary vitamin C increment. Results also demonstrated an effect of the different nutrients and their interactions on the activity levels of digestive enzymatic activities. The results of the present study highlight the importance of the interactions between Ca/P, LC-PUFAs and vitamins C and E, suggesting their essential roles as key nutritional factors influencing pikeperch larval development.


Influence of four diets containing approximately 11% protein (dry weight) on uric acid, sodium urate, and ammonium urate urine activity product ratios of healthy beagles.
Urine activity product ratios of uric acid (APRua), sodium urate (APRna), and ammonium urate (APRau), and urinary excretion of 10 metabolites were determined in 24-hour urine samples produced by 6 healthy Beagles during periods of consumption of 4 diets containing approximately 11% protein (dry weight) and various protein sources: a 72% moisture, casein-based diet; a 10% moisture, egg-based diet; a 72% moisture, chicken-based diet; and a 71% moisture, chicken-based, liver-flavored diet. Significantly (P < 0.05) higher APRua, APRna, and APRau were observed when dogs consumed the egg-based diet, compared with the other 3 diets; there were no differences in these ratios among the other 3 diets. Twenty-four-hour urinary excretions of chloride, potassium, phosphorus, and oxalic acid were significantly (P < 0.05) higher when dogs consumed the egg-based diet. Twenty-four-hour urinary excretions of sodium were significantly (P < 0.05) higher when dogs consumed the egg-based diet, compared with the casein-based diet and the chicken-based, liver-flavored diet, but were not significantly different between the egg-based diet and chicken-based diet. Twenty-four-hour urine volume was similar when dogs consumed the 4 diets. Twenty-four-hour endogenous creatinine clearance was significantly (P < 0.05) lower when dogs consumed the casein-based diet; there were no differences among the other 3 diets. Although consumption of all diets was associated with production of alkaline urine, the 24-hour urine pH was significantly (P < 0.05) higher when dogs consumed the egg-based diet.(ABSTRACT TRUNCATED AT 250 WORDS)


Adolescent anemia screening during ambulatory pediatric visits in the United States.
The Centers for Disease Control and Prevention recommends anemia screening for reproductive age women every 5-10 years and annually for those with risk factors. Due to the lower risk of anemia among males, screening for men is recommended only if risk factors exist. The study objective was to examine health care professionals' current anemia screening patterns for male and female adolescents. Data are from the 2001 -2004 National Ambulatory Medical Care Survey, a nationally representative sample of ambulatory visits to primary care practices. The frequency of anemia screening during preventive care visits by 12-21-year-olds was estimated by sex using a reported hemoglobin/hematocrit or complete blood count as an indicator of screening. Multivariable logistic regression identified patient, provider and practice-level factors associated with screening. During the study period, 1,263 preventive care visits occurred for 12-21 year-olds. In bivariate analysis, higher odds of anemia screening were observed for both younger females (OR 1.85; 95 % CI 1.09-3.14) and older males [1.83 (1.02-3.26)] compared to older females (≥ 16 years). In the multivariable model, odds of screening increased with non-white race [3.29 (1.84-5.88)], tobacco use [3.57 (1.94-6.58)], longer visit length [1.03 (1.01-1.06)], and practice site acceptance of managed care plans [2.08 (1.04-4.14)]. Patient sex and age were not statistically significant predictors of screening. Although anemia is more prevalent among older adolescent females, they were not more likely to be screened. This suggests providers are not targeting groups at highest risk of anemia for screening.


