Subclinical slipped capital femoral epiphysis. Relationship to osteoarthrosis of the hip.
We examined the femora of 2665 adult human skeletons from an osteological collection to determine the prevalence of post-slip morphology termed femoral head-tilt deformity by Murray and pistol-grip deformity by Stulberg et al. The hypothesis was that primary osteoarthrosis of the hip is a secondary manifestation of a subclinical developmental disorder of the hip. The prevalence of post-slip morphology was 8 per cent (215 of 2665 skeletons). Severe osteoarthrosis was more prevalent in association with post-slip morphology (116 [38 per cent] of 306 hips) than in the matched controls (seventy-nine [26 per cent] of 306 hips) (p < 0.005). In the skeletons that had unilateral post-slip morphology, severe osteoarthrosis was more prevalent in the involved hips (thirty-one [37 per cent] of eighty-three) than in the contralateral, normal hips (eighteen [22 per cent] of eighty-three) (p < 0.05). Post-slip morphology, which was unrelated to age, was found to be a major risk factor for the development of high-grade osteoarthrosis. We noted evidence of high-grade osteoarthrosis in sixty-three (68 percent) of the ninety-three hips with minimum post-slip morphology in skeletons from individuals who had been fifty-six years old or more at the time of death compared with forty-five (48 percent) of the ninety-three control hips. This difference was significant (p < 0.025) [corrected]. The osteoarthrosis in the hips with post-slip morphology was distinctly characterized by anterior flattening of the acetabulum, cystic degeneration in the anterior metaphyseal-epiphyseal region, and progression to global osteoarthrosis of the hip.


[Experimental evaluation of the allergen activity of a peptide preparation produced from an enzymatic hydrolysate of milk proteins using ultrafiltration].
Noninbred guinea-pig experiments were performed to investigate specific potential allergenicity of cow milk proteins (CMP) consisting of casein (80%) and serum proteins (20%), of low-molecular peptides (LMP 20/80) produced from CMP 20/80 by enzymatic hydrolysis and ultrafiltration; to evaluate nonspecific effect of test diet CMP 20/80 and LMP 20/80 on anaphylactic response of the animals to ovalbumin and histamine LD50. LMP 20/80 versus CMP 20/80 had a hypoallergenic effect. Potential mechanisms of low anaphylactic sensitivity induced by LMP 20/80 are discussed.


Comparing patients' and their physicians' assessments of pain.
Patients and their physicians were asked to estimate the pain from needle aspiration and/or injection of joints or soft tissue using the visual analogue scale. On a 10-point scale, the mean score for patients prior to and after the procedure was 4.76 +/- 2.97 and 4.01 +/- 3.51, respectively, and for physicians was 4.15 +/- 2.45 and 3.36 +/- 2.08. Analysis of correlations revealed that prior to the procedure patients could predict their 'true' pain (after the procedure assessment) better (r = 0.765) than physicians could predict patients' pain (r = 0.542). However, physicians significantly improved their estimates of patients' scores by observing the procedure. After the procedure correlation between physician and patient scores increased to 0.62 (P = 0.003). The overall pattern of results suggests that experienced patients may be somewhat better than their physicians in predicting the level of pain they experience with a procedure, but that physicians' estimates appear to be accurate enough to allow them to give useful information about the degree of discomfort that a patient will experience during an invasive procedure.


Relation between climacteric symptoms and ovarian hypofunction in middle-aged and older Japanese women.
To gain insight into the characteristics and current status of climacteric symptoms reported by middle-aged and older women in Japan, we surveyed women presenting at our menopause clinic. The participants included 1,069 women, ranging in age from 40 to less than 60 years (mean age, 50.2 y). Climacteric (indefinite) symptoms were objectively assessed with the use of the Keio questionnaire, which grades the severity of 40 types of symptoms classified into 20 subgroups. The total scores obtained for the 40 symptoms were used to calculate symptom prevalence and severity. To evaluate ovarian function, concentrations of estradiol and follicle-stimulating hormone (FSH) in sera were measured. The most frequent symptom was general fatigue, reported by 88.2% of the women. Shoulder stiffness was the symptom rated to be severe by the highest percentage of women (38.1%). The prevalence and severity of hot flushes (and sweats) were slightly higher in perimenopausal and early postmenopausal women than in premenopausal and late postmenopausal women. The prevalence and severity of hot flushes and sweats were higher in women with estradiol < 25 pg/mL and FSH > 40 mIU/mL than in those with estradiol > or = 25 pg/mL and FSH < or = 40 mIU/mL. General fatigue and shoulder stiffness, symptoms with low hormone dependence, are the two most frequent climacteric symptoms in our clinic. Hot flushes and sweats, symptoms with high hormone dependence, are also common symptoms.


Seroprevalence of SARS-Coronavirus 2 among asymptomatic healthy blood donors from healthcare and non-healthcare settings: Implications for safety of blood donors and blood collection staff during blood donation.
SARS-Coronavirus-2 pandemic has adversely affected blood supply as potential blood donors were afraid of acquiring infection in hospital settings. We aimed to compare COVID-19 seroprevalence among asymptomatic blood donors from healthcare and non-healthcare setting to analyse the difference in exposure level of each group as well as the risk of acquiring infection during the process of blood donation. Analysis of whole blood donors tested for SARS-CoV-2 IgG antibodies was carried out after categorizing them into healthcare workers (HCW) and non-healthcare workers (NHCW). NHCW were further categorized into residents of containment and non-containment zones and seroprevalence analyzed. Seroprevalence among different ABO blood groups was also analyzed. 1191 blood donors were tested for SARS-CoV-2 antibodies with 9.5 % seropositivity. Significantly lower seropositivity of 3.2 % (p < 0.001) was observed among HCW as compared to 10.9 % seropositivity in NHCW. Among NHCW no difference in seropositivity was observed based on residence in containment or non-containment zone. Significantly higher (p = 0.012) seroprevalence was observed among A blood group donors (12.5 %) as compared to O blood group donors (6.8 %). Results suggests that a blood donor, in a hospital setting is less likely to be exposed to COVID-19 disease than when participating in activities of daily living. It is postulated that the lower seroprevalence among HCW as compared to NHCW reflects differences in knowledge and practice of preventive measures among these groups. The findings should instil confidence among blood donors and motivate them to donate blood without fear.


Microwave-induced fast crystallization of amorphous hierarchical anatase microspheres.
The fabrication of hierarchical anatase microspheres with potential photocatalytic properties eventually comprises a consolidation step in which a high degree of crystalline order is typically achieved through conventional electric heating treatments. This however entails a substantial reduction in the specific surface area and porosity of the powders, with the consequent deterioration in their photocatalytic response. Here, we have tested the employ of microwave heating as an alternative energy-saving sintering method to promote fast crystallization. The results obtained suggest that under the microwave radiation, the TiO2 hierarchical structures can effectively crystallize in a drastically reduced heating time, allowing the specific surface area and the porosity to be kept in the high values required for an improved photocatalytic performance.


Limited therapeutic effect of addition of buspirone in fluvoxamine-refractory obsessive-compulsive disorder.
The authors found that buspirone added to the treatment of 33 patients with obsessive-compulsive disorder who were refractory to the serotonin reuptake inhibitor fluvoxamine was no better than placebo in reducing obsessive-compulsive, depressive, or anxiety symptoms. This finding suggests that addition of buspirone to ongoing fluvoxamine therapy is not an effective treatment strategy for most patients with obsessive-compulsive disorder.


Novel variants, muscle imaging, and myopathological changes in Chinese patients with VCP-related multisystem proteinopathy.
The objective of this research was to study the clinical features, genetic characteristics, muscle imaging, and muscle pathological changes of a cohort of Chinese patients with mutations in the valosin-containing protein (VCP) gene. Nine patients from seven Chinese pedigrees were recruited. Variants were detected by next-generation sequencing and confirmed by Sanger sequencing. Thigh muscle MRIs were performed in five patients. All the patients received muscle biopsies. Seven variants in VCP were identified, and two were novel. All the patients presented with adult-onset muscle weakness. The appearance of "isolated island sign" or "contra-isolated island sign" was observed in four of the five the patients on muscle MRIs. Muscle biopsies demonstrated the combination of neuropathic and myopathic changes in seven patients and muscle dystrophic changes in two patients. Notably, rimmed vacuoles and cytoplasmic VCP and p62-positive protein aggregates were observed in all the patients. Our finding of novel variants expanded the mutational spectrum of the VCP gene. This cohort of Chinese patients with VCP mutations mainly present with inclusion body myopathy with predominant limb-girdle distribution. The characteristic pattern of fatty infiltration, especially the "isolated island" and "contra-isolated island" on muscle MRI, along with rimmed vacuoles in muscle biopsy, provides valuable clues for guiding genetic diagnostic workup.


The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone.
In clinical approaches to benign prostatic hyperplasia (BPH) and prostate cancer (PCa), steroidogenesis or the disruption thereof is the main thrust in treatments restricting active androgen production. Extensive studies have been undertaken focusing on testosterone and dihydrotestosterone (DHT). However, the adrenal C11-oxy C19 steroid, 11β-hydroxyandrostenedione (11OHA4), also contributes to the active androgen pool in the prostate microenvironment, and while it has been shown to impact castration resistant prostate cancer, the C11-oxy C19 steroids together with the C11-oxy C21 steroids have not been studied in BPH. The study firstly investigated the metabolism of these adrenal steroids in the BPH-1 model. Comprehensive profiles identified 11keto-testosterone as the predominant active androgen in the metabolism of the C11-oxy C19 steroids, and we identified, for the first time, 11β-hydroxy-5α-androstane-3α,17β-diol, a novel steroid in the 11OHA4-pathway. Analysis of the inactivation and reactivation of the metabolites showed that DHT is more readily inactivated than 11keto-dihydrotestosterone (11KDHT). The conversion of 11β-hydroxyprogesterone (11βOHPROG) yielded 11keto-progesterone (11KPROG), while the latter yielded 11keto-dihydroprogesterone (11KDHPROG). BPH tissue analysis identified high levels of 11β-hydroxyandrosterone (4-14 ng/g) and 11keto-androsterone (9-160 ng/g), together with androstenedione (A4; ∼7.5 ng/g). The major C11-oxy C21 steroids detected were 11βOHPROG (∼46 ng/g), 11KPROG (∼130 ng/g) as well as 11KDHPROG (∼282 ng/g). While circulatory 11βOHPROG was detected below the limit of quantification, 11KPROG and 11KDHPROG were detected at 6 and 8.5 nmol/L, respectively. Glucuronide derivatives of both 11KPROG and pregnanetriol were also detected. 11OHA4 was the major free androgen in circulation at 85.9 nmol/L, ±12-fold higher than A4, together with 5α-androstane-3α,17β-diol quantified at 69.3 nmol/L. Circulatory C11-oxy C19 steroids levels were also significantly higher (8-fold) than the C11-oxy C21 steroid levels, while the former were similar to the C19 steroid levels, in contrast to levels in PCa. The study highlights the contribution of adrenal C11-oxy steroids to the androgen pool in BPH underscoring their limited reactivation and elimination, and significant inter-individual variations regarding steroid levels and conjugation. Targeted steroid metabolome analysis is critical to understanding prostate steroidogenesis and disease progression, and analysis of circulatory C11-oxy C19 and C11-oxy C21 steroids, together with intraprostatic levels, add to our current understanding of BPH.


