Supra-arcuate free fascial MS-TRAM, a modified technique to reduce donor site morbidity in obese population-comparative study.
Abdomen-based free flaps represent the gold standard option in the armamentarium of breast reconstruction. The natural evolution to more preservation with less invasive forms of these flaps has been driven by both patient and surgeon satisfaction. Nevertheless, obese patients are challenging due to the increased risk of compromised flap perfusion and donor site morbidity. This challenge is compounded by the prevalence of obesity worldwide, resulting in more free abdominal flaps being performed for breast reconstruction in obese patients. The authors present the outcomes of a modified supra-arcuate fascial muscle-sparing transverse rectus abdominus myocutaneous (FMS-TRAM) technique compared to standard muscle-sparing transverse rectus abdominus myocutaneous (MS-TRAM) technique to reduce the donor site morbidity while providing a well-vascularized large volume of autologous tissue. A retrospective comparative data analysis was conducted at two centers: Cairo University Hospitals, Egypt, and University Hospitals Birmingham, United Kingdom. Standard MS-TRAM was performed in 65 patients between 2008 and 2011 (Group 1) versus 275 patients between 2011 and 2020 (Group 2) who underwent FMS-TRAM. The modified technique involved limiting the fascial incision to above or at the level of the arcuate line to preserve the integrity of the anterior rectus sheath caudally. All patients included were of the obese population (BMI≥30 kg/m2 ) and underwent unilateral post-mastectomy reconstruction. Patient demographics, comorbidities, operative details, and outcomes focusing on donor site morbidity and flap complications were recorded and compared between the two groups. The median age and BMI for Group 1 were 43 and 32, respectively. While for Group 2, they were 47 and 33, respectively. Flap weight ranged from 560 to 1470 g (Mean 705) for Group 1, while Group 2 ranged from 510 to 1560 (mean 715). The majority (280/340 [82%]) of the patients in both groups received radiotherapy. 7.7% of Group 1 were smokers, while in Group 2 it was 4.7%. The percentage of delayed versus immediate reconstruction in Group 1 was 60%/40%, while in Group 2, it was 43%/56%. The incidence of fat necrosis, partial necrosis, and total necrosis was 7.6%.1.5%, and 3%, respectively, for Group 1 and 8%, 1.4%, and 2.6%, respectively, for Group 2. The two-tailed p-value demonstrated a significant statistical difference (p < 0.00001) in donor site morbidity between both groups, with more bulge 20% (13/65) and hernia 1.5% (2/65) occurrence in Group 1 versus 1.9% (5/275) and 0.7% (2/275) in Group 2 respectively, over a follow-up period ranging from 24 to 60 months (mean 32). FMS-TRAM flaps are safe, robust, and reliable with less donor site morbidity while maintaining optimal flap perfusion for large volume flaps in obese patients with excellent, durable outcomes. It should be considered a valuable tool in the reconstructive armamentarium of breast reconstruction.


Alexithymia, Suicide Ideation, C-Reactive Protein, and Serum Lipid Levels Among Outpatients with Generalized Anxiety Disorder.
The aim of the present study was to investigate the relationships between alexithymia, suicide ideation, C-Reactive Protein (CRP), and serum lipid levels in adult outpatients with a DSM-IV diagnosis of Generalized Anxiety Disorder (GAD). Seventy consecutive patients with GAD were recruited and evaluated. Measures were the Hamilton Anxiety Scale, the Toronto Alexithymia Scale (TAS-20), the Scale of Suicide Ideation (SSI), and the Montgomery Åsberg Depression Rating Scale (MADRS). All patients were assessed for: CRP, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglyceridaemia (TG), and very-low-density lipoprotein cholesterol (VLDL-C). TC/HDL-C and LDL-C/HDL-C ratios were also evaluated. Alexithymic patients showed higher scores on almost all rating scales and altered serum CRP and lipid levels vs. non-alexithymics. In the hierarchical regression model, the presence of higher MADRS scores together with higher scores at the Difficulty in Identifying Feelings dimension of TAS-20 were associated with higher rates of suicide ideation. Although alexithymic subjects with GAD may show a CRP and cholesterol dysregulation, this latter seems independent on increased suicide ideation, rather to Difficulty in Identifying Feelings, and subthreshold depressive symptoms. Study limitations and future research implications are discussed.


Cohort and age effects of mass drug administration on prevalence of trachoma: a longitudinal study in rural Tanzania.
Mass drug administration (MDA) is part of the SAFE strategy for trachoma elimination. This study examined the effect of three annual MDAs on prevalence of trachoma among 13 longitudinal cohorts of Tanzanian children. Children younger than 10 years were assigned to cohorts based on age at baseline and followed annually for 3 years, with newborns assigned to new cohorts over time. Annual MDA consisted of topical tetracycline for children younger than 6 months and oral azithromycin for those 6 months and older. Follicular trachoma (TF) and Chlamydia trachomatis infection status were assessed annually before the next MDA. Prevalence and risk factors for TF and infection at each age were compared across cohorts. At each survey, most age groups and cohorts had MDA coverage of more than 80% and showed decreased TF prevalence after every MDA. One cohort had consistently lower coverage, higher-than-expected TF and infection at ages 6 and 7, and elevated risk of TF at age 7 relative to the preceding cohort in spite of receiving one additional MDA (odds ratio 2.3, 95% confidence interval 1.0-5.2). Cohorts aged 1 or older at baseline generally showed reductions in TF and infection after each MDA, whereas younger cohorts showed decreased infection but increased TF over time. Successive cohorts of never-treated children younger than 1 year showed sequential TF and infection reductions with each MDA (P < 0.001). Multiple MDAs significantly reduce trachoma prevalence and appear to increasingly protect children born into these communities. The youngest children show declining/stable rates of infection but increasing rates of trachoma, which may reflect longer duration of clinical signs.


Drugs in upper respiratory tract infections in paediatric patients in North Trinidad.
We explored the prescribing patterns of physicians in North Trinidad in treating upper respiratory tract infections (URTI) in paediatric patients and the appropriateness of drugs prescribed. A retrospective observational study was conducted, with a sample size of 523 paediatric patients, diagnosed with an URTI during the period of June 2003 to 22 June 2005. The study was conducted at five Primary Health Care Facilities in North Trinidad. The three most frequent URTIs diagnosed were non-specific URTI, common cold, and acute tonsillitis in rank order. Four patterns of prescribing were identified, (1) no drug therapy [1.9%]; (2) antibiotic therapy alone [6.1%]; (3) antibiotic and symptomatic therapy [53.0%]; and (4) symptomatic therapy alone [39.0%]. The, most frequently prescribed antibiotics were penicillins (amoxicillin [46.3%] and amoxicillin/clavulanate [5.3%]) and a macrolide (erythromycin [6.1%]). The three symptomatic agents most frequently prescribed were paracetamol [40.1%]; diphenhydramine [29.1%]; and normal saline nasal drops [14.2%]. In 112 cases with swab analyses done, of these, 98.2% revealed a growth of commensals only, while 1.8% grew pathogenic micro-organisms. Of the cases showing commensal growth only, 84.6% were treated with an antibiotic, 14.5% were treated with symptomatic agents alone and 0.9% received no drug therapy at all. A large proportion of paediatric patients diagnosed with an URTI in North Trinidad was prescribed antibiotics although not indicated The inappropriate use of antibiotics can potentiate the worldwide trend of antimicrobial resistance.


Epilepsy in primary intracranial tumors in a neurosurgical hospital in Enugu, South-East Nigeria.
Seizures may be manifestation of intracranial tumor (IT) and demand thorough neurological evaluation. This paper examines epidemiology, lesion characteristics and outcome of seizures associated with primary IT. Retrospective analysis of medical records, computed tomography and magnetic resonance imaging of patients diagnosed with IT who presented with seizure from 2003 to 2013 at Memfys Hospital for Neurosurgery Enugu. Postoperative seizure outcome was based on Engel classification and correlated with tumor histology, patient age, anatomical location, time of presentation and extent of tumor resection. Data were analyzed using descriptive and inferential statistics. Sixty-two patients (34.6%) presenting with seizures were analyzed. Peak age at presentation was in 6 th decade. Age of seizure onset had bimodal peak at 4 th and 6 th decades. Apart from IT located in posterior fossa with mortality of 62.5%, postoperative mortality did not depend on anatomical location of tumor. Postoperative seizure outcome and mortality depend on tumor histology (P = 0.025) and preoperative seizure duration (P = 0.036). Seizure duration shorter than 1 month had poor postoperative seizure outcome and high mortality. Although more patients with meningioma experienced seizures compared to glioma (P = 0.025), there was no difference in proportion of patients with meningioma and glioma who presented with seizure (P = 1.00). Extent of resection predicts postoperative seizure outcome based on meningioma sub-group analysis. Overall, 59.7% of patients had good postoperative seizure outcome, 21.0% had poor outcome and 19.3% died. Seizures of short duration, IT located in posterior fossa and gliomas are associated with poor postoperative seizure outcome and high patient mortality. Tumor histology does not seem to affect seizure predisposition. Most seizures associated with IT occur in fifth and sixth decades of life and affect frontal lobe most often.


Academicians' awareness, attitude, and use of open access during the COVID-19 pandemic.
The aim of this research is to reveal academics' awareness, attitude, and use of open access. In line with the research purpose, the survey research design is adopted. This research consists 151 academics from 12 basic research areas; eight of them being Professor Dr, 17 being Associate Professor Dr, 49 being Doctor Lecturer, and 77 being Research Assistant or Lecturer. A questionnaire consisting of 19 open access and five demographic information questions was used for the data collection tool. The research results show that 75% of the academics have open access awareness and that their awareness is generally created by information that they obtain through the Internet and their friends. In addition, most of the academics indicate that their awareness of open access has increased during the pandemic period. When considering the level of academics' use of open access, it is found that 75% of the academics use articles in open access journals for their own research and 51% of the academics do not publish any articles in open access journals.