Effect of periarticular corticosteroid injections during total knee arthroplasty. A double-blind randomized trial.
Multimodal pain-control protocols that include periarticular injections have been reported to decrease pain and improve early outcomes following total knee arthroplasty. While injections containing a corticosteroid have been demonstrated to be safe and effective, we are not aware of any randomized trials in which the specific effect of the corticosteroid on early postoperative outcomes has been evaluated. The purpose of this double-blind study was to compare the clinical efficacy of periarticular injections consisting of bupivacaine, morphine, epinephrine, clonidine, and cefuroxime as well as a corticosteroid (methylprednisolone acetate) with the efficacy of periarticular injections consisting of the same agents but without the inclusion of a corticosteroid. Seventy-six patients were randomized to either the no-steroid group (thirty-seven patients) or the steroid group (thirty-nine patients). Pain and narcotic consumption during the inpatient stay and the length of the hospital stay were recorded. Knee Society scores, the range of motion, and the occurrence of any complications were recorded preoperatively and at six and twelve weeks after the surgery. The hospital stay was significantly shorter for patients in the steroid group (2.6 days compared with 3.5 days in the no-steroid group; p = 0.01). No significant group differences in terms of pain, narcotic consumption, outcome scores, or motion were identified. There were three complications in the steroid group: two patients required a manipulation under anesthesia, and the knee joint became infected in another patient, leading to numerous complications and ultimately death. The periarticular injection of a corticosteroid may reduce the length of the hospital stay following total knee arthroplasty, but it does not appear to improve pain relief, motion, or function in the early postoperative period. While we cannot definitively state that the corticosteroid was a causative factor in the development of the infection at the site of the prosthetic joint, we cannot rule it out either, which raises concern regarding the role of corticosteroids in perioperative pain management following total knee arthroplasty.


The Medial Septum Is Insulin Resistant in the AD Presymptomatic Phase: Rescue by Nerve Growth Factor-Driven IRS1 Activation.
Basal forebrain cholinergic neurons (BFCN) are key modulators of learning and memory and are high energy-demanding neurons. Impaired neuronal metabolism and reduced insulin signaling, known as insulin resistance, has been reported in the early phase of Alzheimer's disease (AD), which has been suggested to be "Type 3 Diabetes." We hypothesized that BFCN may develop insulin resistance and their consequent failure represents one of the earliest event in AD. We found that a condition reminiscent of insulin resistance occurs in the medial septum of 3 months old 3×Tg-AD mice, reported to develop typical AD histopathology and cognitive deficits in adulthood. Further, we obtained insulin resistant BFCN by culturing them with high insulin concentrations. By means of these paradigms, we observed that nerve growth factor (NGF) reduces insulin resistance in vitro and in vivo. NGF activates the insulin receptor substrate 1 (IRS1) and rescues c-Fos expression and glucose metabolism. This effect involves binding of activated IRS1 to the NGF receptor TrkA, and is lost in presence of the specific IRS inhibitor NT157. Overall, our findings indicate that, in a well-established animal model of AD, the medial septum develops insulin resistance several months before it is detectable in the neocortex and hippocampus. Remarkably, NGF counteracts molecular alterations downstream of insulin-resistant receptor and its nasal administration restores insulin signaling in 3×Tg-AD mice by TrkA/IRS1 activation. The cross-talk between NGF and insulin pathways downstream the insulin receptor suggests novel potential therapeutic targets to slow cognitive decline in AD and diabetes-related brain insulin resistance.


The role of high-dose therapy and autologous hematopoietic stem cell transplantation for mantle cell lymphoma.
Although mantle cell lymphoma (MCL) is a distinct disease entity with well described clinical and pathological features, little information exists regarding its therapy. This paper will evaluate patients with MCL receiving either induction therapy with an anthracycline or high-dose chemotherapy and autologous hematopoietic stem cell transplantation for relapsed disease. The cases of 14 previously untreated patients with MCL who received an anthracycline-containing combination chemotherapy regimen on Nebraska Lymphoma Study Group protocols from 3/83 to 2/92 were reviewed. During the same time period, a different set of nine patients with recurrent MCL were referred for high-dose chemoradiotherapy and autologous stem cell rescue as salvage therapy. The five year overall (OS) and failure-free (FFS) survivals from the initiation of chemotherapy for the patients receiving an induction therapy with an anthracycline containing regimen were 23% and 8%, respectively. At the time of this analysis, three of the nine transplant patients remain progression-free 7, 12, and 25 months post-transplant. Two year overall and FFS for all nine patients was 34%. Longer follow-up of greater patient numbers is required to determine whether high-dose therapy can overcome the chemoresistance and increase the cure rate of MCL. Since most patients with this disease have minimal chance of cure with standard chemotherapy, the optimal timing for high dose therapy may be as part of front-line treatment. Further clinical trials are required to investigate the potential benefits of high-dose therapy for patients with MCL.


