Prevalence of shoulder and upper-limb disorders among workers in the fish-processing industry.
A cross-sectional study was conducted among fish-processing workers to evaluate the prevalence of shoulder and upper-limb discomforts and to assess the associated ergonomic risk factors. A prestructured interview, a medical check-up, and job analyses were performed to determine musculoskeletal disorders among 207 workers in eight factories. The results showed shoulder girdle pain (30.9%), epicondylitis (14.5%), and carpal tunnel syndrome (15.0%) as the three most common soft-tissue disorders. The odds ratio of shoulder girdle pain was 1.6 (95% CI 1.1-2.5) among the workers who performed tasks with repetitive movement of their upper limbs, while it was 1.8 (95% CI 1.2-2.5) for the workers who sustained forceful movement of their upper limbs during work. Women taking oral contraceptives had a 2.0 times higher odds ratio for carpal tunnel syndrome than did other women. It would appear that untrained or unskilled workers were prone to suffer from musculoskeletal disorders.


Substrate specificity of human metallocarboxypeptidase D: Comparison of the two active carboxypeptidase domains.
Metallocarboxypeptidase D (CPD) is a membrane-bound component of the trans-Golgi network that cycles to the cell surface through exocytic and endocytic pathways. Unlike other members of the metallocarboxypeptidase family, CPD is a multicatalytic enzyme with three carboxypeptidase-like domains, although only the first two domains are predicted to be enzymatically active. To investigate the enzymatic properties of each domain in human CPD, a critical active site Glu in domain I and/or II was mutated to Gln and the protein expressed, purified, and assayed with a wide variety of peptide substrates. CPD with all three domains intact displays >50% activity from pH 5.0 to 7.5 with a maximum at pH 6.5, as does CPD with mutation of domain I. In contrast, the domain II mutant displayed >50% activity from pH 6.5-7.5. CPD with mutations in both domains I and II was completely inactive towards all substrates and at all pH values. A quantitative peptidomics approach was used to compare the activities of CPD domains I and II towards a large number of peptides. CPD cleaved C-terminal Lys or Arg from a subset of the peptides. Most of the identified substrates of domain I contained C-terminal Arg, whereas comparable numbers of Lys- and Arg-containing peptides were substrates of domain II. We also report that some peptides with C-terminal basic residues were not cleaved by either domain I or II, showing the importance of the P1 position for CPD activity. Finally, the preference of domain I for C-terminal Arg was validated through molecular docking experiments. Together with the differences in pH optima, the different substrate specificities of CPD domains I and II allow the enzyme to perform distinct functions in the various locations within the cell.


Antidepressants for insomnia in adults.
Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long-term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer-term use of hypnotics and the limited availability of psychological treatments. To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults. This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review. Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual. Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction. The search identified 23 RCTs (2806 participants).Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence).There were either no adverse events or they were not reported (very low quality evidence).Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) -0.39, 95% confidence interval (CI) -0.56 to -0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD -4.27 minutes, 95% CI -9.01 to 0.48; 4 studies; 510 participants).There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence).'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD -0.34, 95% CI -0.66 to -0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI -2.87 to 5.63; 169 participants) (low quality evidence).There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst). We identified relatively few, mostly small studies with short-term follow-up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long-term antidepressant use for insomnia. High-quality trials of antidepressants for insomnia are needed.


Differences in food preferences between individuals and populations of domestic cats Felis silvestris catus.
The food preferences of 64 cats, of which 28 were domestic pets and 36 were free-ranging animals on three farms, were tested using five food types; a sixth type was also tested on the farm cats. Information was also gathered on the background diet of the house cats (individually) and of each farm cat colony. Consistent differences were found between the predefined groups of cats in their preferences for three foods, Hard Dry (HD), Canned Meat (CM) and Raw Beef (RB), the greatest differences being between house cats and farm cats as a whole. The three colonies of farm cats showed distinct differences in preference, for RB and/or CM, and for the sixth food, Soft Dry (SD). Differences between farms could be explained by a reduced preference for items similar to major components of the background diet of each colony, i.e. selection in favour of foods that were temporally rare. Differences between house and farm cats, and within the house cats, could not be explained in this way; the house cats were neophobic towards RB, and the farm cats ate little of the HD food, possibly because they found it difficult to ingest.