Design, organisation and impact of treatment optimisation studies in breast, lung and colorectal cancer: The experience of the European Organisation for Research and Treatment of Cancer.
Treatment optimisation studies (TOSs) are clinical trials which aim to tackle research questions that are often left unaddressed within the current drug development paradigm due to a lack of financial and regulatory incentives to undertake them. Examples include comparative effectiveness, therapeutic sequencing and dose de-escalation studies. Trials of this nature have historically been primarily carried out by academic institutions and not-for-profit organisations such as the European Organisation for Research and Treatment of Cancer (EORTC). Our objective was to conduct an in-depth analysis of the breast, lung and colorectal cancer TOSs that have been performed by the EORTC in the past four decades. We searched the EORTC clinical trials database for relevant studies and subsequently analysed them based on a number of predefined criteria relating to their design, organisation and scientific impact. The 113 EORTC TOSs examined in this analysis were mainly standard-sized, international, multicentre phase III trials using a relatively simple, randomised, open-label design and comparing pharmacological combination regimens against standard-of-care treatments in terms of their potential to improve overall survival of patients with cancer. Although they were typically financially and/or materially supported by the industry, their legal sponsor was nearly always an independent party that did not benefit monetarily from their outcomes. If meaningful findings were obtained, their results, regardless of whether positive or negative, were published in high-impact journals, and the corresponding articles usually received a considerable number of citations. Our analysis provides an empirical framework for setting up future TOSs based on the EORTC experience in oncology.


Is VMAT beneficial for patients undergoing radiotherapy to the head and neck?
Volumetric Intensity-Modulated Arc Therapy (VMAT) offers solutions to the time consuming, higher monitor unit (MU) delivery of Intensity-Modulated Radiotherapy (IMRT) for patients undergoing radiotherapy for head and neck cancer (HNC). Thus the aim was to determine whether VMAT would be beneficial for these patients. The majority of literature was planning comparative studies with only two studies on early clinical experience. Main themes arising from literature were conformity and homogeneity, organs at risk (OAR), MU and delivery time. VMAT provides plans with similar conformity, better homogeneity and results for improved sparing of OAR compared to IMRT. Thus it is clear that VMAT would be able to match the performance of IMRT plans, with the ability to treat patients in a short space of time and less MU. There is little clinical data on the side effects of VMAT, and more is needed to further evaluate the efficacy of VMAT. Overall these are encouraging results of VMAT for patients with HNC.


The role of Siah2 in tumorigenesis and cancer therapy.
Seven in absentia homolog 2 (Siah2), an RING E3 ubiquitin ligases, has been characterized to play the vital role in tumorigenesis and cancer progression. Numerous studies have determined that Siah2 promotes tumorigenesis in a variety of human malignancies such as prostate, lung, gastric, and liver cancers. However, several studies revealed that Siah2 exhibited tumor suppressor function by promoting the proteasome-mediated degradation of several oncoproteins, suggesting that Siah2 could exert its biological function according to different stages of tumor development. Moreover, Siah2 is subject to complex regulation, especially the phosphorylation of Siah2 by a variety of protein kinases to regulate its stability and activity. In this review, we describe the structure and regulation of Siah2 in human cancer. Moreover, we highlight the critical role of Siah2 in tumorigenesis. Furthermore, we note that the potential clinical applications of targeting Siah2 in cancer therapy.


High salt diet contributes to hypertension by weakening the medullary tricarboxylic acid cycle and antioxidant system in Dahl salt-sensitive rats.
High salt diet (HSD, 8% NaCl) contributes to salt-sensitive hypertension, this study aimed to determine the effect of HSD on salt-sensitive hypertension by combining proteomic with metabolomics methods. Salt-sensitive rats were fed on HSD and normal salt diet (NSD, 0.4% NaCl) for two weeks before further analysis. Proteomic analysis showed the differential expression proteins (DEPs) were primarily mapped in the tricarboxylic acid (TCA)-cycle, glycolysis/gluconeogenesis, and other pathways associated with multiple amino acids. HSD decreased the medullary activities and protein expression level of two key enzymes of TCA-cycle, MDH and NADP+-IDH. Metabolomics showed three serous TCA-cycle-associated compounds, including decreased malic acid, decreased citric acid, and increased fumaric acid were differentially detected, which resulted in a decrease in NO content and an increase in H2O2 content in serum. The content of GSH, GSH/GSSG ratio, and synthesis substrates of GSH-cysteine and glycine, were significantly decreased by HSD, thus attenuated the antioxidant system in the renal medulla. HSD enhanced the medullary pentose phosphate pathway, which finally increased the concentration of NADPH and NADP+, NADPH/NADP+, and the activity of NADPH oxidase in the renal medulla. Additionally, HSD enhanced the glycolysis pathway in the renal medulla. In summary, HSD significantly weakened the TCA cycle, and attenuated the antioxidant system in the renal medulla, which finally contributed to salt-sensitive hypertension.


Evaluation of the effects of anti-pruritic drugs on scratch responses using histamine H1 receptor-deficient mice.
The effects of anti-pruritic drugs on scratching behavior associated with passive cutaneous anaphylaxis in histamine H(1) receptor-deficient and wild-type mice were studied. Passive sensitization with mouse monoclonal anti-dinitrophenyl-immunoglobulin E (IgE) resulted in an increase in the incidence of scratching behavior induced by intravenous injection of dinitrophenyl-ovalbumin in both wild-type and histamine H(1) receptor-deficient mice. The histamine H(1) receptor antagonist diphenhydramine inhibited scratching behavior induced by antigen in passively sensitized wild-type mice, whereas no effect was observed in histamine H(1) receptor-deficient mice. On the other hand, oxatomide inhibited scratching behavior in both mice, although the effect in wild-type mice was more potent than that in histamine H(1) receptor-deficient mice. Tranilast inhibited scratching behavior with the same potency in both mice. We concluded that the scratching behavior associated with passive cutaneous anaphylaxis involves not only histamine H(1) receptors but also other chemical mediators. Furthermore, the results of the present study indicated that oxatomide has an antagonistic effect on histamine H(1) receptors as well as anti-pruritic effect in vivo.


Effect of renal failure on peak troponin Ic level in patients with acute myocardial infarction.
Peak troponin Ic (cTnI) level could be influenced by renal function. We evaluated the effect of moderate to severe renal failure on peak cTnI level during acute myocardial infarction (AMI). One hundred and twenty-five consecutive patients admitted to the coronary care unit of a university hospital in France for primary angioplasty during AMI were retrospectively studied. The correlations between peak cTnI level, peak creatine phosphokinase (CK) level, peak cTnI/peak CK ratio and creatinine clearance (CrCl) were assessed. The peak cTnI/peak CK ratio was considered in order to standardize the peak cTnI level with the extent of myocardial necrosis. There was no significant correlation between CrCl and peak CK (r = 0.01, p = 0.95), peak cTnI (r = -0.08, p = 0.38) or the peak cTnI/peak CK ratio (r = -0.14, p = 0.13). There was a trend towards higher peak cTnI in patients with moderate to severe renal failure. The peak cTnI/peak CK ratio did not significantly differ among patients according to CrCl stratification, whereas the ratio of log-transformed values was significantly higher in patients with moderate to severe renal failure. In patients with AMI, the peak cTnI level seemed to be influenced by renal function.


Info-gap theory to determine cost-effective eradication of invasive species.
Invasive species eradication campaigns often fail due to stochastic arrival events, unpredictable detectability and incorrect resource allocation. Severe uncertainty in model parameter estimates may skew the eradication policy results. Using info-gap decision theory, this research aims to provide managers with a method to quantify their confidence in realizing successful eradication of particular invasive species within their specified eradication budgets (i.e. allowed eradication cost) in face of information-gaps. The potential introduction of the Asian house gecko Hemidactylus frenatus to Barrow Island, Australia is used as a case study to illustrate the model. Results of this research demonstrate that, more robustness to uncertainty in the model parameters can be earnt by (1) increasing the allowed eradication cost (2) investment in pre-border quarantine and border inspection (i.e. prevention) or (3) investment in post-border detection surveillance. The combination of a post-border spatial dispersal model and info-gap decision theory demonstrates a novel and spatially efficient method for managers to evaluate the robustness of eradication policies for incursion of invasive species with unexpected behaviour. These methods can be used to provide insight into the success of management goals, in particular the eradication of invasive species on islands or in broader mainland areas. These insights will assist in avoiding eradication failure and wasteful budget allocation and labour investment.


The emerging role of aldehyde:ferredoxin oxidoreductases in microbially-catalyzed alcohol production.
The development of a bio-refinery industry based on liquid fuels is presumably key to successful replacement of fossil fuels and a reduction of carbon dioxide (CO2) emissions. Ethanol and longer-chain alcohols are supposed to play a key role since they are relatively easy to produce, using microorganisms as whole-cell biocatalysts. Alcohols may be produced from lignocellulose-derived biomass or from synthesis gas (hydrogen, H2; CO2, carbon monoxide, CO). In anaerobes, common pathways involve the reduction of the intermediate acetyl-CoA with NAD(P)H by aldehyde (ALDH) and alcohol dehydrogenases (ADH). Alternatively, alcohols may be produced by the direct reduction of externally added or intermediately produced organic acids with reduced ferredoxin (Fdred). The key enzyme catalyzing this thermodynamically difficult reaction is aldehyde:ferredoxin oxidoreductase (AOR), an oxygen sensitive protein present in some anaerobic bacteria and archaea. Here, we present increasing evidence for the importance of the AOR-ADH pathway in alcohol producing anaerobes. AOR heavily depends on compounds with a low redox potential, and reactions potentially coupled to the pathway are discussed. The putative ancient AOR-ADH pathway may be relatively widespread among anaerobes, and it may play an important role in a sustainable bioenergy concept via the reduction of organic acids to their corresponding alcohols.