Depletion of poly(ADP-ribose) polymerase-1 reduces host cell reactivation of a UV-damaged adenovirus-encoded reporter gene in human dermal fibroblasts.
In response to ultraviolet radiation (UV), mammalian cells rapidly activate a nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP), and we recently showed that one of the causes for PARP-activation is UV-induced direct DNA photolesions which are repaired by nucleotide excision repair process (NER). To determine whether PARP can play a role in NER, we stably depleted PARP in NER-proficient human skin fibroblasts GM637 by DNA vector-based RNAi. In these cells, we examined host cell reactivation (HCR) of UVB or UVC-irradiated recombinant adenovirus AdCA35lacZ, encoding a beta-galactosidase (beta-gal) reporter gene. The depletion of PARP decreased the HCR of UVB- or UVC-damaged reporter gene to a similar extent, indicating the role of PARP in NER. Moreover, PARP-depletion reduced the HCR capacity of the NER-competent GM637 cells to a level closer to that in the XP-C and CS-B cell lines, which are deficient in the lesion recognition steps of the global genome repair (GGR) and transcription-coupled repair (TCR) sub-pathways of NER, respectively. In order to identify the potential role of PARP in these two sub-pathways of NER from that of its known role in base excision repair (BER) of UVB-induced oxidant damage, we depleted PARP from XP-C and CS-B cells and examined HCR of the reporter gene damaged by UVB, UVC or photoactivated methylene blue, the latter causing predominantly 8-oxo-2'-deoxyguanosine damage that is repaired by BER. Interestingly, a decreased HCR due to PARP-depletion was observed in both the NER-deficient cell lines in response to virus damaged by these three agents, albeit with different kinetics from 12 to 44h after infection. The role of PARP in NER was highlighted by a decreased clonogenic survival of UV-irradiated NER-competent GM637 cells depleted of PARP. Our results, while confirming the role of PARP in base excision repair, suggest a novel role of PARP in both the GGR and TCR sub-pathways of NER.


On the usefulness of animals as a model system (part I): Overview of criteria and focus on robustness.
Banning or reduction of the use of animals for laboratory experiments is a frequently-discussed societal and scientific issue. Moreover, the usefulness of animals needs to be considered in any decision process on the permission of specific animal studies. This complex issue is often simplified and generalized in the media around the question, "Are animals useful as a model?" To render an often emotional discussion about animal experimentation more rational, it is important to define "usefulness" in a structured and transparent way. To achieve such a goal, many sub-questions need to be asked, and the following aspects require clarification: (i) consistency of animal-derived data (robustness of the model system); (ii) scientific domain investigated (e.g., toxicology vs disease modelling vs therapy); (iii) measurement unit for "benefit" (inte-grating positive and negative aspects); (iv) benchmarking to alternatives; (v) definition of success criteria (how good is good enough); (vi) the procedure to assess benefit and necessity. This series of articles discusses the overall benchmarking process by specifying the six issues. The goal is to provide guidance on what needs to be clarified in scientific and political discussions. This framework should help in the future to structure available information, to identify and fill information gaps, and to arrive at rational decisions in various sub-fields of animal use. In part I of the series, we focus on the robustness of animal models. This describes the capacity of models to produce the same output/response when faced with the "same" input. Follow-up articles will cover the remaining usefulness aspects.


Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermogenic alteration.
Body weight gain is a worrying side effect of many new antipsychotic drugs. The mechanisms by which antipsychotic drugs increase weight in humans are not known. Attempts to model the metabolic effects of antipsychotic drugs in the animal have not been successful. Female rats appear to be sensitive to the effects of antipsychotics, but male rats less, and this does not match the clinical situation in humans. In previous rodent studies, antipsychotics were always given by daily gavage or injections. Antipsychotics have different pharmacokinetics in rodents and humans, and in the present study, we tested the hypothesis that the insensitivity of male rats to the effects of antipsychotics could be related to their mode of administration. Thus, we administered antipsychotic drugs mixed with the food. Animals were treated during 6 weeks with haloperidol (1mg/kg), olanzapine (1mg/kg), ziprasidone (10mg/kg), or a control solution. Animals were allowed to self-select food among three macronutrients (carbohydrates, lipids and proteins). Food selection was measured throughout the study. At the end of the study, body composition was measured by dissection and weighing of the rat's main organs and tissues. Mitochondrial thermogenesis was measured in brown adipose tissue in olanzapine-treated animals. Circulating leptin, insulin, glucose, triglycerides, cholesterol, high-density lipoprotein (HDL) were also assayed at the end of the study. The results show that none of the antipsychotic treatments modified caloric intake, food selection or body weight. Olanzapine did not alter mitochondrial thermogenesis. However, haloperidol and olanzapine induced a significant increase in adiposity and circulating leptin. Ziprasidone produced a moderate fat accumulation. It is concluded that mixing antipsychotic treatments with the food provides a reliable animal model of antipsychotic-induced fat accumulation.


In-vitro evaluation on drug release kinetics and antibacterial activity of dextran modified polyurethane fibrous membrane.
pH stimuli drug release nanofibrous membranes of polyurethane/dextran were developed for tailoring of antibacterial wound dressings. Incorporation of dextran in polyurethane (PU) showed increment in hydrophilicity, vapour transmission rate, percentage sorption values, and biodegradability. Dextran also acts as reinforcement filler in PU matrix. Dextran induces a high degree of platelet adhesion and hemostasis potential which is essential for promoting the wound healing process. Moreover, 20 wt% dextran loaded membranes (PU/20D) exhibited enhanced cell proliferation, attachment and viability against 3T3 fibroblasts. Curcumin loaded PU/20 dextran membrane exhibited pH-controlled drug release potency and synergistic antibacterial activity against gram-positive bacteria. It is confirmed that, PU/20D membranes could promote, pH-controlled drug release and synergistic antibacterial activity for a promising wound dressing material.


Season of birth is associated with first-lactation milk yield in Holstein Friesian cattle.
The aim of the present research was to assess factors associated with first-lactation milk yield in dairy heifers, including maternal and environmental factors, factors related to the development of the heifer and factors related to its offspring such as gender of the calf. In addition, the potential underlying mechanism, in particular metabolic adaptations, was further explored. Data on body growth, reproduction and milk yield of 74 Holstein Friesian heifers on three herds in Flanders (Belgium) were collected. At birth, body measurements of the heifers were recorded and blood samples were taken (in order) to determine basal glucose and insulin concentrations. Body measurements were assessed every 3 months until first calving, and gender and weight of their first calf were recorded. Information on fertility and milk yield of the heifer and its dam were collected from the herd databases. Daily temperature and photoperiod were recorded from the database of the Belgian Royal Meteorological Institute. Linear mixed models were run with herd as a random factor, to account for differences in herd management. Heifers grew 867±80.7 g/day during their first year of life and were inseminated at 14.8±1.34 months. First calving took place at 24.5±1.93 months, at a weight of 642±61.5 kg and heifers produced 8506±1064 kg energy corrected milk during their first 305-day lactation. Regression models revealed that none of the maternal factors such as milk yield and parity, nor the growth of the heifer during the 1st year of life were associated with milk yield during first lactation. Age, and to a lesser extent BW at first parturition were positively associated with first-lactation milk yield. In addition, the season of birth, but not calving, had a significant influence on milk yield, with winter-born heifers producing less than heifers born in any other season. The lower yielding winter-born heifers had higher insulin concentrations at birth, whereas glucose concentrations were similar, the latter being suggestive for lower insulin sensitivity of the peripheral tissues. Furthermore, environmental temperature at the end of gestation was negatively correlated with neonatal insulin concentrations. In conclusion, results of the present study suggest heifers born during the hotter months are born with a higher peripheral insulin sensitivity, finally leading to a higher first-lactation milk yield.


Effects of third ventricle injection of norepinephrine analogue on LH secretion of the non-laying SIJI goose.
The effect of norepinephrine analogue (NA) and norepinephrine antagonists on luteinizing hormone releasing hormone (LHRH) secretion in geese was investigated by monitoring serum levels of LH. Twenty non-laying geese were selected and randomly assigned to 4 groups of 5 each. The geese received a single intraventricular injection of saline (control), NA (12 microg/6 microl), phentolamine (1 microg/6l) plus NA or yohimbine (10 microg/6 microl). Phentolamine, a non-selective adrenoreceptor blocker was given 5 min before NA, but yohimbine, an alpha2-adrenoreceptor blocker, was delivered without NA injection. The results showed that serum levels of LH began to increase 20 min after injection of NA, and that high serum levels of LH were maintained until 105 min, followed by a decline to the basal level 125 min later. Significantly high levels of serum LH were observed at 50 and 105 min after the injection as compared with the respective control. Treatment with phentolamine completely blocked the stimulatory effect of NA on serum levels of LH in NA treated geese. Serum levels of LH increased by yohimbine treatment 5 min after the injection and the high levels of serum LH were maintained until 125 min later. Five out of 8 points were significantly high as compared with their respective control values. The present study also suggested that there is presynaptic modulation in the a-noradrenergic neural pathways which mediate the release of LHRH, and that this modulation may be carried out by alpha2-adrenoreceptor blocker.


Career plans for trainees in internal medicine residency programs.
Fewer medical students are pursuing residency training in primary care disciplines. This report describes the career plans of residents enrolled in internal medicine training programs and their reasons for pursuing either generalist or subspecialist career paths. From 1998 to 2003, questionnaires were administered to residents participating in the Internal Medicine In-Training Examination. Each year, the survey included questions on career choices. In 2002, residents completed a more detailed survey about the specific reasons for their career choices. The authors report their responses. There has been a steady decline in the percentage of internal medicine residents planning to pursue generalist careers. In 1998, 54% of PGY3s planned to practice general internal medicine compared with 27% in 2003. Strikingly, in 2003, only 19% of PGY1s planned to pursue careers in general medicine. Residents choosing careers as generalists were influenced by opportunities for long-term relationships with patients, a broad content area of practice, caring for ambulatory patients, and time with family. The specific reasons for choosing one subspecialty over another varied greatly among the subspecialty disciplines. Women residents preferred disciplines that allowed more time for family. Both genders were attracted to a particular subspecialty for similar reasons. There has been a dramatic decrease in the number of internal medicine residents planning to pursue careers in general medicine. This trend will likely continue for the next few years, at least, and may have an impact on the manner in which the health needs of patients are met in the future.