Comparison of the Abilities of SD-OCT and SS-OCT in Evaluating the Thickness of the Macular Inner Retinal Layer for Glaucoma Diagnosis.
To compare the abilities of spectral-domain optical coherence tomography (OCT) (SD-OCT; Spectralis, Heidelberg Engineering) and swept-source OCT (SS-OCT; DRI-OCT1 Atlantis system, Topcon) for analyzing the macular inner retinal layers in diagnosing glaucoma. The study included 60 patients with primary open-angle glaucoma (POAG) and 60 healthy control subjects. Macular cube area was scanned using SD-OCT and SS-OCT on the same day to assess the thicknesses of the macular retinal nerve fiber layer (mRNFL), ganglion cell layer plus inner plexiform layer (GCIPL), and total retinal layer in nine subfields defined by the Early Treatment Diabetic Retinopathy Study (ETDRS). The abilities of the parameters to discriminate between the POAG and control groups were assessed using areas under the receiver operating characteristic curves (AUCs). Glaucoma-associated mRNFL and GCIPL thinning was more common in the outer zones than inner zones for both SD-OCT and SS-OCT. The mRNFL and GCIPL measurements showed distinct pattern differences between SD-OCT and SS-OCT in each ETDRS subfield. Although the glaucoma-diagnosis ability was comparable between SD-OCT and SS-OCT for most of the parameters, AUC was significantly larger for SD-OCT measurements of the GCIPL thickness in the outer temporal zones (p = 0.003) and of the mRNFL thickness in the outer nasal zones (p = 0.001), with the former having the largest AUC for discriminating POAG from healthy eyes (AUC = 0.894). Spectralis SD-OCT and DRI SS-OCT have similar glaucoma-diagnosis abilities based on macular inner layer thickness analysis. However, Spectralis SD-OCT was potentially superior to DRI SS-OCT in detecting GCIPL thinning in the outer temporal zone, where the glaucomatous damage predominantly occurs.


ThT 101: a primer on the use of thioflavin T to investigate amyloid formation.
Thioflavin T (ThT) has been widely used to investigate amyloid formation since 1989. While concerns have recently been raised about its use as a probe specific for amyloid, ThT still continues to be a very valuable tool for studying kinetic aspects of fibrillation and associated inhibition mechanisms. This review aims to provide a conceptual instruction manual, covering appropriate considerations and pitfalls related to the use of ThT. We start by giving a brief introduction to amyloid formation with focus on the morphology of different aggregate species, followed by a discussion of the quality of protein needed to obtain reliable fibrillation data. After an overview of the photochemical basis for ThT's amyloid binding properties and artifacts that may arise from this, we describe how to plan and analyze ThT assays. We conclude with recommendations for complementary techniques to address shortcomings in the ThT assay.


Cutaneous drug reaction case reports: from the world literature.
Skin disorders are the most common adverse reactions attributed to drugs. Any skin disorder can be imitated, induced or aggravated by drugs. To help you keep up-to-date with the very latest skin reactions occurring with both new and established drugs, this section of the journal brings you information selected from the adverse drug reaction alerting service Reactions Weekly. The following case reports are selected from the very latest to be published in the world dermatology literature. Any claim of a first report has been verified by a search of AdisBase (a proprietary database of Adis International) and Medline. In addition, the World Health Organization (WHO) Adverse Drug Reactions database is also searched. This database, maintained by the Uppsala Monitoring Centre in Sweden, is the largest and most comprehensive adverse drug reaction source in the world, with information obtained from National Centers of around 70 affiliate countries. Each case report is assessed for seriousness using the FDA MedWatch definition of serious (patient outcome is: death; life-threatening; hospitalization; disability; congenital anomaly; or requires intervention to prevent permanent impairment or damage).