The problem of obesity and dietary nudges.
From a psychological perspective, Cass R. Sunstein's 2016 book The Ethics of Influence is an insightful examination of the ethics of using social and cognitive psychological principles to influence behavior and decision-making. The United States has been experiencing what can only be described as an obesity epidemic. Scientists know that this epidemic has been brought about in part by the prevailing choice architecture, which influences what we eat, how much we eat, and how little we exercise. From a public health perspective, the policy issue centers on how a democracy can employ a combination of bans, mandates, and nudges to reshape our dietary habits to combat obesity. In this article, I will address how policymakers must nudge and change the existing psychological and physical choice architecture to combat obesity. The obesity epidemic cannot be won solely by increasing taxes, mandates, and bans on certain food items as that infringes on the personal liberty, welfare, autonomy, and dignity of citizens.


Surfactant protein genetics in community-acquired pneumonia: balancing the host inflammatory state.
Community-acquired pneumonia is a common disease. Abnormalities in the first step of host defense may severely compromise subsequent steps of successfully combating infections. In the previous issue of Critical Care, García-Laorden and colleagues reported genetic associations between single-nucleotide polymorphisms and haplotypes of the surfactant proteins with susceptibility, severity, and outcome of community-acquired pneumonia. Although the limited information shows regulatory differences among variants, it is currently unknown how the difference in surfactant protein A genotypes in this and other studies affects the individual's phenotype. The lung is continually exposed to a host of irritants yet maintains health. It is plausible that, under physiologic conditions, surfactant protein A, in addition to having a dominant effect on anti-inflammatory processes, mediates a low level of proinflammatory processes that are essential for the health of the lung. Understanding the maintenance of the balance of the inflammatory state may be one of the keys to understanding pulmonary disease progression.


Direct carotid puncture for endovascular thrombectomy in acute ischemic stroke.
Mechanical thrombectomy is the standard of care for acute ischemic strokes with proximal intracranial occlusion. Arterial access is commonly achieved with femoral artery puncture, although this is not always possible. In this case series, we describe 11 cases of anterior circulation stroke where direct carotid puncture was used to obtain vascular access. A review of a prospectively maintained thrombectomy database over a 2-year period (August 2016 - August 2018) was undertaken to identify cases where direct carotid access was performed. CT and angiographic imaging were reviewed. Indications for carotid access, techniques used, technical success of procedure, recanalization rates, procedure-related complications, and patient outcomes were assessed. Eleven patients out of 498 overall thrombectomy procedures (2.2% thrombectomies) underwent direct carotid access. Median National Institutes of Health Stroke Scale was 20. Seventy three percent of patients received intravenous thrombolysis. The direct carotid approach was performed following the failed femoral approach due to unfavorable aortic arch anatomy, vessel tortuosity, and severe atherosclerotic disease. Direct carotid puncture was successful in 10 patients, and unsuccessful in one. Successful recanalization (TICI 2b-3) was achieved in eight patients. One patient had spontaneously recanalized on angiography. There was failed recanalization in one patient with tandem ICA and M1 occlusion. Carotid access complications included one patient with both neck hematoma and asymptomatic ICA dissection, and one of delayed central retinal artery occlusion. This case series highlights direct carotid puncture as a successful alternative when the femoral approach is not possible, allowing thrombectomy in patients who would otherwise be unsuitable.