Personalized biomechanical insights in atrial fibrillation: opportunities & challenges.
Atrial fibrillation (AF) is an increasingly prevalent and significant worldwide health problem. Manifested as an irregular atrial electrophysiological activation, it is associated with many serious health complications. AF affects the biomechanical function of the heart as contraction follows the electrical activation, subsequently leading to reduced blood flow. The underlying mechanisms behind AF are not fully understood, but it is known that AF is highly correlated with the presence of atrial fibrosis, and with a manifold increase in risk of stroke. In this review, we focus on biomechanical aspects in atrial fibrillation, current and emerging use of clinical images, and personalized computational models. We also discuss how these can be used to provide patient-specific care. Understanding the connection betweenatrial fibrillation and atrial remodeling might lead to valuable understanding of stroke and heart failure pathophysiology. Established and emerging imaging modalities can bring us closer to this understanding, especially with continued advancements in processing accuracy, reproducibility, and clinical relevance of the associated technologies. Computational models of cardiac electromechanics can be used to glean additional insights on the roles of AF and remodeling in heart function.


Aureusidin ameliorates 6-OHDA-induced neurotoxicity via activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway in SH-SY5Y cells and Caenorhabditis elegans.
Movement disorder Parkinson's disease (PD) is the second most common neurodegenerative disease in the world after Alzheimer's disease, which severely affects the quality of patients' lives and imposes an increasingly heavy socioeconomic burden. Aureusidin is a kind of natural flavonoid compound with anti-inflammatory and anti-oxidant activities, while its pharmacological action and mechanism are rarely reported in PD. This study aimed to explore the neuroprotective effects and potential mechanisms of Aureusidin in PD. The present study demonstrated that Aureusidin protected SH-SY5Y cells from cell damage induced by 6-hydroxydopamine (6-OHDA) via inhibiting the mitochondria-dependent apoptosis and activating the Nrf2/HO-1 antioxidant signaling pathway. Additionally, Aureusidin diminished dopaminergic (DA) neuron degeneration induced by 6-OHDA and reduced the aggregation toxicity of α-synuclein (α-Syn) in Caenorhabditis elegans (C. elegans.) In conclusion, Aureusidin showed a neuroprotective effect in the 6-OHDA-induced PD model via activating Nrf2/HO-1 signaling pathway and prevented mitochondria-dependent apoptosis pathway, and these findings suggested that Aureusidin may be an effective drug for the treatment of PD.


Physiological adaptation along environmental gradients and replicated hybrid zone structure in swordtails (Teleostei: Xiphophorus).
Local adaptation is often invoked to explain hybrid zone structure, but empirical evidence of this is generally rare. Hybrid zones between two poeciliid fishes, Xiphophorus birchmanni and X. malinche, occur in multiple tributaries with independent replication of upstream-to-downstream gradients in morphology and allele frequencies. Ecological niche modelling revealed that temperature is a central predictive factor in the spatial distribution of pure parental species and their hybrids and explains spatial and temporal variation in the frequency of neutral genetic markers in hybrid populations. Among populations of parentals and hybrids, both thermal tolerance and heat-shock protein expression vary strongly, indicating that spatial and temporal structure is likely driven by adaptation to local thermal environments. Therefore, hybrid zone structure is strongly influenced by interspecific differences in physiological mechanisms for coping with the thermal environment.


Usefulness of aerobic microbial culture and cytologic evaluation of corneal specimens in the diagnosis of infectious ulcerative keratitis in animals.
To determine the diagnostic value of aerobic microbial culture and cytologic evaluation of corneal specimens in the diagnosis of infectious ulcerative keratitis (IUK). Prospective study. 48 animals (26 dogs, 13 horses, 7 cats, 1 bird, and 1 llama) with corneal ulcers. Scrapings from corneal ulcers were examined cytologically. Corneal swab specimens were submitted for microbial culture. Animals were grouped according to whether they had been receiving antimicrobials at the time of admission. Of the 38 animals receiving antimicrobials, 19 had positive results for IUK on cytologic evaluation, 20 on microbial culture, and 26 on cytologic evaluation, microbial culture, or both. Of the 10 animals not receiving antimicrobials at the time of admission, 7 had positive results for IUK on cytologic evaluation, and 9 had positive results on microbial culture. In this group of 10 animals, additional animals with IUK were not identified on the basis of cytologic evaluation alone. When all 48 animals were considered irrespective of antimicrobial treatment, 26 and 29 had positive results for IUK on cytologic evaluation and microbial culture, respectively, whereas IUK was confirmed in 35 animals on the basis of cytologic evaluation, microbial culture results, or both. Microbial culture and cytologic evaluation of corneal specimens maximizes identification of IUK, especially in animals receiving antimicrobial treatment. Because of serious consequences of untreated IUK, we recommend that both diagnostic tests be used to tailor treatment and reduce risk of vision impairment in animals.


Patient Attitudes Toward Individualized Recommendations to Stop Low-Value Colorectal Cancer Screening.
Guidelines for colorectal cancer (CRC) screening recommend an individualized approach in older adults that is informed by consideration of life expectancy and cancer risk. However, little is known about how patients perceive individualized screening recommendations. To assess veterans' attitudes toward and comfort with cessation of low-value CRC screening (defined as screening in a patient for whom the benefit is expected to be small based on quantitative estimates from hypothetical risk calculators). This survey study included patients older than 50 years who had undergone prior screening colonoscopy with normal results at the Veterans Affairs Ann Arbor Healthcare System. A total of 1500 surveys were mailed to potential participants from November 1, 2010, to January 1, 2012. Survey data were analyzed from January 1, 2016, to December 31, 2017. Response to the question, "If you personally had serious health problems that were likely to shorten your life and your doctor did not think screening would be of much benefit based on the calculator, how comfortable would you be with not getting any more screening colonoscopies?" Of the 1500 surveys mailed, 85 were returned to sender, leaving 1415 potential respondents; 1054 of these respondents (median age range, 60-69 years; 884 [85.9%] white and 965 [94.2%] male) completed the survey (response rate, 74.5%). A total of 300 (28.7%) were not at all comfortable with cessation of low-value CRC screening, and 509 (49.3%) thought that age should never be used to decide when to stop screening. In addition, 332 (31.7%) thought it was not at all reasonable to use life expectancy calculators, and 255 (24.3%) thought it was not at all reasonable to use CRC risk calculators to guide these decisions. In ordered logistic regression analysis, factors associated with more comfort with screening cessation were (1) higher trust in physician (odds ratio [OR], 1.19; 95% CI, 1.07-1.32), (2) higher perceived health status (OR, 1.41; 95% CI, 1.23-1.61), and (3) higher barriers to screening (OR, 1.20; 95% CI, 1.11-1.30). Factors that were associated with less comfort with screening cessation included (1) greater perceived effectiveness of screening (OR, 0.86; 95% CI, 0.80-0.94) and (2) greater perceived threat of CRC (OR, 0.81; 95% CI, 0.73-0.89). The findings suggest that many veterans have strong preferences against screening cessation even when given detailed information about why the benefit may be low. Efforts to tailor screening recommendations may be met by resistance unless they are accompanied by efforts to address underlying perceptions about the benefit of screening.


A Multifactorial Approach for Sarcopenia Assessment: A Literature Review.
Sarcopenia refers to a progressive and generalized weakness of skeletal muscle as individuals age. Sarcopenia usually occurs after the age of 60 years and is associated with a persistent decline in muscle strength, function, and quality. A comparison of the risk factors associated with sarcopenia based on the European Working Group on Sarcopenia (1 and 2) in Older People, the Asian Working Group for Sarcopenia (1 and 2), the International Working Group on Sarcopenia, and the Foundation for the National Institutes of Health revealed no consistent patterns. Accordingly, the identification of a single risk factor for sarcopenia is unpredictable due to its "multifactorial" pathogenesis, with the involvement of a multitude of factors. Therefore, the first aim of this review was to outline and propose that the multiple factors associated with sarcopenia need to be considered in combination in the design of new experimentation in this area. A secondary aim was to highlight the biochemical risk factors that are already identified in subjects with sarcopenia to assist scientists in understanding the biology of the pathophysiological mechanisms affecting the old people with sarcopenia. We also briefly discuss primary outcomes (physical) and secondary outcomes (social and financial) of sarcopenia. For future investigative purposes, this comprehensive review may be useful in considering important risk factors in the utilization of a panel of biomarkers emanating from all pathways involved in the pathogenesis of this disease. This may help to establish a uniform consensus for screening and defining this disease. Considering the COVID-19 pandemic, its impact may be exacerbated in older populations, which requires immediate attention. Here, we briefly suggest strategies for advancing the development of smart technologies to deliver exercise in the COVID-19 era in an attempt regress the onset of sarcopenia. These strategies may also have an impact on sarcopenia's primary and secondary outcomes.


[Removal of bisphenol A and tetrabromobisphenol A membrane by nanofiltration from water source].
The removal efficiency of BPA and TBBPA by nanofiltration membrane Desal 5 DK has been investigated with a lab-scale dead-end filtration module and the role of adsorption of two molecules on membrane was also explored to understand the filtration mechanism. The results showed that the R(obs) of BPA decreased from 89% to 47% as the accumulated adsorption quantity of BPA onto the membrane increased to 30 microg x m(-2). The high BPA concentration in adsorption layer caused the water flux decline especially at high pressure. The high TBBPA rejection of over 95% by Desal 5 DK was obtained due to the molecular weight and molecular structure although the accumulated adsorption quantity of TBBPA reached 50 microg x m(-2). The desorption test showed that the TBBPA could not pass through the membrane for its structure at the 5 x 10(5) Pa, while BPA could diffuse through the membrane and the peak concentration was obtained after 30 mL filtration. The quantity of BPA released from the membrane contributed 30% of the total amount adsorbed by the membrane Desal 5 DK.