DNA-derived nanostructures selectively capture gram-positive bacteria.
We report the first demonstration of the efficient bacteria targeting properties of DNA-based polymeric micelles with high-density DNA corona. Nanoscale polymer micelles derived from DNA-b-polystyrene (DNA-b-PS) efficiently selected most tested Gram-positive strains over Gram-negative strains; single-strand DNAs were 20-fold less selective. We demonstrate that these targeting properties were derived from the interaction between densely packed DNA strands of the micelle corona and the peptidoglycan layers of Gram-positive bacteria. DNA-b-PS micelles incorporating magnetic nanoparticles (MNPs) can efficiently capture and concentrate Gram-positive bacteria suggesting the simple applications of these DNA block copolymer micelles for concentrating bacteria. Adenine (A), thymine (T), cytosine (C), and guanine (G)-rich nanostructures were fabricated, respectively, for investigating the effect of sequence on Gram-selective bacteria targeting. T-rich micelles showed the most efficient targeting properties. The targeting properties of these DNA nanostructures toward Gram-positive bacteria may have applications as a targeted therapeutic delivery system.


Spigelian hernia: A rare case presentation and review of literature.
Spigelian hernias are rare abdominal wall defects that occur at the semilunar line lateral to the rectus abdominis muscle. They are located between the muscular layers of the abdominal wall and can be easily overlooked because of abdominal obesity. They are difficult to diagnose because of their location and vague symptoms. The diagnosis has been considerably aided by the introduction of ultrasonography and Computed Tomography. We report a case of 60 years old male who presented with swelling and vague abdominal discomfort in the right lower abdomen and was diagnosed with the help of CT scan in prone position. The patient underwent transabdominal preperitoneal repair laparoscopically. His recovery was uneventful. Spigelian hernia constitutes about 0.12 to 0.2 % of all abdominal hernias. It commonly occurs in semilunaris line, well-defined defect in the Spigelian aponeurosis at the "Spigelian hernia" belt. Ultrasound scanning is recommended as first line imaging investigation in suspected case. Prompt surgical repair is recommended for spigelian hernia to prevent subsequent strangulation. Since spigelian hernia is a rare entity a high index of suspicion is required for accurate diagnosis. Once diagnosis is made, operative management is required to prevent incarceration.


Unfolding by Cdc48/p97: different strokes for different folks.
The protein unfoldase Cdc48/p97 targets a wide variety of cellular substrates, but the molecular basis of substrate turnover remains incompletely understood. Two recent reports, by Ji et al. and van den Boom et al., provide detailed insights into the unfolding process and reveal pronounced flexibility of substrate handling by Cdc48/p97.


Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.
Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530. The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies. Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.


Effectiveness of supplementation with quercetin-type flavonols for treatment of viral lower respiratory tract infections: Systematic review and meta-analysis of preclinical studies.
Viral infections of the lower respiratory tract are considered a public health problem. They affect millions of people worldwide, causing thousands of deaths, and are treated with expensive medicines, such as antivirals or palliative measures. In this study, we conducted a systematic review to describe the use of quercetin-type flavonols against lower respiratory tract viruses and discussed the preclinical impact of this approach on different signs and clinical mechanisms of infection. The systematic review was performed in PubMed/MEDLINE, Scopus, Scielo, and Biblioteca Virtual de Saúde (BVS). After the database search, 11 relevant studies were identified as eligible. The analysis of these studies showed evidence of antiviral activity of quercetin-type flavonols with significantly reduced mortality rate (M-H = 0.19, 95% CI: 0.05 to 0.65, p-value = 0.008) of infected animals and a reduction in the average viral load (IV = -1.93, 95% CI: -3.54 to -0.31, p-value = 0.02). Additionally, quercetin and its derivatives reduced the amount of proinflammatory cytokines, chemokines, reactive oxygen species, mucus production, and airway resistance in animals infected with a respiratory virus. Overall, supplementation with quercetin-type flavonols is a promising strategy for treating viral-induced lower respiratory tract infections.


Lumbosacral Spondylolysis and Spondylolisthesis.
Repetitive stress on the lumbosacral spine during sporting activity places the athletic patient at risk of developing symptomatic pars defect. Clinical history, physical examination, and diagnostic imaging are important to distinguish spondylolysis from other causes of lower back pain. Early pars stress reaction can be identified with advanced imaging, before the development of cortical fracture or vertebral slip progression to spondylolisthesis. Conservative management is first-line for low-grade injury with surgical intervention indicated for refractory symptoms, severe spondylolisthesis, or considerable neurologic deficit. Prompt diagnosis and management of spondylolysis leads to good outcomes and return to competition for most athletes.


The "lazy-V" de-epithelialised turn-over fasciocutaneous flap in the reconstruction of skin defects after tendo Achilles repair.
Few methods of closure of skin defects lying over the tendo Achilles have been described. The de-epithelialised turn-over flap is one of them but it cannot be used in the presence of a scar proximal to the defect. We describe a modification ("The Lazy-V") of the de-epithelialised turn-over flap which gives it a rotation arc, thus enhancing the versatility of the procedure. This modification is presented with an illustrative case report and a review of the literature.


The transcriptional dynamics during de novo shoot organogenesis of Ma bamboo (Dendrocalamus latiflorus Munro): implication of the contributions of the abiotic stress response in this process.
De novo shoot organogenesis is an important biotechnological tool for fundamental studies in plant. However, it is difficult in most bamboo species, and the genetic control of this highly dynamic and complicated regeneration process remains unclear. In this study, based on an in-depth analysis at the cellular level, the shoot organogenesis from calli of Ma bamboo (Dendrocalamus latiflorus Munro) was divided into five stages. Subsequently, single-molecule long-read isoform sequencing of tissue samples pooled from all five stages was performed to generate a full-length transcript landscape. A total of 83 971 transcripts, including 73 209 high-quality full-length transcripts, were captured, which served as an annotation reference for the subsequent RNA sequencing analysis. Time-course transcriptome analysis of samples at the abovementioned five stages was conducted to investigate the global gene expression atlas showing genome-wide expression of transcripts during the course of bamboo shoot organogenesis. K-means clustering analysis and stage-specific transcript identification revealed important dynamically expressed transcription regulators that function in bamboo shoot organogenesis. The majority of abiotic stress-responsive genes altered their expression levels during this process, and further experiments demonstrated that exogenous application of moderate but not severe abiotic stress increased the shoot regeneration efficiency. In summary, our study provides an overview of the genetic flow dynamics during bamboo shoot organogenesis. Full-length cDNA sequences generated in this study can serve as a valuable resource for fundamental and applied research in bamboo in the future.


[Immunohistochemical profile of renal cell tumours].
Kidney cancer is among the 10 most frequent cancers in the world, each year about 270,000 cases are diagnosed and 116,000 people die from the disease. Approximately 90% of all solid kidney neoplasms are renal cell carcinomas. The incidence in Colombia is approximately 500-1000 cases per year. To characterize through the use of immunohistochemical markers the different renal cell tumours diagnosed in the pathology laboratory of the San José Hospital (HSJ) and the University Infantil Hospital of San José (HUISJ) in Bogotá. A retrospective review was performed of the Hematoxylin and eosin and immunohistochemistry slides of all renal cell carcinomas diagnosed in women and men over 18 years in the pathology laboratory of the HSJ and the HUISJ from Bogotá from January 2014 to December 2016. The antibodies used were: CAIX (carbonic anhydrase), RCC (renal cell carcinoma marker), vimentin, CD10, CK7, TFE3 (transcription factor binding to IGHM enhancer 3), CD117, CD15, CK20, cadherin and PAX8. Absolute and relative frequencies of the different markers were reported through univariate and bivariate analyses with a chi-square test. Comparing the expression of statistically significant markers, an immunoprofile resulted for clear cell carcinoma (CRCC) versus RCC chromophobe (ChRCC) as follows: CRCC positive markers: CAIX, vimentin, CD15, CD10, cadherin and negative markers: CK7, CD117; ChRCC positive markers: CK7, CD117, CD10, cadherin and CAIX negative markers: vimentin, CD15. The PAX8 marker was positive or negative in both tumors. Five markers demonstrated utility and validity to differentiate between histological subtypes of CRCC and ChRCC. We propose the combination of markers (CAIX, CK7, vimentin, CD15 and CD117) for the differential diagnosis between CRCC versus ChRCC.


Defective neutrophil chemotaxis and bactericidal power in a child with hyperimmunoglobulinemia E.
An 11-year-old boy with a life-long history of atopic-like dermatitis and recurrent staphylococcal abscesses was found to have defective neutrophil chemotaxis, impaired-T-lymphocyte functions, hyperimmunoglobulinemia E, and delayed neutrophil bactericidal power. This latter defect has never been found in such patients. The patient's mother revealed a panhypogammaglobulinemia, while his sister and maternal grandmother who had repeated infections were immunologically normal.


Copy number variation of the HPGDS gene in the Ashidan yak and its associations with growth traits.
Copy number variation (CNV) is a structural variation at the submicroscopic level of the genome, which can affect gene-related phenotypes by changing genes dosage and transcript structure. Hematopoietic prostaglandin D synthase (HPGDS) is a member whose functions are closely related to weight gain and inflammatory diseases of the glutathione S-transferase (GSTs) family. In this study, the growth characteristics (body weight, withers height, body length, and chest girth) of 336 Ashidan yaks were monitored at four stages (6 months, 12 months, 18 months, and 30 months). In addition, CNV of the HPGDS gene was detected, discovered relationships of CNV with growth traits, and explored the level of gene expression. Based on the statistical analysis by IBM SPSS software, significant correlations were observed between HPGDS-CNV and body weight in 12-month-old yak (P < 0.01), 18-month-old yak (P < 0.001) and 30-month-old yak (P < 0.001) and body length in 18-month-old yak (P < 0.05) and 30-month-old yak (P < 0.05), respectively. Additionally, the individuals with gain copy number type performed better in body weight and body length than those with normal or loss copy number type. To our best of knowledge, this is the first time to make efforts to probe into the role of HPGDS-CNV and its interaction with livestock growth traits. Our results suggested that the CNV of the HPGDS gene may be an active candidate gene for the marker-assisted selection (MAS) of yaks.