Migration rates and genetic structure of two Hungarian ethnic groups in Transylvania, Romania.
Transylvania's ethnic mosaic is composed of Romanians, German Saxons and Hungarians. The ethnic groups of the Hungarian minority that settled in Romania show differences in dialects, customs and religious affiliations. In this study entire mtDNA control region sequences from 360 individuals of Hungarian ethnicity from two populations (the Csángó and the Székely), settled in the historical region of Transylvania in Romania, were generated and analyzed following high quality sequencing standards. Phylogenetic analyses were used for haplogroup determination, quasi-median network analyses were applied for the visualization of character conflicts, and median joining reconstructions were used for depicting haplotype structures. Affiliation of haplotypes to major west Eurasian haplogroups was confirmed using coding region SNPs. Gene flow between the two populations was low and biased towards a higher migration rate from the Csángó to the Székely than vice versa. Phylogeographic analyses revealed effects of genetic isolation within the Csángó population, which is, in its genetic structure, clearly different from the Székely population. The pronounced genetic divergence between the two populations is in sharp contrast to the expectation of high genetic similarity due to the close geographic proximity of their native homelands. The population data will be incorporated in the EMPOP database (http://www.empop.org).


Neuroexcitatory effects of digoxin in the cat.
The effect of intravenous injections of digoxin (20 mug/kg every 15 minutes) on spontaneously occurring activity in autonomic efferent nerves, motor nerves, afferent nerves, electrocardiogram and on arterial blood pressure was evaluated in chloralose-anesthetized cats. Administration of digoxin enhanced neural activity in pre- and postganglionic cardiac synpathetic nerves and this enhancement occurred near the time the disturbances in ventricular rhym were noted. Neural activity continued to increase during ventricular tachycardia and maximum enhancement was observed just proir to ventricular fibrillation. Similar results were observed when digoxin was administered to animals in which neural activity was recorded from preganglionic splanchnic and superior cervical nerves. Digoxin administration also increased discharge frequency from vagus (efferent fibers), phrenic and carotid sinus nerves. Denervation of cardiovascular reflexogenic areas prevented the increased discharge in vagus nerves, reduced it in phrenic nerves, but did not affect nerve discharge in sympathetic nerves. These results suggest that digoxin-induced hyperactivity in synpathetic nerves was related to a central nervous system effect of the drug, whereas the mechanism for the digoxin-induced hyperactivity in vagus nerves involved a peripheral reflex effect of the drug. Both sites were involved in the digoxin-induced hyperactivity in phrenic nerves. Enhancement of cardiac sympathetic nerve activity appeared to be responsible for the ventricular arrhythmias provoked by digoxin as 1) a temporal relationship was observed between augmented nerve activity and arrhythmia development, 2) a centrally acting sympathetic nervous system depressant drug, clonidine, converted the ventricular arrhythmia to normal rhythm, and 3) removal of sympathetic influence to the heart by spinal cord transection decreased the sensitivity of the heart to the arrhythmogenic effect of digoxin. These results suggest that digoxin partially responsible for its cardiotoxic effects.


Speed of lexical decision correlates with diffusion anisotropy in left parietal and frontal white matter: evidence from diffusion tensor imaging.
Speed of visual word recognition is an important variable affecting linguistic competence. Although speed of visual word recognition varies widely between individuals, the neural basis of reaction time (RT) differences is poorly understood. Recently, a magnetic resonance technique called diffusion tensor imaging (DTI) has been shown to provide information about white matter (WM) microstructure in vivo. Here, we used DTI to explore whether visual word recognition RT correlates with regional fractional anisotropy (FA) values in the WM of healthy young adults. Participants completed a speeded lexical decision task that involved visual input, linguistic processes, and a motor response output. Results indicated that lexical decision RT was correlated negatively with FA in WM of inferior parietal and frontal language regions rather than in WM of visual or motor regions. Voxels within the inferior parietal and frontal correlation clusters were composed primarily of DTI-based tracts oriented in the anterior-posterior orientation at or near the superior longitudinal fasciculus (SLF) and likely including other smaller association fibers. These results provide new microstructural evidence demonstrating that speed of lexical decision is associated with the degree to which portions of frontal and parietal WM are directionally oriented.