Effects of magnetic doping on weak antilocalization in narrow Bi2Se3 nanoribbons.
We report low-temperature, magnetotransport measurements of ferrocene-doped Bi(2)Se(3) nanoribbons grown by vapor-liquid-solid method. The Kondo effect, a saturating resistance upturn at low temperatures, is observed in these ribbons to indicate presence of localized impurity spins. Magnetoconductances of the ferrocene-doped ribbons display both weak localization and weak antilocalization, which is in contrast with those of undoped ribbons that show only weak antilocalization. We show that the observed magnetoconductances are governed by a one-dimensional localization theory that includes spin orbit coupling and magnetic impurity scattering, yielding various scattering and dephasing lengths for Bi(2)Se(3). The power law decay of the dephasing length on temperature also reflects one-dimensional localization regime in these narrow Bi(2)Se(3) nanoribbons. The emergence of weak localization in ferrocene-doped Bi(2)Se(3) nanoribbons presents ferrocene as an effective magnetic dopant source.


Cortical neurons from intrauterine growth retardation rats exhibit lower response to neurotrophin BDNF.
Intrauterine growth retardation (IUGR) is putatively involved in the pathophysiology of schizophrenia. The animal model of IUGR induced by synthetic thromboxane A2 (TXA2) is useful to clarify the effect of IUGR on pups' brains, however, analysis at the cellular level is still needed. Brain-derived neurotrophic factor (BDNF), which plays a role in neuronal survival and synaptic plasticity in the central nervous system (CNS), may also be associated with schizophrenia. However, the possible relationship between IUGR and BDNF function remains unclear. Here, we examined how IUGR by TXA2 impacts BDNF function by using dissociated cortical neurons. We found that, although BDNF levels in cultured neurons from the cerebral cortex of low birth weight pups with IUGR were unchanged, TrkB (BDNF receptor) was decreased compared with control-rats. BDNF-stimulated MAPK/ERK1/2 and PI3K/Akt pathways, which are downstream intracellular signaling pathways of TrkB, were repressed in IUGR-rat cultures. Expression of glutamate receptors such as GluA1 and GluN2A was also suppressed in IUGR-rat cultures. Furthermore, in IUGR-rat cultures, anti-apoptotic protein Bcl2 was decreased and BDNF failed to prevent neurons from cell death caused by serum-deprivation. Taken together, IUGR resulted in reductions in cell viability and in synaptic function following TrkB down-regulation, which may play a role in schizophrenia-like behaviors.


Efficient calculation of the Gauss-Newton approximation of the Hessian matrix in neural networks.
The Levenberg-Marquardt (LM) learning algorithm is a popular algorithm for training neural networks; however, for large neural networks, it becomes prohibitively expensive in terms of running time and memory requirements. The most time-critical step of the algorithm is the calculation of the Gauss-Newton matrix, which is formed by multiplying two large Jacobian matrices together. We propose a method that uses backpropagation to reduce the time of this matrix-matrix multiplication. This reduces the overall asymptotic running time of the LM algorithm by a factor of the order of the number of output nodes in the neural network.


Static and dynamic autonomic response with increasing nausea perception.
Nausea is a commonly occurring symptom typified by epigastric discomfort with urge to vomit. The relationship between autonomic nervous system (ANS) outflow and increasing nausea perception is not fully understood. Our study employed a nauseogenic visual stimulus (horizontally translating stripes) while 17 female subjects freely rated transitions in nausea level and autonomic outflow was measured (heart rate, HR; heart rate variability, HRV; skin conductance response, SCR; respiratory rate). We also adopted a recent approach to continuous high-frequency (HF) HRV estimation to evaluate dynamic cardiovagal modulation. HR increased from baseline for all increasing nausea transitions, especially transition to strong nausea (15.0 +/- 11.4 bpm), but decreased (-6.6 +/- 4.6 bpm) once the visual stimulus ceased. SCR also increased for all increasing nausea transitions, especially transition to strong nausea (1.76 +/- 1.68 microS), but continued to increase (0.52 +/- 0.65 microS) once visual stimulation ceased. LF/HF HRV increased following transition to moderate (1.54 +/- 2.11 a.u.) and strong (2.57 +/- 3.49 a.u.) nausea, suggesting a sympathetic shift in sympathovagal balance. However, dynamic HF HRV suggested that bursts of cardiovagal modulation precede transitions to higher nausea, perhaps influencing subjects to rate higher levels of nausea. No significant change in respiration rate was found. Our results suggest that increasing nausea perception is associated with both increased sympathetic and decreased parasympathetic ANS modulation. These findings corroborate past ANS studies of nausea, applying perception-linked analyses and dynamic estimation of cardiovagal modulation in response to nausea.


FIZZ2/RELM-β induction and role in pulmonary fibrosis.
Found in inflammatory zone (FIZZ) 2, also known as resistin-like molecule (RELM)-β, belongs to a novel cysteine-rich secreted protein family named FIZZ/RELM. Its function is unclear, but a closely related family member, FIZZ1, has profibrotic activities. The human ortholog of rodent FIZZ1 has not been identified, but human FIZZ2 has significant sequence homology to both rodent FIZZ2 (59%) and FIZZ1 (50%). Given the greater homology to rodent FIZZ2, analyzing the role of FIZZ2 in a rodent model of bleomycin-induced pulmonary fibrosis would be of greater potential relevance to human fibrotic lung disease. The results showed that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines, which was mediated via STAT6 signaling. The FIZZ2 induction in murine lungs was found to be essential for pulmonary fibrosis, as FIZZ2 deficiency significantly suppressed pulmonary fibrosis and associated enhanced extracellular matrix and cytokine gene expression. In vitro analysis indicated that FIZZ2 could stimulate type I collagen and α-smooth muscle actin expression in lung fibroblasts. Furthermore, FIZZ2 was shown to have chemoattractant activity for bone marrow (BM) cells, especially BM-derived CD11c(+) dendritic cells. Notably, lung recruitment of BM-derived cells was impaired in FIZZ2 knockout mice. These findings suggest that FIZZ2 is a Th2-associated multifunctional mediator with potentially important roles in the pathogenesis of fibrotic lung diseases.


[To proliferation of mesangial cells in ontogenesis].
The article presents a review of the literature on the modern mechanisms of proliferation of mesangial cells, which underlie the development of proliferative forms of glomerulonephritis: the role of cytokines, growth factors, PIP-complex and vasoconstrictive factors.


Kinetic probes for inter-domain co-operation in human somatic angiotensin-converting enzyme.
s-ACE (the somatic form of angiotensin-converting enzyme) consists of two homologous domains (N- and C-domains), each bearing a catalytic site. Negative co-operativity between the two domains has been demonstrated for cow and pig ACEs. However, for the human enzyme there are conflicting reports in the literature: some suggest possible negative co-operativity between the domains, whereas others indicate independent functions of the domains within s-ACE. We demonstrate here that a 1:1 stoichiometry for the binding of the common ACE inhibitors, captopril and lisinopril, to human s-ACE is enough to abolish enzymatic activity towards FA {N-[3-(2-furyl)acryloyl]}-Phe-GlyGly, Cbz (benzyloxycarbonyl)-Phe-His-Leu or Hip (N-benzoylglycyl)-His-Leu. The kinetic parameters for the hydrolysis of seven tripeptide substrates by human s-ACE appeared to represent average values for parameters obtained for the individual N- and C-domains. Kinetic analysis of the simultaneous hydrolysis of two substrates, Hip-His-Leu (S1) and Cbz-Phe-His-Leu (S2), with a common product (His-Leu) by s-ACE at different values for the ratio of the initial concentrations of these substrates (i.e. sigma=[S2]0/[S1]0) demonstrated competition of these substrates for binding to the s-ACE molecule, i.e. binding of a substrate at one active site makes the other site unavailable for either the same or a different substrate. Thus the two domains within human s-ACE exhibit strong negative co-operativity upon binding of common inhibitors and in the hydrolysis reactions of tripeptide substrates.


[Nervous-mental health of children who had perinatal damage of the nervous system].
The paper presents the results of somatic, neurologic and neurophysiologic examination of 614 children which had hypoxic-ischemic encephalopathy of a moderate degree during the period from the birth till 3 years old. A period of gestation was characterised by some signs of fetoplacental insufficiency in 44.3% of children. Disorders in labor activity were revealed in 83.7% of mothers. Delay in nervous-mental development (77.3%), deviations in forming rhythmic EEG activity (75%), signs of morphologic immaturity of brain (38.8%) testified to inhibition of postnatal neuroontogenesis. All that together with high frequency of motor disorders (73.3%) and disorders in cerebral blood flow (43.8%) during the 1-st year of life were found to underlie development of psychoneurologic diseases in children of early age and necessitates early rehabilitation of these children.


Specialized science.
As the body of scientific knowledge in a discipline increases, there is pressure for specialization. Fields spawn subfields that then become entities in themselves that promote further specialization. The process by which scientists join specialized groups has remarkable similarities to the guild system of the middle ages. The advantages of specialization of science include efficiency, the establishment of normative standards, and the potential for greater rigor in experimental research. However, specialization also carries risks of monopoly, monotony, and isolation. The current tendency to judge scientific work by the impact factor of the journal in which it is published may have roots in overspecialization, as scientists are less able to critically evaluate work outside their field than before. Scientists in particular define themselves through group identity and adopt practices that conform to the expectations and dynamics of such groups. As part of our continuing analysis of issues confronting contemporary science, we analyze the emergence and consequences of specialization in science, with a particular emphasis on microbiology, a field highly vulnerable to balkanization along microbial phylogenetic boundaries, and suggest that specialization carries significant costs. We propose measures to mitigate the detrimental effects of scientific specialism.