Plant hypersensitive induced reaction protein facilitates cell death induced by secreted xylanase associated with the pathogenicity of Sclerotinia sclerotiorum.
Necrotrophic fungal plant pathogens employ cell death-inducing proteins (CDIPs) to facilitate infection. However, the specific CDIPs and their mechanisms in pathogenic processes of Sclerotinia sclerotiorum, a necrotrophic pathogen that causes disease in many economically important crop species, have not yet been clearly defined. This study found that S. sclerotiorum secretes SsXyl2, a glycosyl hydrolase family 11 xylanase, at the late stage of hyphal infection. SsXyl2 targets the apoplast of host plants to induce cell death independent of xylanase activity. Targeted disruption of SsXyl2 leads to serious impairment of virulence, which can be recovered by a catalytically impaired SsXyl2 variant, thus supporting the critical role of cell death-inducing activity of SsXyl2 in establishing successful colonization of S. sclerotiorum. Remarkably, infection by S. sclerotiorum induces the accumulation of Nicotiana benthamiana hypersensitive-induced reaction protein 2 (NbHIR2). NbHIR2 interacts with SsXyl2 at the plasma membrane and promotes its localization to the cell membrane and cell death-inducing activity. Furthermore, gene-edited mutants of NbHIR2 displayed increased resistance to the wild-type strain of S. sclerotiorum, but not to the SsXyl2-deletion strain. Hence, SsXyl2 acts as a CDIP that manipulates host cell physiology by interacting with hypersensitive induced reaction protein to facilitate colonization by S. sclerotiorum. These findings provide valuable insights into the pathogenic mechanisms of CDIPs in necrotrophic pathogens and lead to a more promising approach for breeding resistant crops against S. sclerotiorum.


Corrigendum to "MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer's Disease".
[This corrects the article DOI: 10.1155/2021/8635088.].


MT5-MMP regulates adult neural stem cell functional quiescence through the cleavage of N-cadherin.
The identification of mechanisms that maintain stem cell niche architecture and homeostasis is fundamental to our understanding of tissue renewal and repair. Cell adhesion is a well-characterized mechanism for developmental morphogenetic processes, but its contribution to the dynamic regulation of adult mammalian stem cell niches is still poorly defined. We show that N-cadherin-mediated anchorage of neural stem cells (NSCs) to ependymocytes in the adult murine subependymal zone modulates their quiescence. We further identify MT5-MMP as a membrane-type metalloproteinase responsible for the shedding of the N-cadherin ectodomain in this niche. MT5-MMP is co-expressed with N-cadherin in adult NSCs and ependymocytes and, whereas MT5-MMP-mediated cleavage of N-cadherin is dispensable for the regulation of NSC generation and identity, it is required for proper activation of NSCs under physiological and regenerative conditions. Our results indicate that the proliferative status of stem cells can be dynamically modulated by regulated cleavage of cell adhesion molecules.


Chemical modification of proteins.
The two most widely used applications for chemical modification are in primary structure analysis and in the identification of essential groups involved in the binding and catalytic sites of proteins. The methods discussed here are those used frequently in primary structure analysis. Chemical modifications involving protein "active center" identification are the subject of a review by Pfleiderer (1).


Prediction of the removal efficiency of emerging organic contaminants in constructed wetlands based on their physicochemical properties.
This study investigates the prediction of the removal efficiency of emerging organic contaminants (EOCs) (pharmaceuticals-PhCs, personal care products-PCPs, and steroidal hormones-SHs) in constructed wetlands based on their physicochemical properties (e.g., molecular weight-MW, octanol-water partition coefficient-Log Kow, soil organic carbon sorption coefficient-Log Koc, octanol-water distribution coefficient-Log Dow, and dissociation constant-pKa). The predictive models are formed based on statistical analysis underpinned by principle component, correlation, and regression analyses of a global data set compiled from peer-reviewed publications. The results show that the physicochemical properties of EOCs emerged as good predictors of their removal efficiency. Log Koc, Log Dow, and Log Kow are the most significant predictors, and combination with MW and/or pKa often improved the reliability of the predictions. The best performing model for PhCs was composed of MW, Log Dow, and Log Koc (coefficient of determination-R2: 0.601; probability value-p < 0.05; root mean square error-RMSE: training set: 11%; test set: 27%). Log Kow and Log Koc for PCPs (R2: 0.644; p < 0.1; RMSE: training set: 14%; test set: 14%), and a combination of MW, Log Kow, and pKa for SHs (R2: 0.941; p < 0.1; RMSE: training set: 3%; test set: 15%) formed the plausible models for predicting the removal efficiency. Similarly, reasonably good combined models could be formed in the case of PhCs and SHs or PCPs and SHs, although their individual models were comparatively better. A novel decision support tool, named as REOCW-PCP, was developed to readily estimate the removal efficiency of EOCs, and facilitate the decision-making process.


Applicability of boosting techniques in calibrating safety performance functions for freeways.
Safety performance functions (SPFs) are indispensable analytical tools that usually play a crucial role in estimating crash frequencies, identifying hotspots, analyzing crash contributing factors, and assessing the effectiveness of safety countermeasures. Due to the limited availability of safety data, municipalities tended to adopt SPFs from Highway Safety Manual or other neighboring jurisdictions. Recently, boosting algorithms have been frequently exploited for data analysis and statistical regression modeling problems. This research, therefore, aims to examine the efficiency of boosting calibration techniques to transfer the SPF using the limited region data in an international context. To this end, AdaBoost.R2, an adaptive boosting algorithm, Two-stage TrAdaBoost.R2, an instance-based transfer learning algorithm, and Gradient Boosting algorithm were employed to investigate their efficiencies in acquiring knowledge from the available source domain data to predict crashes in the target domain. As a comparison, the calibration factor method was adopted to transfer the traditional negative binomial (NB) regression model. Two training dataset groups were developed to train the four calibration techniques. The first group was used to examine the adaptability of the employed calibration techniques to the limited target region data. While the second group was utilized to further investigate the influence of larger vital information on the performance of transferred models. This study was conducted between two U.S. states, Florida and New York, and two Chinese cities, Shanghai and Suzhou. According to the goodness-of-fit results, boosting calibration techniques showed better prediction accuracy than the calibrated NB-based model using the limited target region data. In addition, the amount and distribution of the training dataset were considered the two significant factors that influence the proficiency of the boosting calibration techniques.


Insomnia medication: do published studies reflect the complete picture of efficacy and safety?
Selective publication can have a deleterious effect on evidence based medicine, health policy decision making and treatment guidelines. Using the European Public Assessment Reports (EPARs) as reference, this study examined selective publication and selective reporting of efficacy and safety of insomnia medication. EPARs of with three insomnia medications were used to identify all clinical trials that were performed between 1998 and 2007 for the purpose of registration in the EU. The matching publication for each trial was searched through a systematic literature search. Accuracy of information in the publications was examined by comparison to the information in the EPARs. Only 55% of the trials with insomnia medications identified in EPARs were published. Positive trials were approximately two times more likely to be published. The lag time from study completion to publication was shorter for the positive compared to the negative trials. Sample size did not correlate with publication of negative trials. The meta-analysis of the effect size of insomnia medication was 1.6 times larger in the published data compared to the complete data. While the primary end points of the trials were reported reliably in the publications, remarkable inconsistencies were detected in the reporting of the secondary end points, methods, results and, especially safety. In conclusion, selective publication and reporting lead to an overestimation of efficacy and underestimation of safety of insomnia products. Authors of treatment guidelines should be aware of this bias. EPARs/FDA reviews provide a more unbiased view of the benefit-risk balance of insomnia and other medications and hence these documents should be consulted by e.g. authors of meta-analyses and of treatment guidelines.


[Acute retinal necrosis syndrome following chickenpox].
A 34-year-old male patient developed acute retinal necrosis in his left eye about three weeks after the onset of chickenpox. Systemic antiviral treatment with intravenous acyclovir (10 mg/kg/8 hours) and systemic corticosteroids (1 mg/kg/day) controlled the retinitis and the patient suffered no loss of visual acuity. Acute retinal necrosis is an unusual complication of chickenpox. A mild form of this entity has been described during the course of primary varicella-zoster infection. Adequate and early therapy during the acute phase of the disease with intravenous acyclovir and systemic corticosteroids is recommended to achieve a satisfactory visual acuity and prevent complications.


Getting in the loop: new insights into the mechanism of poly(A) site recognition.
In this issue, Yang et al. (2011) show that the 3' end processing factor CFI(m) interacts with RNA in manner that facilitates RNA looping, suggesting mechanistic roles for this factor in the regulation of poly(A) site selection.


SNARE zippering is hindered by polyphenols in the neuron.
Fusion of synaptic vesicles with the presynaptic plasma membrane in the neuron is mediated by soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor (SNARE) proteins. SNARE complex formation is a zippering-like process which initiates at the N-terminus and proceeds to the C-terminal membrane-proximal region. Previously, we showed that this zippering-like process is regulated by several polyphenols, leading to the arrest of membrane fusion and the inhibition of neuroexocytosis. In vitro studies using purified SNARE proteins reconstituted in liposomes revealed that each polyphenol uniquely regulates SNARE zippering. However, the unique regulatory effect of each polyphenol in cells has not yet been examined. In the present study, we observed SNARE zippering in neuronal PC12 cells by measuring the fluorescence resonance energy transfer (FRET) changes of a cyan fluorescence protein (CFP) and a yellow fluorescence protein (YFP) fused to the N-termini or C-termini of SNARE proteins. We show that delphinidin and cyanidin inhibit the initial N-terminal nucleation of SNARE complex formation in a Ca(2+)-independent manner, while myricetin inhibits Ca(2+)-dependent transmembrane domain association of the SNARE complex in the cell. This result explains how polyphenols exhibit botulinum neurotoxin-like activity in vivo.