Recognition of hypovolemic shock: using base deficit to think outside of the ATLS box.
Base deficit has frequently been utilized as an informal adjunct in the initial evaluation of trauma patients to assess the extent of their physiologic derangements. However, the current Advanced Trauma Life Support (ATLS) classification system for hypovolemic shock does not include base-deficit measurements and relies primarily on alterations in vital signs (heart rate, systolic blood pressure) and mental status (Glasgow Coma Scale) to estimate blood loss. The authors of this paper propose that the current ATLS system may not accurately reflect the degree of hypovolemic shock in many patients and that base-deficit measurements should be used in its place. The proposed system showed a greater correlation with transfusion requirements, need for massive transfusion, and mortality when compared with the ATLS classification system. Based on these findings, base-deficit measurement should be strongly considered during the initial trauma evaluation to identify the presence of hypovolemic shock and to guide blood product administration.


Neural networks for Braille reading by the blind.
To explore the neural networks used for Braille reading, we measured regional cerebral blood flow with PET during tactile tasks performed both by Braille readers blinded early in life and by sighted subjects. Eight proficient Braille readers were studied during Braille reading with both right and left index fingers. Eight-character, non-contracted Braille-letter strings were used, and subjects were asked to discriminate between words and non-words. To compare the behaviour of the brain of the blind and the sighted directly, non-Braille tactile tasks were performed by six different blind subjects and 10 sighted control subjects using the right index finger. The tasks included a non-discrimination task and three discrimination tasks (angle, width and character). Irrespective of reading finger (right or left), Braille reading by the blind activated the inferior parietal lobule, primary visual cortex, superior occipital gyri, fusiform gyri, ventral premotor area, superior parietal lobule, cerebellum and primary sensorimotor area bilaterally, also the right dorsal premotor cortex, right middle occipital gyrus and right prefrontal area. During non-Braille discrimination tasks, in blind subjects, the ventral occipital regions, including the primary visual cortex and fusiform gyri bilaterally were activated while the secondary somatosensory area was deactivated. The reverse pattern was found in sighted subjects where the secondary somatosensory area was activated while the ventral occipital regions were suppressed. These findings suggest that the tactile processing pathways usually linked in the secondary somatosensory area are rerouted in blind subjects to the ventral occipital cortical regions originally reserved for visual shape discrimination.


The rex gene of bacteriophage lambda is really two genes.
Complementation tests among previously isolated rex- mutants of bacteriophage lambda reveal that the mutants comprise two complementation groups, designated rexA and rexB. Because rexB- mutants complement prm- mutants, but rexA- mutants do not, it appears that the rexA gene is coordinately controlled with the cI (repressor) gene under the direction of PRM promoter, but that some other promoter is capable of directing the expression of rexB.


A novel assay for endonucleases acting at apurinic sites and its use in measuring AP endonuclease activity in repair-deficient mutants of Saccharomyces cerevisiae.
A quick and convenient assay for depurination and AP endonuclease activities has been developed. (The term 'AP endonuclease' refers to a nuclease that acts on apurinic and probably apyrimidinic sites on DNA.) It is based on the observation that different topological forms of DNA, such as open circular DNA and covalently closed circular DNA, bind different amounts of the fluorescent intercalator ethidium bromide, and can therefore be distinguished by their fluorescence. This assay has been used to measure AP endonuclease activity in 22 repair-deficient mutants of Saccharomyces cerevisiae. All 22 had normal or nearly normal AP endonuclease activity. The AP endonuclease activity was partially characterized.


Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative.
Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.


The autism diagnostic observation schedule: Patterns in individuals with anorexia nervosa.
Studies have used the Autism Diagnostic Observation Schedule (the ADOS-2) in individuals with anorexia nervosa (AN), but the patterns of scores have not been assessed. We examined which subset of the ADOS-2 items best discriminate individuals with AN from healthy controls (HC), and assessed the potential clustering of AN participants based on different profiles of the ADOS-2 item scores. We combined datasets from two previous studies, and (a) compared mean ranks between young AN participants (N = 118) and HC (N = 42), (ii) replicated the item selection procedure of the existing ADOS-2 algorithm to assess sensitivity of items in the AN group, and (c) applied a two-step clustering analysis in the AN group (N = 149). AN participants displayed significantly higher mean ranks than HC participants in five of 32 items. All five items are part of the existing ADOS-2 algorithm. We found two clusters of AN participants; one representing normal social behaviour, comprising 68% of the individuals with AN, and one representing less efficient social behaviour, comprising 32% of individuals with AN. The items comprising the social affective cluster of the existing ADOS-2 algorithm are well suited to assess difficulties with social functioning in individuals with AN.