Effect of a major histocompatibility complex class I peptide on insulin-like growth factor-I receptor internalization and biological signaling.
Previous studies have shown that a peptide derived from the murine major histocompatibility complex class 1 (MHC-1) antigen inhibits insulin receptor internalization and enhances insulin action. Consequently, we have studied the effect of this peptide [Dk-(62-85)] derived from the MHC-1 antigen on insulin-like growth factor-I (IGF-I) internalization and action. When Chinese hamster ovary cells that overexpress human IGF-I receptors were incubated in the presence or absence of 30 microM Dk-(62-85), IGF-I internalization was inhibited by 43.9 +/- 1.7% (P < 0.005). This inhibitory effect was dose responsive, with a half-maximal effect at 8 microM and a maximal effect at 30 microM. The peptide did not affect IGF-I receptor autophosphorylation or ligand-induced phosphorylation of an endogenous substrate, pp185, in vivo. When added alone, the peptide increased glucose transport into Chinese hamster ovary cells by 66.3 +/- 16.0%, whereas when the peptide was added together with IGF-I, ligand-stimulated glucose transport was inhibited. In conclusion, 1) the MHC-1-derived peptide Dk-(62-85) inhibits IGF-I internalization in a dose-responsive fashion; 2) Dk-(62-85) does not affect receptor kinase activity, as IGF-I receptor autophosphorylation and endogenous substrate phosphorylation are unaltered; and 3) Dk-(62-85) stimulates glucose transport by itself, but inhibits IGF-I stimulated transport.


Determinants of the longevity of socially learned food preferences of Norway rats.
We conducted three experiments to examine variables that might influence the longevity of socially induced food preferences in Norway rats. The duration of social influence on the food choices of 42-day-old rats (1) increased with both increasing numbers of demonstrators and increasing numbers of demonstrations by a single demonstrator, (2) varied with the temporal distribution of demonstrations, but (3) did not vary with the age of demonstrators. The results suggest that a single episode of social learning produces short-term, but not long-term, effects on a Norway rat's food choices. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.


Construction and characterization of type II collagen complementary deoxyribonucleic acid clones.
The mRNA for type II collagen was purified from embryonic chick sternum or from purified sternal chondrocytes with guanidine thiocyanate as the extractant. Double-stranded cDNAs to procollagen mRNAs from sternum were synthesized and dC-tailed. After annealing with PstI-cleaved, dG-tailed pBR322, this DNA was used to transform Escherichia coli X1776. Transformed colonies were screened by colony hybridization to type I and II collagen cDNAs. Clones that preferentially hybridized to type II cDNA were characterized further. Four such cDNA clones, pCgII-2, 3, 10 and 12, with inserts of 400, 320, 260 and 750 bp, have been identified as type II collagen cDNA clones by several criteria, including their preference for hybridizing with type II rather than type I collagen mRNAs in hybrid-selected translation experiments.


First-in-Man Trial of SiO2 Inert-Coated Bare Metal Stent System in Native Coronary Stenosis - The AXETIS FIM Trial.
A novel bare metal stent with an SiO2coating was developed to prevent excessive neointimal hyperplasia by inertization of the metallic stent surface. The efficacy of the device was demonstrated in a preclinical model. The aim of this first-in-man trial was to assess the safety and feasibility of the new device.Methods and Results:This prospective non-randomized single-arm trial was designed to enroll 35 patients with a de novo coronary lesion. Quantitative coronary angiography and optical coherence tomography (OCT) were performed at the baseline procedure and at the 6-month follow-up. Stent implantation was performed with OCT guidance according to optimal stent implantation criteria. The trial was terminated upon the advice of the data safety monitoring board after enrolling 14 patients due to the high incidence of re-intervention. Optimal OCT implantation criteria were achieved in only 8.3% of lesions. At 6 months, angiographic in-stent late lumen loss as the primary endpoint was 0.77±0.44 mm, and binary restenosis occurred in 33.3% of lesions. At the 6-month OCT, neointimal volume obstruction was 32.8±15.6% with a neointimal thickness of 237±117 µm. At 12 months, the device-oriented composite endpoint (defined as cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization rate) was 33.3%. In contrast with the preclinical study, the Axetis stent did not efficiently suppress neointimal hyperplasia in humans in this trial.


Perceived knowledge and training needs in adolescent pregnancy prevention: results from a multidisciplinary survey.
To examine health care professionals' knowledge and interest in training in adolescent pregnancy prevention and whether an association exists between perceived knowledge and interest in training. A cross-sectional mailed survey. Random, stratified sample design that identified 800 psychologists, 800 social workers, 1,000 nurses, and 400 pediatricians from national professional membership lists. Response rate to the mailed survey was 51%. After removing respondents who did not currently work with adolescents, 1,242 surveys (41%) were available for analyses. Descriptive analyses were conducted on self-report data concerning perceived knowledge and interest in training about adolescent pregnancy prevention separately for each of the 4 disciplines. Within disciplines, perceived knowledge and interest in training were correlated for each of 3 content areas (ie, sex education and contraceptive counseling, adolescent pregnancy, and counseling after a negative pregnancy test) and for a summary measure of the content areas. Less than half of the nursing, pediatrics, psychology, and social work professionals reported high perceived knowledge in the 3 content areas. Psychologists and social workers reported the lowest perceived knowledge. However, with the exception of psychologists, more than two thirds of the other respondents reported moderate or high interest in training in the 3 content areas. Interest in training was not strongly correlated with perceived knowledge within any discipline. The need to integrate psychosocial components into adolescent health care is a core assumption in the field, yet these data indicate that psychologists and social workers perceive low levels of knowledge and interest in training. These disciplines may benefit from more targeted professional training about their role in preventing adolescent pregnancy.


Hierarchy of stroma-derived factors in supporting growth of stroma-dependent hemopoietic cells: membrane-bound SCF is sufficient to confer stroma competence to epithelial cells.
Hemopoiesis takes place in a microenvironment where hemopoietic cells are closely associated with stroma by various interactions. Stroma coregulates the proliferation and differentiation of hemopoietic cells. Stroma-hemopoietic-cell contact can be supported by locally produced membrane associated growth factors. The stroma derived growth factor, stem cell factor (SCF) is important in hemopoiesis. We examined the different biological interactions of membrane bound and soluble SCF with human hemopoietic cells expressing the SCF receptor, c-kit. To analyze the function of the SCF isoforms in inducing the proliferation of hemopoietic TF1 or Cord blood (CB) CD34+ cells we used stroma cell lines that differ in their presentation of no SCF, membrane SCF, or soluble SCF. We established a new coculture system using an epithelial cell line that excludes potential interfering effects with other known stroma encoded hemopoietic growth factors. We show that soluble SCF, in absence of membrane-bound SCF, inhibits long term clonal growth of primary or established CD34+ hemopoietic cells, whereas membrane-inserted SCF "dominantly" induces long term proliferation of these cells. We demonstrate a hierarchy of these SCF isoforms in the interaction of stroma with hemopoietic TF1 cells. Membrane-bound SCF is "dominant" over soluble SCF, whereas soluble SCF acts epistatically in interacting with hemopoietic cells compared with other stroma derived factors present in SCF deficient stroma. A hierarchy of stroma cell lines can be arranged according to their presentation of membrane SCF or soluble SCF. In our model system, membrane-bound SCF expression is sufficient to confer stroma properties to an epithelial cell line but soluble SCF does not.


Efficacy and Safety of Endoscopic Full-Thickness Resection in the Colorectum: Results From the German Colonic FTRD Registry.
Endoscopic full-thickness resection (EFTR) is a powerful option for resection of colorectal lesions not amenable to conventional endoscopic resection. The full-thickness resection device (FTRD) allows clip-assisted EFTR with a single-step technique. We report on results of a large nationwide FTRD registry. The "German colonic FTRD registry" was created to further assess efficacy and safety of the FTRD System after approval in Europe. Data were analyzed retrospectively. Sixty-five centers contributed 1,178 colorectal FTRD procedures. Indications for EFTR were difficult adenomas (67.1%), early carcinomas (18.4%), subepithelial tumors (6.8%), and diagnostic EFTR (1.3%). Mean lesion size was 15 × 15 mm and most lesions were pretreated endoscopically (54.1%). Technical success was 88.2% and R0 resection was achieved in 80.0%. R0 resection was significantly higher for subepithelial tumor compared with that for other lesions. No difference in R0 resection was found for smaller vs larger lesions or for colonic vs rectal procedures. Adverse events occurred in 12.1% (3.1% major events and 2.0% required surgical treatment). Endoscopic follow-up was available in 58.0% and showed residual/recurrent lesions in 13.5%, which could be managed endoscopically in most cases (77.2%). To date, this is the largest study of colorectal EFTR using the FTRD System. The study demonstrated favorable efficacy and safety for "difficult-to-resect" colorectal lesions and confirms results of previous studies in a large "real-world" setting. Further studies are needed to compare EFTR with other advanced resection techniques and evaluate long-term outcome.


Testing the hospital value proposition: an empirical analysis of efficiency and quality.
To assess the relationship between hospitals' X-inefficiency levels and overall care quality based on the National Quality Forum's 27 safe practices score and to improve the analytic strategy for assessing X-inefficiency. The 2005 versions of the American Hospital Association and Leapfrog Group's annual surveys were the basis of the study. Additional case mix indices and market variables were drawn from the Centers for Medicare and Medicaid Services data sources and the Area Resource File. Data envelopment analysis was used to determine hospitals' X-inefficiency scores relative to their market-level competitors. Regression was used to assess the relationship between X-inefficiency and quality, controlling for organizational and market characteristics. Expenses (total and labor expenditures), case-mix-adjusted admissions, length of stay, and licensed beds defined the X-inefficiency function. The overall National Quality Forum's safe practice score, health maintenance organization penetration, market share, and teaching status served as independent control variables in the regression. The National Quality Forum's safe practice scores are significantly and positively correlated to hospital X-inefficiency levels (beta = .105, p < or = .05). The analysis of the value proposition had very good explanatory power (adjusted R(2) = .414; p < or = .001; df = 7, 265). Contrary to earlier findings, health maintenance organization penetration and being a teaching hospital were positively related to X-inefficiency. Similar with others' findings, greater market share and for-profit ownership were negatively associated with X-inefficiency. Measurement of overall hospital quality is improving but can still be made better. Nevertheless, the National Quality Forum's measure is significantly related to efficiency and could be used to create differential pay-for-performance programs. A market-segmented analytic strategy for studying hospitals' efficiency yields results with a high degree of explanatory power.