Tremor, Daily Functioning, and Health-Related Quality of Life in Solid Organ Transplant Recipients.
Solid organ transplant recipients (SOTR) frequently report tremor. Data concerning tremor-related impairment and its potential impact on health-related quality of life (HRQoL) are lacking. This cross-sectional study assesses impact of tremor on activities of daily living and HRQoL using validated questionnaires among SOTR enrolled in the TransplantLines Biobank and Cohort Study. We included 689 SOTR (38.5% female, mean [±SD] age 58 [±14] years) at median [interquartile range] 3 [1-9] years after transplantation, of which 287 (41.7%) reported mild or severe tremor. In multinomial logistic regression analyses, whole blood tacrolimus trough concentration was an independent determinant of mild tremor (OR per µg/L increase: 1.11, 95% CI: 1.02 to 1.21, p = 0.019). Furthermore, in linear regression analyses, severe tremor was strongly and independently associated with lower physical and mental HRQoL (β = -16.10, 95% CI: -22.23 to -9.98, p < 0.001 and β = -12.68, 95% CI: -18.23 to -7.14, p < 0.001 resp.). SOTR frequently report tremor-related impairment of activities of daily living. Tacrolimus trough concentrations appeared as a main determinant of tremor among SOTR. The strong and independent association of tremor-related impairment with lower HRQoL warrants further studies into the effects of tacrolimus on tremor. Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT03272841.


Sleep disturbances and sleep disorders in adults living with chronic pain: a meta-analysis.
Chronic pain, with or without an identified diagnosis or cause, is widespread and commonly associated with sleep disturbances. However, research has often used poor quality measures of sleep and focused on specific pain conditions, thereby limiting its reliability and applicability to the wider CP population. This study meta-analysed the findings from studies that used objective polysomnographic measures of sleep or examined diagnosed sleep disorders in people with CP. Three databases were searched (PubMed, PsychINFO, Embase; inception to June 2017) for case-controlled polysomnography studies and studies that reported the prevalence of diagnosed sleep disorders in adults with CP. Hedge's g effect sizes and prevalence rates were calculated using the data from 37 studies. Polysomnographic measures of sleep onset latency and efficiency, time awake after sleep onset and awakenings were all significantly worse in those with CP when compared to healthy controls (large effects). Total sleep time, light sleep duration (NREM 1), number of stage-shifts, respiratory-related events and periodic limb-movements were also worse for those with CP, albeit to a lesser extent (small to medium effects). The pooled prevalence of sleep disorders in CP was 44%, with insomnia (72%), restless legs syndrome (32%) and obstructive sleep apnea (32%) being the most common diagnoses. Objective polysomnographic measures indicate that individuals with CP experience significant sleep disturbances, particularly with respect to sleep initiation and maintenance. Clinically diagnosed sleep disorders are also very prevalent. It is imperative that sleep disturbances and disorders be assessed and treated in conjunction with the CP.


Aryl hydrocarbon reporter gene bioassay for screening polyhalogenated dibenzo-p-dioxins/furans and dioxin-like polychlorinated biphenyls in hydrochar and sewage sludge.
The suitability of the AhR reporter gene bioassays to screen the presence of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in sewage sludge (SL) and related hydrochar (HC) was here investigated. Samples of SL obtained from six WWTPs were processed by hydrothermal carbonization to obtain the resultant HCs and both tested with DR-CALUX® bioassay. Levels of PCDD/Fs and dl-PCBs were also determined analytically in the same samples by GC-MS/MS. Bioanalytical Toxicity Equivalent values (BEQ) resulted in one order of magnitude higher in HC compared to SL samples and those obtained from the dl-PCBs fraction higher than those from PCDD/Fs. BEQ and TEQWHO values, the latter obtained by GC-MS/MS analysis on the same matrices, were highly correlated showing also a similar trend in the six WWTPs (RS= 0.8252, p < 0.001; Pearson's R RP =0.8029, p < 0.01). The suitability of AhR bioassays and in particular of the DR-CALUX® to screen the presence and biological activity of legacy organohalogen compounds in both SL and HC matrices was demonstrated for the first time which support their usage for the assessment of potential risks associated with their further environmental applications.


Analysis of the Nanoparticle Dispersion and Its Effect on the Crystalline Microstructure in Carbon-Additivated PA12 Feedstock Material for Laser Powder Bed Fusion.
Driven by the rapid development of additive manufacturing technologies and the trend towards mass customization, the development of new feedstock materials has become a key aspect. Additivation of the feedstock with nanoparticles is a possible route for tailoring the feedstock material to the printing process and to modify the properties of the printed parts. This study demonstrates the colloidal additivation of PA12 powder with laser-synthesized carbon nanoparticles at >95% yield, focusing on the dispersion of the nanoparticles on the polymer microparticle surface at nanoparticle loadings below 0.05 vol%. In addition to the descriptors "wt%" and "vol%", the descriptor "surf%" is discussed for characterizing the quantity and quality of nanoparticle loading based on scanning electron microscopy. The functionalized powders are further characterized by confocal dark field scattering, differential scanning calorimetry, powder rheology measurements (avalanche angle and Hausner ratio), and regarding their processability in laser powder bed fusion (PBF-LB). We find that heterogeneous nucleation is induced even at a nanoparticle loading of just 0.005 vol%. Finally, analysis of the effect of low nanoparticle loadings on the final parts' microstructure by polarization microscopy shows a nanoparticle loading-dependent change of the dimensions of the lamellar microstructures within the printed part.


Retraction: Fabrication of divalent ion substituted hydroxyapatite/gelatin nanocomposite coating on electron beam treated titanium: mechanical, anticorrosive, antibacterial and bioactive evaluations.
[This retracts the article DOI: 10.1039/C5RA05624A.].


Biologic and clinical features of benign solid and cystic lesions of the liver.
The widespread use of imaging analyses, either routinely or to evaluate symptomatic patients, has increased the detection of liver lesions (tumors and cysts) in otherwise healthy individuals. Although some of these incidentally discovered masses are malignant, most are benign and must be included in the differential diagnosis. The management of benign hepatic tumors ranges from conservative to aggressive, depending on the nature of the lesions. New imaging modalities, increased experience of radiologists, improved definition of radiologic characteristics, and a better understanding of the clinical features of these lesions have increased the accuracy of diagnoses and reduced the need for invasive diagnostic tests. These advances have led to constant adjustments in management approaches to benign hepatic lesions. We review the biologic and clinical features of some common hepatic lesions, to guide diagnosis and management strategies.


The use of utilization review records as a source of data on nursing home care.
Data form the Utah nursing home Utilization Review Program, 1970-73, provide a description of the population of nursing home patients in Utah and changes over time in patient medication and measures of activity. These data are analyzed according to type of care in home: personal, intermediate, or comprehensive. The collection of data in utilization review programs can help to evaluate the quality of care as well as appropriateness of placement, provided the information collected is designed with these ends in mind.


Genetic evidence for involvement of the alternative sigma factor SigI in controlling expression of the cell wall hydrolase gene lytE and contribution of LytE to heat survival of Bacillus subtilis.
The Bacillus subtilis cell wall hydrolase LytE is involved in cell wall turnover and cell separation during vegetative growth. lytE transcription is known to be driven by a YycF-activated SigA-dependent promoter. The cell wall regulator SigI is an alternative sigma factor that has been shown to be heat stress-inducible and to be essential for survival of B. subtilis at high temperature. However, none of the previously identified target genes of SigI contribute to heat resistance. We now demonstrate that lytE expression is heat-inducible and that heat induction of lytE expression is strongly dependent on SigI. We have also found that the lytE mutant shows the same growth defect at high temperature as the sigI mutant. Introducing an extra copy of lytE into the sigI mutant could rescue its growth defect. Our data strongly suggest that SigI-dependent lytE expression under heat stress is important for heat survival of B. subtilis.


Decadal differences in polycyclic aromatic compound (PAC) concentrations in two seabird species in Arctic Canada.
Seabirds are exposed to a variety of environmental contaminants in the Arctic. While the persistence, bioaccumulation, and toxicity of some groups of contaminants have been well-studied in seabirds since the 1970s, there is less known about polycyclic aromatic compounds (PACs). With increased vessel traffic, and potential oil and gas development in the Arctic region, there is a need to understand existing PAC exposure in biota against which to compare potential effects of anticipated increases of PACs in the marine region. Thick-billed murres (Uria lomvia) and northern fulmars (Fulmarus glacialis) collected in the Baffin Bay - Davis Strait region during the International Polar Year (IPY; 2007-08), and during a recent Strategic Environmental Assessment (2018; SEA) were examined for hepatic PAC concentrations. We found that fulmars generally had higher concentrations of PACs than the murres, but murres and fulmars sampled in 2007/08 had higher concentrations of most groups of PACs compared to birds from 2018. The one exception to this pattern was that the sum of the alkylated congeners of the heterocyclic aromatic compounds containing a sulfur atom (dibenzothiophene; ΣAHET) was significantly higher in murres in the more recent sampling period (2018) as compared to 2007/08. ΣAHETs likely reflect recent exposure to more refined petroleum products associated with small boats, such as diesel, gasoline and motor oil. This work highlights the need for longitudinal studies on PAC concentrations in biota for us to gain a better understanding of how Arctic biota are exposed to this group of contaminants, and the potential deleterious effects associated with PACs.


Feeding System Effects on Dairy Cow Rumen Function and Milk Production.
Good rumen function, which is largely influenced by the diet of the cow, is essential to optimise animal performance. This study, conducted over the course of a full lactation in a spring-calving milk production system, compared the rumen function and milk production of cows offered one of three dietary treatments: (1) Cows grazing grass-only swards receiving 250 kg nitrogen (N)/ha/year (Grass), (2) Cows grazing grass-white clover swards receiving 250 kg N/ha/year (Grass-Clover), and (3) Cows offered a total mixed ration diet and housed indoors (TMR). Treatment significantly affected milk production; milk yield and milk solids yield were generally highest on the TMR treatment. There was no effect of treatment on rumen pH. However, treatment significantly altered the rumen volatile fatty acid (VFA), and ammonia and lactic acid profiles. Clover inclusion in the sward led to higher (p < 0.05) total VFA and ammonia concentrations compared to the Grass and TMR treatments. The increased rumen ammonia concentration was associated with a significantly greater milk urea nitrogen (MUN) content in the milk from cows fed on Grass-Clover, indicating a greater excess of dietary protein in that treatment. It was concluded that a clover-based dairy cow feeding system could significantly alter rumen function, milk composition and milk yield.