The aetiology of medical device-related pressure ulcers and how to prevent them.
This article provides an introduction to the aetiology of medical device-related pressure ulcers (MDRPUs), describes the vicious cycle that leads to these injuries and highlights bioengineering methodologies and findings that connect the aetiology to the clinical practice of preventing MDRPUs. Specifically, the vicious cycle of MDRPUs is triggered by the sustained tissue deformations induced by a skin-contacting device. The primary, deformation-inflicted cell damage leads to a secondary inflammatory-oedema-related damage and then to tertiary ischaemic damage. Each of these three factors contributes to cumulative cell death and tissue damage under and near the applied device. The damage therefore develops in an escalated manner, as a result of the added contributions of the above three factors. This phenomenon is exemplified through two common clinical scenarios. First, through the use of continuous positive airway pressure (CPAP) masks, which are being applied extensively in the current COVID-19 pandemic, and, second, through the use of doughnut-shaped head positioners, which are applied to surgical patients and sometimes to bedridden individuals who receive intensive care in a supine position. These two medical devices cause intense, localised mechanical loads in the facial skin and underlying tissues (CPAP mask) and at the occipital scalp (doughnut-shaped positioner), where the soft tissues cannot swell in response to the inflammatory oedema as, in both cases, the tissues are sandwiched between the device and the skull. Accordingly, the two device types result in characteristic MDRPUs that are avoidable through appropriate prophylactic interventions, that is, preventive dressings under the CPAP mask and replacement of the doughnut device by a soft, shape-conforming support aid to alleviate and disperse the localised soft tissue deformations. Hence, understanding the aetiology of MDRPUs targets and focuses effective clinical interventions.


Evaluation of a nonpeptidic ligand for imaging of cholecystokinin 2 receptor-expressing cancers.
Tumor-specific targeting ligands were recently exploited to deliver both imaging and therapeutic agents selectively to cancer tissues in vivo. Because the cholecystokinin 2 receptor (CCK2R) is overexpressed in various human cancers (e.g., lung, medullary thyroid, pancreatic, colon, and gastrointestinal stromal tumors) but displays limited expression in normal tissues, natural ligands of CCK2R were recently explored for use in the imaging of CCK2R-expressing cancers. Unfortunately, the results from these studies revealed not only that the peptidic CCK2R ligands were unstable in vivo but also that the ligands that mediated good uptake by tumor tissues also promoted a high level of retention of the radioimaging agent in the kidneys, probably because of capture of the conjugates by peptide-scavenging receptors. In an effort to reduce the normal organ retention of CCK2R-targeted drugs, we synthesized a nonpeptidic ligand of CCK2R and examined its specificity for CCK2R both in vitro and in vivo. Nonpeptidic agonists and antagonists of CCK2R described in the literature were evaluated for their affinities and specificities for CCK2R. Z-360, a benzodiazepine-derived CCK2R antagonist with subnanomolar affinity, was selected for complexation to (99m)Tc via multiple spacers. After synthesis and purification, 4 complexes with different physicochemical properties were evaluated for binding to CCK2R-transfected HEK 293 cells. The best conjugate, termed CRL-3-(99m)Tc, was injected into mice bearing CCK2R tumor xenografts and examined by γ scintigraphy and SPECT/CT. The uptake of the conjugate in various organs was also quantified by tissue resection and γ counting. CRL-3-(99m)Tc was shown to bind with low nanomolar affinity to CCK2R in vitro and was localized to tumor tissues in athymic nu/nu mice implanted with CCK2R-expressing tumors. At 4 h after injection, tumor uptake was measured at 12.0 ± 2.0 percentage injected dose per gram of tissue. Because the uptake of CRL-3-(99m)Tc by nonmalignant tissues was negligible and retention in the kidneys was only transient, we suggest that CRL-3-(99m)Tc may be a useful radioimaging agent for the detection, sizing, and monitoring of CCK2R-expressing tumors.