The aetiological relationship between herpes simplex virus type 2 and carcinoma of the cervix: an unanswered or unanswerable question?
After two decades of investigation the proposed aetiological link between herpes simplex virus type 2 (HSV2) and human carcinoma of the cervix remains unproved. The initial seroepidemiological studies, which were of a retrospective nature, were in favour of the aetiological relationship, whereas the more recent prospective studies suggest that HSV infection is a co-variable. The detection of HSV genes and their products in tumour tissues has been plagued by problems of cross reactivity, but the most recent results indicate that while HSV2 DNA can be detected in a small proportion of cancer tissues, HSV proteins or tumour antigens probably do not persist in the tumours. The same situation applies with respect to in vitro transformation. Although HSV, and isolated DNA fragments from the viral genome, can transform tissue culture cells (mainly of rodent origin) and under some conditions can cause cervical abnormalities (including cancer) in experimental animals, in no instance need the viral genes be maintained in the transformed cells. A number of mechanisms, including viral mutagenesis, have been proposed to explain this unusual feature, but the relevance of this work to the induction of human cervical carcinoma by HSV2 in vivo may be difficult to prove.


The Society of Thoracic Surgeons expert consensus for the surgical treatment of hyperhidrosis.
Significant controversies surround the optimal treatment of primary hyperhidrosis of the hands, axillae, feet, and face. The world's literature on hyperhidrosis from 1991 to 2009 was obtained through PubMed. There were 1,097 published articles, of which 102 were clinical trials. Twelve were randomized clinical trials and 90 were nonrandomized comparative studies. After review and discussion by task force members of The Society of Thoracic Surgeons' General Thoracic Workforce, expert consensus was reached from which specific treatment strategies are suggested. These studies suggest that primary hyperhidrosis of the extremities, axillae or face is best treated by endoscopic thoracic sympathectomy (ETS). Interruption of the sympathetic chain can be achieved either by electrocautery or clipping. An international nomenclature should be adopted that refers to the rib levels (R) instead of the vertebral level at which the nerve is interrupted, and how the chain is interrupted, along with systematic pre and postoperative assessments of sweating pattern, intensity and quality-of-life. The recent body of literature suggests that the highest success rates occur when interruption is performed at the top of R3 or the top of R4 for palmar-only hyperhidrosis. R4 may offer a lower incidence of compensatory hyperhidrosis but moister hands. For palmar and axillary, palmar, axillary and pedal and for axillary-only hyperhidrosis interruptions at R4 and R5 are recommended. The top of R3 is best for craniofacial hyperhidrosis.


Autoimmune phenomena and hepatitis C virus in lymphoproliferative and connective tissue disorders.
Since hepatitis C virus (HCV) infection is frequently detected in patients with lymphoproliferative or autoimmune disorders and since the virus may infect lymphocytes, the question is raised whether malignant transformation and autoimmune manifestations in the presence of HCV are HCV-related or merely fortuitous. A close association has been firmly established between HCV infection and essential type II mixed cryoglobulinemia (ECM), an indolent lymphoproliferative disorder characterized by cryoprecipitable immune-complexes (IC) that may evolve into classical non Hodgkin's lymphomas (NHL) retaining the ability to produce cryoprecipitable rheumatoid factor (RF). It is reasonable to consider HCV as one cofactor in lymphomagenesis, even if the precise pathogenetic relationship between HCV infection, the chronic presence of cryoprecipitable IC and the development of NHL have not been established yet. Several epidemiological studies have documented the ability of chronic HCV infection to favour the production of autoAb. It is not clear why only some patients with HCV infection develop autoAb, nor why the most frequent autoAb detected in HCV-infected subjects are cryoglobulins. Though a high prevalence of anti-HCV has been found in a variety of systemic and organ-specific autoimmune diseases, it is likely that several of these associations are fortuitous with the notable exception of membranoproliferative glomerulonephritis. As HCV can provoke or exacerbate inflammatory signs and cause the production of RF, it is reasonable to suspect that HCV infection may be able to trigger the development of some connective tissue diseases or to exacerbate their clinical course. Nonetheless, it is clinically prudent to conclude that the pathogenetic relationships of Sjögren syndrome, rheumatoid arthritis and polyarthritis with HCV infection are more likely to be regarded as mediated via the intermediate development of ECM.


Oral contraceptives and breast neoplasia: a retrospective study.
Between 1 December 1968 and 31 December 1971 345 women aged 16-39 years with a lump in the breast (90 malignant and 255 benign) were interviewed at five London teaching hospitals together with 347 matched controls suffering from acute medical or surgical conditions or admitted to hospital for routine elective surgery. Questions were asked about each patient's medical, obstetric, menstrual, contraceptive, and social histories.The data do not suggest that the use of oral contraceptives is related in any way to the risk of breast cancer but provide some evidence that the preparations may actually protect against benign breast disease. This protective effect is largely confined to women who continue to use oral contraceptives and have used them altogether for more than two years. Such women appear to have only about 25% as great a risk of being admitted to hospital for a breast biopsy as women who have never used oral contraceptives at all.


Effects of information about group members on young children's attitudes towards the in-group and out-group.
Research shows that being a member of a group is sufficient to instigate more positive attitudes towards the in-group than an out-group in young children. The present study assessed whether children's intergroup attitudes during the middle childhood years are moderated by additional information about in-group and out-group members, as proposed by Aboud's (1988) socio-cognitive theory (ST). To a minimal group 6-, 8-, and 10-year-old children (N = 159) were assigned, and received information, or no information, about the interests and activities of the in-group and out-group members. Results indicated that the in-group was always rated more positively than the out-group, and that the in-group's ratings were unaffected by either the in-group or out-group information. In contrast, out-group ratings were affected by out-group information, but only when there was no information available about the in-group. The implications of the findings for ST, and for social identity development theory, are discussed.


Harnessing the Promise of Moral Distress: A Call for Re-Orientation.
Despite over three decades of research into the sources and costs of what has become an "epidemic" of moral distress among healthcare professionals, spanning many clinical disciplines and roles, there has been little significant progress in effectively addressing moral distress. We believe the persistent sense of frustration, helplessness, and despair still dominating the clinical moral distress narrative signals a need for re-orientation in the way moral distress is understood and worked with. Most fundamentally, moral distress reveals moral investment and energy. It is the troubled call of conscience, an expression of fidelity to moral commitments seen as imperiled or compromised. It is crucial that we find ways to empower clinicians in heeding this call-to support clinicians' moral agency and voice, foster their moral resilience, and facilitate their ability to contribute to needed reform within the organizations and systems in which they work. These objectives must inform creative expansion in the design of strategies for addressing moral distress in the day-to-day of clinical practice. We include suggestions about promising directions such strategies might take in the hope of spurring further innovation within clinical environments.


NaV channel variants in patients with painful and nonpainful peripheral neuropathy.
To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy. Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful). We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (≤3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations. These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease "mutations," are more important for the development of painful neuropathy than previously discussed.


[Aminooxypropylamine--an effective inhibitor of ornithine decarboxylase in vitro and in vivo].
Hydroxylamine-containing analogues of putrescine and cadaverine have been found effective in inhibiting the mouse liver ornithine decarboxylase, the best among synthesized were 1-aminooxy-3-aminopropane (I50 2.10(-8) M) and 1-aminooxy-4-aminobutane (I50 2.10(-7) M). The inhibitory effect of these substances on the mouse liver ornithine-transaminase and S-adenosylmethionine decarboxylase from E. coli was displayed at concentrations higher by several orders of magnitude, that demonstrated the specificity of the compounds of this type. 1-Aminooxy-3-aminopropane in experiments in vivo suppressed the ornithine decarboxylase activity in mouse liver at 16 mg/kg by 75%, the toxic effect being insignificant.


Mouse model to study the replication of primate foamy viruses.
A mouse model was developed to study the virus-host interaction of molecularly cloned human foamy virus (HFV) in vivo. The infectious process was analysed in two mouse strains, CBA/Ca and C57BL/6J, over a period of 24 weeks by PCR on DNAs from various animal tissues; virus serology was examined by immunoblotting. The infection persisted in both mouse strains and did not induce clinical symptoms. Upon infection of adult CBA/Ca mice HFV became detectable by PCR in an increasing number of organs over time. In contrast, in C57BL/6J mice, after an initial phase of dissemination, viral DNA sequences were found only in a few organs. Interestingly, the different course of infection was accompanied by differences in the antiviral immune response. In particular, C57BL/6J mice were high responders with respect to antibodies to the viral Bet protein, while CBA/Ca mice were low responders.


Electrochemically addressable nanofluidic devices based on PET nanochannels modified with electropolymerized poly-o-aminophenol films.
Nanofluidic field-effect transistors (nFETs) have attracted attention from the scientific community due to their remarkable level of control over ionic transport. Particularly, the combination of nanofluidic systems and electroactive polymers has demonstrated to be an interesting approach to achieve an electrochemically addressable device. In this work, the development of nFETs based on the integration of electropolymerized poly-o-aminophenol (POAP) films into track-etched nanochannels is proposed. The electropolymerization of POAP on the tip side of Au-sputtered asymmetric PET nanochannels not only allowed having a programmable tip diameter but also offered a precise and very rapid control of ionic transport by switching an external bias voltage. Moreover, the system exhibited a reversible behaviour between non-selective and anion-selective states. We believe that this work provides new tools and concepts to design and build high-performance nanofluidic field-effect transistors working under electrochemically controlled conditions.