The relationship between the structure and toxicity of aminoglycoside antibiotics.
Aminoglycoside antibiotics, used to treat persistent gram-negative infections, tuberculosis, and life-threatening infections in neonates and patients with cystic fibrosis, can infer acute kidney injury and irreversible hearing loss. The full repertoire of cellular targets and processes leading to the toxicity of aminoglycosides is not fully resolved, making it challenging to devise rational directions to circumvent their adverse effects. As a result, there has been very limited effort to rationally address the issue of aminoglycoside-induced toxicity. Here we provide an overview of the reported effects of aminoglycosides on cells of the inner ear and on kidney tubular epithelial cells. We describe selected examples for structure-toxicity relationships established by evaluation of both natural and semisynthetic aminoglycosides. The various assays and models used to evaluate these antibiotics and recent progress in development of safer aminoglycoside antibiotics are discussed.


Contextual prediction errors reorganize naturalistic episodic memories in time.
Episodic memories are contextual experiences ordered in time. This is underpinned by associative binding between events within the same contexts. The role of prediction errors in declarative memory is well established but has not been investigated in the time dimension of complex episodic memories. Here we combine these two properties of episodic memory, extend them into the temporal domain and demonstrate that prediction errors in different naturalistic contexts lead to changes in the temporal ordering of event structures in them. The wrongly predicted older sequences were weakened despite their reactivation. Interestingly the newly encoded sequences with prediction errors, seen once, showed accuracy as high as control sequences which were viewed repeatedly without change. Drift-diffusion modelling revealed a lower decision threshold for the newer sequences than older sequences, reflected by their faster recall. Moreover, participants' adjustments to their decision threshold significantly correlated with their relative speed of sequence memory recall. These results suggest a temporally distinct and adaptive role for prediction errors in learning and reorganizing episodic temporal sequences.


An evaluation of the Modified R/B Enteric Differential System for the identification of the Enterobacteriaceae.
Two hundred and twenty-two organisms were identified by conventional methods and by the Modified R/B Enteric Differential System. Two hundred and eighteeen (98-2%) of these organisms were correctly identified by the R/B system. The results of individual tests were also compared. The convenience and general ease of handling of the R/B system are discussed.


An assessment of the transport mechanism and intraneuronal stability of L-carnosine.
L-Carnosine (β-alanyl-L-histidine) is a well-known antioxidant and neuroprotector in various models on animals and cell cultures. However, while there is a plethora of data demonstrating its efficiency as a neuroprotector, there is a distinct lack of data regarding the mechanism of its take up by neurons. According to literature, cultures of rat astrocytes, SKPT cells and rat choroid plexus epithelial cells take up carnosine via the H+-coupled PEPT2 membrane transporter. We've assessed the effectiveness and mechanism of carnosine transport, and its stability in primary rat cortical culture neurons. We demonstrated that neurons take up carnosine via active transport with Km = 119 μM and a maximum velocity of 0.289 nmol/mg (prot)/min. Passive transport speed constituted 0.21∙10-4 nmol/mg (prot)/min (with 119 μM concentration in the medium)-significantly less than active transport speed. However, carnosine concentrations over 12.5 mM led to passive transport speed becoming greater than active transport speed. Using PEPT2 inhibitor zofenopril, we demonstrated that PEPT2-dependent transport is one of the main modes of carnosine take up by neurons. Our experiments demonstrated that incubation with carnosine does not affect PEPT2 amount present in culture. At the same time, after removing carnosine from the medium, its elimination speed by culture cells reached 0.035 nmol/mg (prot)/min, which led to a decrease in carnosine quantity to control levels in culture within 1 h. Thus, carnosine is taken up by neurons with an effectiveness comparable to that of other PEPT2 substrates, but its elimination rate suggests that for effective use as a neuroprotector it's necessary to either maintain a high concentration in brain tissue, or increase the effectiveness of glial cell synthesis of endogenous carnosine and its shuttling into neurons, or use more stable chemical modifications of carnosine.


Multitasking in Driving as Optimal Adaptation Under Uncertainty.
The objective was to better understand how people adapt multitasking behavior when circumstances in driving change and how safe versus unsafe behaviors emerge. Multitasking strategies in driving adapt to changes in the task environment, but the cognitive mechanisms of this adaptation are not well known. Missing is a unifying account to explain the joint contribution of task constraints, goals, cognitive capabilities, and beliefs about the driving environment. We model the driver's decision to deploy visual attention as a stochastic sequential decision-making problem and propose hierarchical reinforcement learning as a computationally tractable solution to it. The supervisory level deploys attention based on per-task value estimates, which incorporate beliefs about risk. Model simulations are compared against human data collected in a driving simulator. Human data show adaptation to the attentional demands of ongoing tasks, as measured in lane deviation and in-car gaze deployment. The predictions of our model fit the human data on these metrics. Multitasking strategies can be understood as optimal adaptation under uncertainty, wherein the driver adapts to cognitive constraints and the task environment's uncertainties, aiming to maximize the expected long-term utility. Safe and unsafe behaviors emerge as the driver has to arbitrate between conflicting goals and manage uncertainty about them. Simulations can inform studies of conditions that are likely to give rise to unsafe driving behavior.


Anti-oxidative, physico-chemical and sensory attributes of burfi affected by incorporation of different herbs and its comparison with synthetic anti-oxidant (BHA).
Six different herbs, viz., turmeric, ginger, clove, curry leaves, basil leaves and small cardamom, were incorporated (@1% of khoa) into burfi, a heat desiccated-sweetened milk product, for their ability to act as natural anti-oxidant and were compared against butylated hydroxyanisole (BHA). Anti-oxidative potential of burfi significantly increased with herbs incorporation, which was in the order of clove > turmeric > basil leaves > curry leaf > ginger > cardamom. However, it was lower when compared to BHA added samples. Gross compositional attributes of burfi remained unaffected upon herb incorporation, however, significant lowering in water activity was observed upon cardamom and clove addition. Hunter color analysis revealed that cloves decreased lightness and increased redness, turmeric increased yellowness, and basil and curry leaves increased greenness in burfi. Texture attributes viz., hardness, springiness and gumminess were significantly higher for clove and cardamom burfi. Sensory evaluation revealed that among the different herbs, cardamom is highly preferred in burfi followed by ginger, turmeric, clove, curry leaves and basil leaves. However, no significant difference in sensory attributes were observed between control, cardamom and BHA added burfi samples.


A re-examination of the GABA-inhibitory action of bicuculline on lobster muscle.
The GABA-inhibitory action of bicuculline on lobster muscle was critically re-examined. Bicuculline (20-100 micrometers) depressed the GABA-evoked conductance increase in a reversible manner, the double reciprocal transformation of the GABA dose/conductance curves remaining linear. If bicuculline was assumed to be a pure non-competitive antagonist, then the observed depression of the GABA curves at high GABA concentrations was underestimated. Also, the action of bicuculline was not in accordance with a dualistic antagonism (competitive and pure non-competitive type). Regarding bicuculline as a "mixed" non-competitive antagonist however, gave a better overall fit to the experimental data. Combinations of bicuculline and picrotoxinin also depressed the GABA response in a manner expected from the combination of two "mixed" non-competitive antagonists. It was concluded that bicuculline (like picrotoxinin and picrotoxin) behaves as a "mixed" non-competitive rather than a pure non-competitive antagonist of GABA on lobster muscle. However bicuculline methochloride proved inactive on the lobster. Moreover, bicuculline itself became less effective in a more acidic solution (pH 5.6, where more of the protonated form would exist). An intracellular or intramembrane site of action of this antagonist was therefore postulated.


Acute intensive care unit resuscitation of severely injured trauma patients: Do we need a new strategy?
Unlike recent advances in blood product resuscitation, intravenous crystalloid (IVF) use after intensive care unit (ICU) admission in hemorrhagic shock has received less attention and current recommendations are based on limited evidence. To address this knowledge gap, we aimed to determine associations between IVF administration during acute ICU resuscitation and outcomes. We hypothesized that larger IVF volumes are associated with worse outcomes. We linked our trauma registry with electronic health record data (2012-2015) to identify adults with an initial lactate level of ≥4 mmol/L and documented lactate normalization (≤2 mmol/L), excluding those with isolated head Abbreviated Injury Scale score ≥3. We focused on the period from ICU admission to lactate normalization, analyzing duration, volume of IVF, and proportion of volume as 1-L boluses. We used linear regression to determine associations with ICU length of stay and duration of mechanical ventilation in survivors, and logistic regression to identify associations with acute kidney injury and home discharge while adjusting for important covariates. We included 337 subjects. Median time to lactate normalization was 15 hours (interquartile range, 7-25 hours), and median IVF volume was 3.7 L (interquartile range, 1.5-6.4 L). The fourfold difference between the upper and lower quartiles of both duration and volume remained after stratifying by injury severity. Hourly volumes tapered over time but persistently aggregated at 0.5 and 1 L, with 167 subjects receiving at least one 0.5-L bolus for 6 hours after ICU admission. Administration of larger volumes was associated with longer ICU length of stay and duration of mechanical ventilation, as well as acute kidney injury. There is substantial variation in volume administered during acute ICU resuscitation, both absolutely and temporally, despite accounting for injury severity. Administration of larger volumes during acute ICU resuscitation is associated with worse outcomes. There is an opportunity to improve outcomes by further investigating and standardizing this important phase of care. Therapeutic/care management, level IV.