Prediction of digestible and metabolizable energy content and standardized ileal amino Acid digestibility in wheat shorts and red dog for growing pigs.
Two experiments were conducted to evaluate the effects of chemical composition of wheat shorts and red dog on energy and amino acid digestibility in growing pigs and to establish prediction models to estimate their digestible (DE) and metabolizable (ME) energy content and as well as their standardized ileal digestible (SID) amino acid content. For Exp. 1, sixteen diets were fed to thirty-two growing pigs according to a completely randomized design during three successive periods. The basal diet was based on corn and soybean meal while the other fifteen diets contained 28.8% wheat shorts (N = 7) or red dog (N = 8), added at the expense of corn and soybean meal. Over the three periods, each diet was fed to six pigs with each diet being fed to two pigs during each period. The apparent total tract digestibility (ATTD) of energy in wheat shorts and red dog averaged 75.1 and 87.9%. The DE values of wheat shorts and red dog averaged 13.8 MJ/kg (range 13.1 to 15.0 MJ/kg) and 15.1 MJ/kg (range 13.3 to 16.6 MJ/kg) of dry matter, respectively. For Exp. 2, twelve growing pigs were allotted to two 6×6 Latin Square Designs with six periods. Ten of the diets were formulated based on 60% wheat shorts or red dog and the remaining two diets were nitrogen-free diets based on cornstarch and sucrose. Chromic oxide (0.3%) was used as an indigestible marker in all diets. There were no differences (p>0.05) in SID values for the amino acids in wheat shorts and red dog except for lysine and methionine. Apparent ileal digestibility (AID) and SID values for lysine in different sources of wheat shorts or red dog, which averaged 78.1 and 87.8%, showed more variation than either methionine or tryptophan. A stepwise regression was performed to establish DE, ME and amino acid digestibility prediction models. Data indicated that fiber content and amino acid concentrations were good indicators to predict energy values and amino acid digestibility, respectively. The present study confirms the large variation in the energy content and amino acid digestibility in wheat shorts and red dog, and describes the factors that influence this variation and presents equations based on chemical composition that could probably be used to predict the DE and ME values as well as the amino acid digestibility of wheat shorts and red dog.


Standards for the Use of Enteral Nutrition in Patients with Diabetes or Stress Hyperglycaemia: Expert Consensus.
(1) Background: Hyperglycaemia that occurs during enteral nutrition (EN) should be prevented and treated appropriately since it can have important consequences for morbidity and mortality. However, there are few quality studies in the literature regarding the management of EN in this situation. The objective of this project was to attempt to respond, through a panel of experts, to those clinical problems regarding EN in patients with diabetes or stress hyperglycaemia (hereinafter referred to only as hyperglycaemia) for which we do not have conclusive scientific evidence; (2) Methods: The RAND/UCLA Appropriateness Method, a modified Delphi panel method, was applied. A panel of experts made up of 10 clinical nutrition specialists was formed, and they scored on the appropriateness of EN in hyperglycaemia, doing so in two rounds. A total of 2992 clinical scenarios were examined, which were stratified into five chapters: type of formula used, method of administration, infusion site, treatment of diabetes, and gastrointestinal complications. (3) Results: consensus was detected in 36.4% of the clinical scenarios presented, of which 23.7% were deemed appropriate scenarios, while 12.7% were deemed inappropriate. The remaining 63.6% of the scenarios were classified as uncertain; (4) Conclusions: The recommendations extracted will be useful for improving the clinical management of these patients. However, there are still many uncertain scenarios reflecting that the criteria for the management of EN in hyperglycaemia are not completely standardised. More studies are required to provide quality recommendations in this area.


Mechanisms Underlying Aggressive Behavior Induced by Antiepileptic Drugs: Focus on Topiramate, Levetiracetam, and Perampanel.
Antiepileptic drugs (AEDs) are effective against seizures, but their use is often limited by adverse effects, among them psychiatric and behavioral ones including aggressive behavior (AB). Knowledge of the incidence, risk factors, and the underlying mechanisms of AB induced by AEDs may help to facilitate management and reduce the risk of such side effects. The exact incidence of AB as an adverse effect of AEDs is difficult to estimate, but frequencies up to 16% have been reported. Primarily, levetiracetam (LEV), perampanel (PER), and topiramate (TPM), which have diverse mechanisms of action, have been associated with AB. Currently, there is no evidence for a specific pharmacological mechanism solely explaining the increased incidence of AB with LEV, PER, and TPM. Serotonin (5-HT) and GABA, and particularly glutamate (via the AMPA receptor), seem to play key roles. Other mechanisms involve hormones, epigenetics, and "alternative psychosis" and related phenomena. Increased individual susceptibility due to an underlying neurological and/or a mental health disorder may further explain why people with epilepsy are at an increased risk of AB when using AEDs. Remarkably, AB may occur with a delay of weeks or months after start of treatment. Information to patients, relatives, and caregivers, as well as sufficient clinical follow-up, is crucial, and there is a need for further research to understand the complex relationship between AED mechanisms of action and the induction/worsening of AB.


The PIR-International Protein Sequence Database.
The Protein Information Resource (PIR; http://www-nbrf.georgetown. edu/pir/) supports research on molecular evolution, functional genomics, and computational biology by maintaining a comprehensive, non-redundant, well-organized and freely available protein sequence database. Since 1988 the database has been maintained collaboratively by PIR-International, an international association of data collection centers cooperating to develop this resource during a period of explosive growth in new sequence data and new computer technologies. The PIR Protein Sequence Database entries are classified into superfamilies, families and homology domains, for which sequence alignments are available. Full-scale family classification supports comparative genomics research, aids sequence annotation, assists database organization and improves database integrity. The PIR WWW server supports direct on-line sequence similarity searches, information retrieval, and knowledge discovery by providing the Protein Sequence Database and other supplementary databases. Sequence entries are extensively cross-referenced and hypertext-linked to major nucleic acid, literature, genome, structure, sequence alignment and family databases. The weekly release of the Protein Sequence Database can be accessed through the PIR Web site. The quarterly release of the database is freely available from our anonymous FTP server and is also available on CD-ROM with the accompanying ATLAS database search program.


A new species of Tinrovia Mamaev, 1987 (Monogenea: Microcotylidae) from the deep-sea fish Notacanthus bonaparte Risso (Notacanthiformes: Notacanthidae) in the Western Mediterranean and the North East Atlantic.
A new microcotylid, Tinrovia mamaevi n. sp. (Monogenea: Polyopisthocotylea), is described from the gills of Notacanthus bonaparte Risso (Notacanthiformes: Notacanthidae), sampled in the Western Mediterranean and North East Atlantic. This species is allocated to the subfamily Syncoelicotylinae Mamaev & Zubchenko, 1978 due to the possession of a symmetrical haptor with two separate frills. The clamps in T. mamaevi n. sp. are of the "microcotylid" type, arranged in two distinct lateral haptoral frills; the genital atrium and the copulatory organ are armed and the vaginal pore is unarmed. The new species differs from the type- and only species of the genus, T. papiliocauda Mamaev, 1987, in having a shorter and narrower haptor with a smaller number of clamps. Clamps are also smaller in the new species, testes are more numerous, the genital atrium is smaller, divided into two lateral lobes (instead of five) with a smaller number of spines and the eggs have a short and a long filament (instead of two short filaments). The host species and locality of T. mamaevi n. sp. also differ as T. papiliocauda which was recorded in Notacanthus sexspinis Richardson from the South Pacific.


Water transport across the peritoneal membrane.
Peritoneal dialysis involves diffusive and convective transports and osmosis through the highly vascularized peritoneal membrane. The capillary endothelium offers the rate-limiting hindrance for solute and water transport. It can be functionally described in terms of a three-pore model including transcellular, ultrasmall pores responsible for free-water transport during crystalloid osmosis. Several lines of evidence have demonstrated that the water channel aquaporin-1 (AQP1) corresponds to the ultrasmall pore located in endothelial cells. Studies in Aqp1 mice have shown that deletion of AQP1 is reflected by a 50% decrease in ultrafiltration and a disappearance of the sodium sieving. Haploinsufficiency in AQP1 is also reflected by a significant attenuation of water transport. Conversely, studies in a rat model and in PD patients have shown that the induction of AQP1 in peritoneal capillaries by corticosteroids is reflected by increased water transport and ultrafiltration, without affecting the osmotic gradient and small-solute transport. Recent data have demonstrated that a novel agonist of AQP1, predicted to stabilize the open-state conformation of the channel, modulates water transport and improves ultrafiltration. Whether increasing the expression of AQP1 or gating the already existing channels would be clinically useful in PD patients remains to be investigated.


Laryngotracheal Stenosis: Risk Factors for Tracheostomy Dependence and Dilation Interval
Objective Laryngotracheal stenosis (LTS) is a fibrotic process that narrows the upper airway and has a significant impact on breathing and phonation. Iatrogenic injury from endotracheal and/or tracheostomy tubes is the most common etiology. This study investigates differences in LTS etiologies as they relate to tracheostomy dependence and dilation interval. Study Design Case series with chart review. Setting Single-center tertiary care facility. Subjects and Methods Review of adult patients with LTS was performed between 2004 and 2015. The association of patient demographics, comorbidities, disease etiology, and treatment modalities with patient outcomes was assessed. Multiple logistic regression analysis and Kaplan-Meier analysis were performed to determine factors associated with tracheostomy dependence and time to second procedure, respectively. Results A total of 262 patients met inclusion criteria. Iatrogenic patients presented with greater stenosis ( P = .023), greater length of stenosis ( P = .004), and stenosis farther from the vocal folds ( P < .001) as compared with other etiologies. Iatrogenic patients were more likely to be African American, use tobacco, and have obstructive sleep apnea, type II diabetes, hypertension, chronic obstructive pulmonary disease, or a history of stroke. Iatrogenic LTS (odds ratio [OR] = 3.1, 95% confidence interval [95% CI] = 1.2-8.2), Cotton-Myer grade 3-4 (OR = 2.6, 95% CI = 1.1-6.4), and lack of intraoperative steroids (OR = 2.9, 95% CI = 1.2-6.9) were associated with tracheostomy dependence. Nonsmokers, patients without tracheostomy, and idiopathic LTS patients had a significantly longer time to second dilation procedure. Conclusion Iatrogenic LTS presents with a greater disease burden and higher risk of tracheostomy dependence when compared with other etiologies of LTS. Comorbid conditions promoting microvascular injury-including smoking, COPD, and diabetes-were prevalent in the iatrogenic cohort. Changes in hospital practice patterns to promote earlier tracheostomy in high-risk patients could reduce the incidence of LTS.


Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study.
Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism. Considering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. There were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64-5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37-3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26-2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008). Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism.


The Effect of Limiting the Scan Range of Computed Tomography Pulmonary Angiography (to Reduce Radiation Exposure) on the Detection of Pulmonary Embolism: A Systematic Review.
(1) Background: Computed tomography pulmonary angiography (CTPA) is the standard imaging test for the evaluation of acute pulmonary embolism (PE), but it is associated with patients' exposure to radiation. Studies have suggested that radiation exposure can be reduced without compromising PE detection by limiting the scan range (the z-axis, going from up to down); (2) Methods: A literature search was conducted in MEDLINE and EMBASE on 17 July 2021. Studies were included if they enrolled patients who had undergone a CTPA and described the yield of PE diagnoses, number of missed filling defects and/or other diagnoses using a reduced z-axis in comparison to a full-length scan. To assess risk of bias, we modified an existing risk of bias tools for observational studies, the Newcastle-Ottawa Scale. Results were synthesized in a narrative review. Primary outcomes were the number of missed PE diagnoses (based on at least one filling defect) and filling defects; the secondary outcome was the number of other missed findings; (3) Results: Eleven cohort studies and one case-control study were included reporting on a total of 3955 scans including 1025 scans with a diagnosis of PE. Six different reduced scan ranges were assessed; the most studied was from the top of the aortic arch to below the heart, in which no PEs were missed (seven studies). One sub-segmental PE was missed when the scan coverage was 10 cm starting from the bottom of the aortic arch and 14.7 cm starting from the top of the arch. Five studies that reported on other findings all found that other diagnoses were missed with a reduced z-axis. Most of the included studies had a high risk of bias; (4) Conclusions: CTPA scan coverage reduction from the top of aortic arch to below the heart reduced radiation exposure without affecting PE diagnoses, but studies were generally at high risk of bias.


Differential production of interleukin-12 mRNA by murine macrophages in response to viable or killed Salmonella spp.
The use of attenuated Salmonella spp. as live oral vaccine carriers fo r foreign antigens has been extensively studied. We have shown that appropriately prepared nonviable organisms are as effective as viable organisms in eliciting humoral immune responses against a foreign antigen delivered by these vectors. It is not clear how strain viability affects the development of a cell-mediated immune response. In the present study, we demonstrate that BALB/c mice orally immunized with viable attenuated Salmonella spp. were protected against subsequent challenge while animals immunized with killed organisms were not. Protection was correlated with increased production of interleukin-12 (IL-12) p40 mRNA in the Peyer's patches within hours of oral administration. Peritoneal macrophages from lipopolysaccharide (LPS)-responsive and LPS-unresponsive mice were also examined for production of IL-12 p40 mRNA following exposure to the viable or killed attenuated Salmonella carrier. There was dramatic upregulation of IL-12 p40 mRNA following exposure of macrophages to either viable or killed organisms. By 4 h postexposure, viable organisms had induced a 27-fold increase in IL-12 p40 mRNA levels while killed organisms had induced a 9-fold increase in IL-12 p40 mRNA levels. This was observed in macrophages isolated from both LPS-responsive and unresponsive mice. The higher levels of IL-12 induced by viable Salmonella spp. may result in the development of a Th1 response and cell mediated immunity, while the lower levels of IL-12 induced by killed Salmonella spp. may not be sufficient to promote a Th1 response.


Establishing the Calibration Curve of a Compressive Ophthalmodynamometry Device.
The relationship between externally applied force and intraocular pressure was determined using an ex-vivo porcine eye model (N=9). Eyes were indented through the sclera with a convex ophthalmodynamometry head (ODM). Intraocular pressure and ophthalmodynamometric force were simultaneously recorded to establish a calibration curve of this indenter head. A calibration coefficient of 0.140 ± 0.009 mmHg/mN was established and was shown to be highly linear (r = 0.998 ± 0.002). Repeat application of ODM resulted in a 0.010 ± 0.002 mmHg/mN increase to the calibration coefficient.Clinical Relevance- ODM has been highlighted as a potential method of non-invasively estimating intracranial pressure. This study provides relevant data for the practical performance of ODM with similar compressive devices.


Evidence of Gender Differences in the Diagnosis and Management of Coronavirus Disease 2019 Patients: An Analysis of Electronic Health Records Using Natural Language Processing and Machine Learning.
Background: The impact of sex and gender in the incidence and severity of coronavirus disease 2019 (COVID-19) remains controversial. Here, we aim to describe the characteristics of COVID-19 patients at disease onset, with special focus on the diagnosis and management of female patients with COVID-19. Methods: We explored the unstructured free text in the electronic health records (EHRs) within the SESCAM Healthcare Network (Castilla La-Mancha, Spain). The study sample comprised the entire population with available EHRs (1,446,452 patients) from January 1st to May 1st, 2020. We extracted patients' clinical information upon diagnosis, progression, and outcome for all COVID-19 cases. Results: A total of 4,780 patients with a confirmed diagnosis of COVID-19 were identified. Of these, 2,443 (51%) were female, who were on average 1.5 years younger than male patients (61.7 ± 19.4 vs. 63.3 ± 18.3, p = 0.0025). There were more female COVID-19 cases in the 15-59-year-old interval, with the greatest sex ratio (95% confidence interval) observed in the 30-39-year-old range (1.69; 1.35-2.11). Upon diagnosis, headache, anosmia, and ageusia were significantly more frequent in females than males. Imaging by chest X-ray or blood tests were performed less frequently in females (65.5% vs. 78.3% and 49.5% vs. 63.7%, respectively), all p < 0.001. Regarding hospital resource use, females showed less frequency of hospitalization (44.3% vs. 62.0%) and intensive care unit admission (2.8% vs. 6.3%) than males, all p < 0.001. Conclusion: Our results indicate important sex-dependent differences in the diagnosis, clinical manifestation, and treatment of patients with COVID-19. These results warrant further research to identify and close the gender gap in the ongoing pandemic.


Chlamydia trachomatis Infection of Endocervical Epithelial Cells Enhances Early HIV Transmission Events.
Chlamydia trachomatis causes a predominantly asymptomatic, but generally inflammatory, genital infection that is associated with an increased risk for HIV acquisition. Endocervical epithelial cells provide the major niche for this obligate intracellular bacterium in women, and the endocervix is also a tissue in which HIV transmission can occur. The mechanism by which CT infection enhances HIV susceptibility at this site, however, is not well understood. Utilizing the A2EN immortalized endocervical epithelial cell line grown on cell culture inserts, we evaluated the direct role that CT-infected epithelial cells play in facilitating HIV transmission events. We determined that CT infection significantly enhanced the apical-to-basolateral migration of cell-associated, but not cell-free, HIVBaL, a CCR5-tropic strain of virus, across the endocervical epithelial barrier. We also established that basolateral supernatants from CT-infected A2EN cells significantly enhanced HIV replication in peripheral mononuclear cells and a CCR5+ T cell line. These results suggest that CT infection of endocervical epithelial cells could facilitate both HIV crossing the mucosal barrier and subsequent infection or replication in underlying target cells. Our studies provide a mechanism by which this common STI could potentially promote the establishment of founder virus populations and the maintenance of local HIV reservoirs in the endocervix. Development of an HIV/STI co-infection model also provides a tool to further explore the role of other sexually transmitted infections in enhancing HIV acquisition.


Nodal Merkel Cell Carcinoma in Head and Neck Lesions with an Unknown Primary: A Case Report in Light of the Literature.
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer. To diagnose nodal MCC with an unknown primary disease is challenging, and it has to be separated from other nodal metastatic neoplasms. We report a unique case of nodal MCC in head and neck lesions with an unknown primary. A 70-year-old woman was admitted to our department with a right submandibular mass. Fine needle aspiration biopsy was performed and indicated malignancy. F-18-fluorodeoxyglucose positron emission tomography (PET) demonstrated abnormal accumulation in the right submandibular lymph node, right palatine tonsil, and right thyroid gland. For diagnostics and treatment, bilateral selective neck lymph node dissection, right tonsillectomy, and right thyroidectomy were performed. Histopathological examination revealed that most parts of the submandibular lymph node were occupied by diffuse sheets of tumor cells. Contrary to our expectation, malignant cells were not detected in the right palatine tonsil and right thyroid. Immunohistochemistry demonstrated a marked positive reaction for AE1/AE3, chromogranin A, synaptophysin, cytokeratin 20 (CK20) and CD56 and a negative reaction for vimentin, leucocyte common antigen (LCA), thyroid transcription factor-1 (TTF1) and cytokeratin 7 (CK7) in the tumor cells. Immunostaining of Merkel cell polyomavirus-large T antigen (MCPyV-LT) showed a positive reaction and MCPyV-positive MCCs were assessed by PCR analysis, demonstrating that viral copy number was 12.8 copies per cell. These histological findings confirmed the diagnosis of Merkel cell carcinoma of the lymph node. In cases of tumors in the lymph node with a neuroendocrine appearance in head and neck lesions, it is necessary to eliminate the possibility of metastasis from MCC.


Systematic in vitro comparison of decellularization protocols for blood vessels.
Decellularization of native blood vessels is a promising technology to generate 3D biological scaffolds for vascular grafting. Blood vessel decellularization has been performed in previous studies under various experimental conditions, that complicates comparison and optimization of suitable protocols. The goal of this work was to systematically compare the decellularization and recellularization efficacy of 5 different protocols utilizing the detergents sodium dodecyl sulfate (SDS), sodium deoxycholate (SDC), CHAPS and TritonX-100 together with DNA-removing enzymes on porcine vena cava in a perfusion bioreactor setup. Additionally, we tested the effect of DNase on the extracellular matrix (ECM) properties. We found that all protocols could efficiently decellularize blood vessels. Mechanical strength, collagen preservation and ECM integrity were similar among all tested detergents, yet TritonX protocols required long-term DNase application for complete decellularization. However, TritonX-based protocols showed the greatest recellularization efficacy with HUVECs in vitro. Furthermore, we developed a novel protocol for TritonX which improved recellularization and reduced total process time and ECM stiffness compared to previous protocols. SDS, SDC and CHAPS based protocols had a lower recellularization potential. In conclusion, decellularization of blood vessels can be achieved with all tested reagents, but TritonX treated ECM can be most efficiently recellularized with endothelial cells.