Microincision bimanual phacoemulsification and Thinoptx implantation through a 1.70 mm incision.
To prospectively assess the efficacy of bimanual phacoemulsification and implantation of Thinoptx, an injectable intraocular lens (IOL), inserted through 1.70 mm clear corneal incision. Department of Ophthalmology, Southend Hospital NHS Trust, UK. A total of 50 eyes of 49 randomly selected patients with cataracts had microincision clear corneal bimanual phacoemulsification (MICS) with implantation of Thinoptx IOL in the capsular bag. All patients underwent full preoperative assessment. Postoperative assessment was carried out at 3 and 6 weeks and at 15 months. In all 50 cases the IOL was inserted through 1.70 mm clear corneal incision. The mean best-corrected visual acuity was 0.02 (6/6-1) at 6 weeks and was 0.17 (6/10) at the final follow-up. The mean final surgically induced astigmatism at 6 weeks was 0.0106. Coloured haloes around artificial lights were perceived by 69.23% of patients at 6 weeks and by 61.29% at the final follow-up. One patient underwent IOL exchange for this. Posterior capsular opacification was noticed in 31.26% at 6 weeks and in 64.51% at 15 months. Anterior capsular opacification was noticed in 5.26% at 6 weeks and in 16.12% at 15 months. In one patient the IOL had to be exchanged because of tilt and displacement of the IOL due to anterior capsular phimosis. We conclude Thinoptx can be safely inserted through 1.70 mm incision used for bimanual phacoemulsification. Distance and near visual acuity achieved with this IOL is satisfactory. There is no significant change in keratometric astigmatism following this procedure. However, posterior capsular opacification rate was significantly higher with this IOL. Haloes around light sources were significant.


Insulin receptor structure and its implications for the IGF-1 receptor.
The insulin receptor (isoforms IR-A and IR-B) and the type-I insulin-like growth factor receptor (IGF-1R) are homologous, multi-domain tyrosine kinases that bind insulin and IGF-1 with differing specificity. IR is involved in metabolic regulation and IGF-1R in normal growth and development. IR-A also binds IGF-2 with an affinity comparable to IGF-1R and, like the latter, is implicated in a range of cancers. The recent structure of the IR ectodomain dimer explains many features of ligand-receptor binding and provides insight into the structure of the intact ligand-binding site in both receptors. The structures of the L1-CR-L2 fragments of IR and IGF-1R reveal major differences in the regions that govern ligand specificity. The IR ectodomain X-ray structure raises doubts about that obtained by STEM reconstruction.


Multivariate analysis of electron detachment dissociation and infrared multiphoton dissociation mass spectra of heparan sulfate tetrasaccharides differing only in hexuronic acid stereochemistry.
The structural characterization of glycosaminoglycan (GAG) carbohydrates by mass spectrometry has been a long-standing analytical challenge due to the inherent heterogeneity of these biomolecules, specifically polydispersity, variability in sulfation, and hexuronic acid stereochemistry. Recent advances in tandem mass spectrometry methods employing threshold and electron-based ion activation have resulted in the ability to determine the location of the labile sulfate modification as well as assign the stereochemistry of hexuronic acid residues. To facilitate the analysis of complex electron detachment dissociation (EDD) spectra, principal component analysis (PCA) is employed to differentiate the hexuronic acid stereochemistry of four synthetic GAG epimers whose EDD spectra are nearly identical upon visual inspection. For comparison, PCA is also applied to infrared multiphoton dissociation spectra (IRMPD) of the examined epimers. To assess the applicability of multivariate methods in GAG mixture analysis, PCA is utilized to identify the relative content of two epimers in a binary mixture.


Oxytocin and vasopressin hexapeptide fragments have opposing influences on conditioned freezing behavior.
We investigated the influence of C-terminal fragments of oxytocin (OT) and arginine vasopressin (AVP) on conditioned freezing behavior. Subcutaneous injections of 0.3 microgram AVP(4-9) or OT(4-9) given to rats after shock training or before behavioral observation significantly altered fear-induced freezing behavior. Animals treated with OT hexapeptide froze less than controls, while animals treated with AVP hexapeptide froze more. These results support the concept that the hexapeptide metabolites of oxytocin and vasopressin can selectively modulate certain behavioral processes, and that these peptides have opposite effects on performance in behavioral tests designed to evaluate memory consolidation and retrieval.


A study of the effects of near UV radiation on the pigmentation of the blue-green alga Gloeocapsa alpicola.
The UV survival characteristics of a wild-type and a UV resistant strain of Gloeocapsa alpicola were compared. Except for a higher carotenoid content the resistant strain was similar to the wild-type. However, on exposure to UV radiation the level of carotenoids in the wild-type fell sharply whereas no such decrease occurred in the resistant strain. Growth of cells in diphenylamine and under red and blue light reduced the survival rate. This phenomenon is linked with a reduced carotenoid level in the cell, indicating that they perform an important protective function.


Culture-based prescribing to improve mental health: a scoping review protocol.
The objective of this review is to investigate what is known about culture-based prescribing to improve mental health and well-being. Culture-based prescribing, where a person is referred by a clinical professional to an arts or cultural activity aimed at improving mental health and well-being, is increasingly used as a community-based source of support. Although culture-based prescribing seems promising, the field is heterogeneous with respect to definition, underlying hypotheses, and cultural activity. This hampers its further development and implementation. We will consider publications that report on or explore culture-based prescribing to improve mental health and well-being for adults with symptoms related to mental health conditions who are seeking care from any clinical professional. We will search 8 electronic literature databases for published or unpublished reports on culture-based prescribing, without date limits. We will also search for gray literature and screen reference lists of relevant reviews. No language restrictions will be applied during the screening process, but for data extraction, we will only extract studies in languages our team has proficiency in. The screening and data extraction will be performed by 2 reviewers, independently. Data analysis will be descriptive, with results tabulated separately for each subquestion. The results will be complemented with a narrative summary. Open Science Framework https://osf.io/ndbqj.


Negative Pressure Wound Therapy for Burns.
Negative pressure wound therapy (NPWT) has become a widely used treatment for acute and chronic wounds. NPWT is indicated for a variety of complex wounds, and some studies validate its use for certain aspects of burn care. Although further research is needed to explore the benefits for burns, NPWT has proven beneficial in its use as a dressing that bolsters skin grafts, promotes integration of bilaminate dermal substitutes, promotes re-epithelialization of skin graft donor sites, and potentially reduces the zone of stasis. This article reviews the literature on NPWT in burns, based on indication/application, and describes our experience with the use of modified NPWT for large burns.


Are empiric antibiotics for acute exudative tonsillitis needed in children?
Empiric antibiotics are frequently given for children with acute exudative tonsillitis. A few studies have investigated the causative agent of acute "exudative" tonsillitis in children to evaluate the necessity of antibiotic therapy. This study tried to explore the common causative agent of acute exudative tonsillitis among children. From April 2009 to March 2010, throat swabs were obtained and cultured for viruses and bacteria from children who visited the pediatric emergency rooms of two medical centers in central Taiwan with acute exudative tonsillitis. Demographic data and microbiological results were analyzed. A total of 294 children with acute exudative tonsillitis were enrolled during the 1-year prospective study, and 173 (58.8%) of them were younger than 7 years. Group A streptococci were isolated from only three (1.0%) children, and they were all older than 6 years. A total of 143 viruses were isolated from 140 (47.6%) children. Adenovirus (18.7%) and enterovirus (16.3%) were the most common viral etiologies, followed by influenza virus (5.4%), parainfluenza virus (5.1%), herpes simplex virus Type 1 (2.7%), and respiratory syncytial virus (0.3%). Group A streptococcus only contributed to a minimal portion of acute exudative tonsillitis. Routine or immediate antibiotic therapy for acute exudative tonsillitis in children is not necessary.


Dynamical systems and cognitive linguistics: toward an active morphodynamical semantics.
We propose a novel dynamical system approach to cognitive linguistics based on cellular automata and spiking neural networks. How can the same relationship 'in' apply to containers as different as 'box', 'tree' or 'bowl'? Our objective is to categorize the infinite diversity of schematic visual scenes into a small set of grammatical elements and elucidate the topology of language. Gestalt-inspired semantic studies have shown that spatial prepositions such as 'in' or 'above' are neutral toward the shape and size of objects. We suggest that this invariance can be explained by introducing morphodynamical transforms, which erase image details and create virtual structures or singularities (boundaries, skeleton), and call this paradigm 'active semantics'. Singularities arise from a large-scale lattice of coupled excitable units exhibiting spatiotemporal pattern formation, in particular traveling waves. This work addresses the crucial cognitive mechanisms of spatial schematization and categorization at the interface between vision and language and anchors them to expansion processes such as activity diffusion or wave propagation.


Effects of long term NOS inhibition on disease and the immune system in MOG induced EAE.
Hypothesising that systemically and intrathecally produced nitric oxide might play different roles in the EAE pathogenesis, we administered the NOS inhibitor N-nitro-methyl-L-arginine-ester intrathecally or systemically via osmotic minipumps to DA rats with MOG induced EAE. We demonstrate an protective effect of the NOS inhibitor on EAE severity, the extent of CNS inflammation, and demyelination. Intrathecal administration was more effective when compared to systemic administration. The observed effect was accompanied by enhanced anti-MOG IgG1 production. In our model, the therapeutic effect was concluded to be due to direct inhibition of the NO pathway in the CNS.


Platelet-activating factor (PAF-acether) induced leukotriene C4 formation and luminol dependent chemiluminescence by human eosinophils.
Human eosinophils are capable of synthesizing almost exclusively the strongly spasmogenic compound LTC4 when stimulated with either the calcium ionophore A 23187 or opsonized zymosan (OZ). Although PAF-acether in concentrations ranging from 10 nM to 1 microM is hardly capable of inducing significant LTC4 synthesis itself, it significantly enhances the OZ-induced LTC4 formation at a concentration of 1 microM. However, at a concentration of 10 microM, PAF-acether itself is capable of inducing LTC4 formation comparable with that induced by OZ. PAF-acether, at a concentration of 10 microM (and not at a concentration of 1 microM) is also capable of inducing a luminol dependent chemiluminescent response by eosinophils. The PAF-acether antagonist BN 52021 at a concentration of 0.1 mM not only partially inhibited the PAF-acether induced LTC4 formation but also the OZ induced LTC4 formation. Since an equal inhibition is found the inhibitory mode of action of BN 52021 is most likely directed towards a common pathway. Taken together, these results suggest that eosinophils may be triggered by high locally reached concentrations of PAF-acether to release inflammatory and bronchoconstrictive mediators. This may be of importance for the pathogenesis of the allergen induced late phase asthmatic reaction.


Corticosteroid prevention of carcinogenesis in benzo[a]pyrene or ultraviolet irradiation-treated Syrian hamster cells in vitro.
Cortisol and dexamethasone, at 10(-9)--10(-11) M, inhibit benzo[a]pyrene and ultraviolet irradiation-induced morphological transformation of hamster embryo fibroblasts without inhibiting cell proliferation in a cell culture model of carcinogenesis. Inhibition varies directly with steroid concentration and is complete at equimolar doses for these glucocorticosteroids possessing a 30-fold difference in anti-inflammatory activity. Corticosteroids are known to affect enzymes metabolizing carcinogenic polycyclic aromatic hydrocarbons (PCH) and to inhibit complete PCH and phorbol ester promotion of PCH tumorigenesis. The pleotropic anti-carcinogenic action of corticosteroids is further demonstrated by the prevention of transformation induced by ultraviolet irradiation, a carcinogen not requiring metabolic activation.


Ciprofloxacin population pharmacokinetics during long-term treatment of osteoarticular infections.
Ciprofloxacin is an antibiotic used in osteoarticular infections owing to its very good bone penetration. Very few pharmacokinetic data are available in this population. To investigate oral ciprofloxacin population pharmacokinetics in adult patients treated for osteoarticular infections and propose guidance for more effective dosing. A retrospective population-pharmacokinetic analysis was performed on 92 consecutive hospitalized patients in the orthopaedic department. Ciprofloxacin plasma samples were obtained on one or two occasions during treatment. Plasma concentration was measured using ultra-performance liquid chromatography system coupled with tandem mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2019R2. A total of 397 plasma samples were obtained with 11.5% and 41.6% of patients being below the therapeutic target for Gram-negative and staphylococcal infections, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model with a first-order absorption. Ciprofloxacin apparent plasma clearances and volumes of distribution were dependent on patients' fat-free mass according to the allometric rule. Elimination clearance was also positively related to renal function through the modification of diet in renal disease equation (MDRD) and rifampicin co-administration. When patients are co-treated with rifampicin, ciprofloxacin dosage should be increased by 50% to 60%. This study showed that free-fat mass was a better size predictor than total body weight for ciprofloxacin clearance and volumes terms. Moreover, both MDRD and rifampicin status were significant predictors of individual ciprofloxacin clearance. Our study suggests that individual adjustment of ciprofloxacin dose in osteoarticular infections with less-susceptible bacteria might be indicated to reach required efficacy targets.


Menopause Is Associated With Immune Activation in Women With HIV.
Persistent immune activation due to gut barrier dysfunction is a suspected cause of morbidity in HIV, but the impact of menopause on this pathway is unknown. In 350 women with HIV from the Women's Interagency HIV Study, plasma biomarkers of gut barrier dysfunction (intestinal fatty acid binding protein; IFAB), innate immune activation (soluble CD14 and CD163; sCD14, sCD163), and systemic inflammation (interleukin-6 and tumor necrosis factor receptor 1; IL-6, TNFR1) were measured at 674 person-visits spanning ≤2 years. Menopause (post- vs premenopausal status) was associated with higher plasma sCD14 and sCD163 in linear mixed-effects regression adjusting for age and other covariates (β = 161.89 ng/mL; 95% confidence interval [CI], 18.37-305.41 and 65.48 ng/mL, 95% CI, 6.64-124.33, respectively); but not with plasma IFAB, IL-6, or TNFR1. In piece-wise linear mixed-effects regression of biomarkers on years before/after the final menstrual period, sCD14 increased during the menopausal transition by 250.71 ng/mL per year (95% CI, 16.63-484.79; P = .04), but not in premenopausal or postmenopausal periods. In women with HIV, menopause may increase innate immune activation, but data did not support an influence on the gut barrier or inflammation. Clinical implications of immune activation during menopausal transition warrant further investigation.


Joint reconstruction following trauma: comparison of microsurgical transfer and conventional methods: a report of 61 cases.
Joint reconstruction at the metacarpophalangeal or proximal interphalangeal levels remains a difficult problem in hand surgery. The authors reviewed sixty-one joints reconstructed acutely or electively allowing to compare Swanson spacer (30 joints), interpositional arthroplasty (4), non vascularized joint transfer (5) and vascularized joint transfer (21). Among these, two different techniques have been used: island compound transfer from a finger bank (10) and free vascularized transfer from the second toe (10) or from a non replantable finger (1). It is not worth while comparing different techniques applied to different indications. The only point which can be stressed is the better average range of movement of metacarpophalangeal reconstruction compared to that obtained at the proximal interphalangeal level.


Incident atrial fibrillation and its risk prediction in patients developing COVID-19: A machine learning based algorithm approach.
The elderly multi-morbid patient is at high risk of adverse outcomes with COVID-19 complications, and in the general population, the development of incident AF is associated with worse outcomes in such patients. There is therefore the need to identify those patients with COVID-19 who are at highest risk of developing incident AF. We therefore investigated incident AF risks in a large prospective population of elderly patients with/without incident COVID-19 cases and baseline cardiovascular/non-cardiovascular multi-morbidities. We used two approaches: main effect modeling and secondly, a machine-learning (ML) approach, accounting for the complex dynamic relationships among comorbidity variables. We studied a prospective elderly US cohort of 280,592 patients from medical databases in an 8-month investigation of with/without newly incident COVID19 cases. Incident AF outcomes were examined in relationship to diverse multi-morbid conditions, COVID-19 status and demographic variables, with ML accounting for the dynamic nature of changing multimorbidity risk factors. Multi-morbidity contributed to the onset of confirmed COVID-19 cases with cognitive impairment (OR 1.69; 95%CI 1.52-1.88), anemia (OR 1.41; 95%CI 1.32-1.50), diabetes mellitus (OR 1.35; 95%CI 1.27-1.44) and vascular disease (OR 1.30; 95%CI 1.21-1.39) having the highest associations. A main effect model (C-index value 0.718) showed that COVID-19 had the highest association with incident AF cases (OR 3.12; 95%CI 2.61-3.710, followed by congestive heart failure (1.72; 95%CI 1.50-1.96), then coronary artery disease (OR 1.43; 95%CI 1.27-1.60) and valvular disease (1.42; 95%CI 1.26-1.60). The ML algorithm demonstrated improved discriminatory validity incrementally over the statistical main effect model (training: C-index 0.729, 95%CI 0.718-0.740; validation: C-index 0.704, 95%CI 0.687-0.72). Calibration of the ML based formulation was satisfactory and better than the main-effect model. Decision curve analysis demonstrated that the clinical utility for the ML based formulation was better than the 'treat all' strategy and the main effect model. COVID-19 status has major implications for incident AF in a cohort with diverse cardiovascular/non-cardiovascular multi-morbidities. Our ML approach accounting for dynamic multimorbidity changes had good prediction for new onset AF amongst incident COVID19 cases.


Effects of exenatide versus insulin glargine on body composition in overweight and obese T2DM patients: a randomized controlled trial.
Weight loss, especially fat mass reduction, helps to improve blood glucose control, insulin sensitivity, and β-cell function. This study aimed to compare the effect of exenatide and glargine on body composition in overweight and obese patients with type 2 diabetes (T2DM) who do not achieve adequate glycemic control with metformin. We performed a prospective, randomized study of 37 overweight or obese patients with T2DM who had inadequate glycemic control with metformin. The patients were treated with either exenatide or glargine for 16 weeks. Dual-energy X-ray absorptiometry was used to assess body composition. Post-intervention weight, body mass index (BMI), waist circumference, body mass, and fat mass were lower in patients treated with exenatide, while weight and BMI significantly increased with glargine. Reductions in weight, BMI, body fat mass, and percent fat mass (except for gynoid) were greater with exenatide than with glargine, and percent lean tissue (other than the limbs) increased with exenatide. In all body regions except for the limbs, fat mass decreased with exenatide to a greater extent than lean tissue. Glucose control, insulin resistance, and β-cell function were not different between the treatment groups. For overweight and obese patients whose T2DM was inadequately controlled with metformin, exenatide and glargine achieved similar improvements in glycemic control, insulin sensitivity, and β-cell function.However, exenatide produced better weight and fat mass reduction, which were beneficial for blood glucose control. Our findings may guide the selection of appropriate drugs for glycemic and weight control. NCT02325960, registered 25 December 2014.


Skateboard head injuries: Are we making progress?
Skateboarding is a popular sport and U.S. trauma centers care for a significant number of skateboard-related injuries (SRIs). However, injury prevention strategies are still underdeveloped. This study was designed to compare the epidemiology, type, and location of skateboard injury as well as the use and influence of protective gear over two time periods. This is a retrospective National Trauma Data Bank study including all patients with SRIs between 2007and 2016. Study groups were divided into two 5-year periods: 2007-2011 and 2012-2016. The incidence and severity of traumatic brain injury (TBI), as well as the compliance and effectiveness of protective gear and skate parks, was assessed in various age groups in the two study periods using univariable and multivariable analyses. Univariable analysis was used to compare the two study periods, logistic regression analysis was performed to identify independent predictors of head injury and severe TBI. 24,903 patients presented with SRIs: 10,594 from 2007 to 2011 and 14,309 from 2012 to 2016. Helmet use was low in both periods (5.7% and 5.4% respectively). The incidence of severe TBI (head AIS≥3) did not change significantly during the two periods (31.6% vs. 30.8%, p = 0.162). In children with severe TBI, there was no significant difference in helmet use across all ages, (10.4% vs. 11.5%, p = 0.467; 6.4% vs. 6.5%, p = 0.753; 4.2% vs. 3.7%, p = 0.201, respectively) with the lowest usage in the older than 16 years age group. On logistic regression, male gender (OR 1.526, 95% CI 1.372-1.698, p<0.001) was associated with increased odds of severe TBI, while helmet use (OR 0.534, 95% CI 0.455-0.627, p<0.001) and injuries at skate parks (OR 0.584, 95% CI 0.541-0.630, p<0.001), near home (OR 0.465, 95% CI 0.418-0.518, p<0.001), and public buildings (OR 0.386, 95% CI 0.440-0.541, p<0.001) were associated with reduced odds of severe TBI. Helmet use in patients with SRIs is low in all pediatric age groups. Helmet use and skate parks are protective against severe TBI. Older age children and male gender are at increased risk of severe TBI after skateboard-related injuries, and more targeted preventive education and legislation are needed.


Atraumatic open reduction with controlled traction in acute slipped capital femoral epiphysis in adolescents.
In the management of slipped capital femoral epiphysis, the modified technique of so-called open traction reduction has proven to be atraumatic, relatively straightforward in terms of surgical technique, and has led to successful outcomes. It seems that additional, that is, surgery-related circulatory disorders of the femoral epiphysis can be avoided by this method.