Resource use and cost of treatment with voriconazole or conventional amphotericin B for invasive aspergillosis.
Voriconazole, a broad-spectrum triazole, has demonstrated significantly improved survival compared with conventional amphotericin B (CAB) as initial therapy for invasive aspergillosis (IA). To compare health care resource use and cost at 12 weeks following first-line treatment with voriconazole compared with CAB for IA using resource use data collected during a clinical trial. Days of hospitalization, intensive care, antifungal drug use, and outpatient care were collected during a large randomized, controlled trial of patients with IA receiving initial treatment with voriconazole or CAB. Unit costs based on published data sources were applied to healthcare use to estimate 12-week costs following initiation of therapy. Resource use and costs were compared for each treatment arm overall and by survival. The sensitivity of total costs to changes in healthcare use and unit costs was examined. Total hospital days and intensive care unit (ICU) days were similar for voriconazole and CAB (total: 27.8 vs. 27.7, P=0.97 and ICU: 5.6 vs. 8.1, P=0.11). Among survivors, voriconazole was associated with similar numbers of total hospital days (29.8 vs. 32.0 days, P=0.54) to CAB, but fewer ICU days (3.9 vs. 8.2, P=0.03). For non-survivors, those treated with voriconazole had a similar number of total hospital days (23.0 vs. 21.8, P=0.73) and ICU days (9.8 vs. 7.9, P=0.44). Patients treated with voriconazole had significantly more days alive and out of the hospital than with CAB at 12 weeks (40.3 vs. 28.4 days, P<0.001). Total costs were similar with voriconazole compared with CAB ($78,860 vs. $83,857, P=0.51). Differences in cost were not sensitive to changes in the input parameter values. Using voriconazole first-line for treatment of IA resulted in significantly fewer deaths and similar treatment costs. Hospital-free survival was significantly greater for patients initially treated with voriconazole.


Wireless GPS-based phase-locked synchronization system for outdoor environment.
Synchronization of data coming from different sources is of high importance in biomechanics to ensure reliable analyses. This synchronization can either be performed through hardware to obtain perfect matching of data, or post-processed digitally. Hardware synchronization can be achieved using trigger cables connecting different devices in many situations; however, this is often impractical, and sometimes impossible in outdoors situations. The aim of this paper is to describe a wireless system for outdoor use, allowing synchronization of different types of - potentially embedded and moving - devices. In this system, each synchronization device is composed of: (i) a GPS receiver (used as time reference), (ii) a radio transmitter, and (iii) a microcontroller. These components are used to provide synchronized trigger signals at the desired frequency to the measurement device connected. The synchronization devices communicate wirelessly, are very lightweight, battery-operated and thus very easy to set up. They are adaptable to every measurement device equipped with either trigger input or recording channel. The accuracy of the system was validated using an oscilloscope. The mean synchronization error was found to be 0.39 μs and pulses are generated with an accuracy of <2 μs. The system provides synchronization accuracy about two orders of magnitude better than commonly used post-processing methods, and does not suffer from any drift in trigger generation.


Cluster headache in Asian populations: Similarities, disparities, and a narrative review of the mechanisms of the chronic subtype.
Headache disorders like migraine show geographic and ethnic differences between Asian and European/North American countries. In cluster headache, these differences are rarely mentioned and discussed. This article aimed to review the characteristics of cluster headache in Asian countries and compare the clinical features to those in European and North American populations. We conducted a narrative literature review on the demographics, clinical presentations, and treatments of cluster headache in Asian countries. Patients with cluster headache in Asian populations showed a stronger male predominance compared to European and North American populations. Chronic cluster headache was rare in Asian countries. The clinical presentation of restlessness was not as common in Asian as it was in European and North American countries, and Asian patients with aura were extremely rare. Patients in Asian countries may have a lower circadian rhythmicity of cluster headache and a lower headache load, as demonstrated by lower attack frequencies per day, bout frequencies, and bout durations. Regional differences in the presentation of cluster headache exist. Greater awareness for cluster headache should be raised in Asian regions, and further studies are warranted to elucidate the mechanisms behind observed differences.


Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein.
N-linked glycosylation of proteins in eukaryotic cells follows a highly conserved pathway. The tetradecasaccharide substrate (Glc3Man9GlcNAc2) is first assembled at the membrane of the endoplasmic reticulum (ER) as a dolichylpyrophosphate (Dol-PP)-linked intermediate, and then transferred to nascent polypeptide chains in the lumen of the ER. The assembly of the oligosaccharide starts on the cytoplasmic side of the ER membrane with the synthesis of a Man5GlcNAc2-PP-Dol intermediate. This lipid-linked intermediate is then translocated across the membrane so that the oligosaccharides face the lumen of the ER, where the biosynthesis of Glc3Man9GlcNAc2-PP-Dol continues to completion. The fully assembled oligosaccharide is transferred to selected asparagine residues of target proteins. The transmembrane movement of lipid-linked Man5GlcNAc2 oligosaccharide is of fundamental importance in this biosynthetic pathway, and similar processes involving phospholipids and glycolipids are essential in all types of cells. The process is predicted to be catalysed by proteins, termed flippases, which to date have remained elusive. Here we provide evidence that yeast RFT1 encodes an evolutionarily conserved protein required for the translocation of Man5GlcNAc2-PP-Dol from the cytoplasmic to the lumenal leaflet of the ER membrane.


Detection of Mycobacterium tuberculosis in sputum samples by polymerase chain reaction using a simplified procedure.
A repetitive sequence of Mycobacterium tuberculosis DNA was amplified by polymerase chain reaction (PCR), from sputum samples, for the diagnosis of pulmonary tuberculosis. The method of heating the sample in a boiling water bath to break down the bacterial cell wall and to release the DNA was compared with that of enzymatic lysis of bacteria and then phenol-chloroform extraction of DNA. Heating the sample was the better method with a sensitivity of approximately 10 microorganisms. A total of 78 sputum specimens prepared by heating were examined by PCR, and the results were compared with the results of acid-fast stained smears, cultures, and clinical data. M. tuberculosis was detected by PCR in all smear- and culture-positive and smear-negative, culture-positive cases. Additionally, PCR was capable of detecting four of nine cases which were smear and culture negative but clinically suspected of tuberculosis. DNA amplification by PCR is a sensitive and specific method for the diagnosis of tuberculosis, and with this simplified DNA isolation procedure it can be used in routine clinical practice.


Computational modeling of fluid flow and intra-ocular pressure following glaucoma surgery.
Glaucoma surgery is the most effective means for lowering intraocular pressure by providing a new route for fluid to exit the eye. This new pathway is through the sclera of the eye into sub-conjunctival tissue, where a fluid filled bleb typically forms under the conjunctiva. The long-term success of the procedure relies on the capacity of the sub-conjunctival tissue to absorb the excess fluid presented to it, without generating excessive scar tissue during tissue remodeling that will shut-down fluid flow. The role of inflammatory factors that promote scarring are well researched yet little is known regarding the impact of physical forces on the healing response. To help elucidate the interplay of physical factors controlling the distribution and absorption of aqueous humor in sub-conjunctival tissue, and tissue remodeling, we have developed a computational model of fluid production in the eye and removal via the trabecular/uveoscleral pathways and the surgical pathway. This surgical pathway is then linked to a porous media computational model of a fluid bleb positioned within the sub-conjunctival tissue. The computational analysis is centered on typical functioning bleb geometry found in a human eye following glaucoma surgery. A parametric study is conducted of changes in fluid absorption by the sub-conjunctival blood vessels, changes in hydraulic conductivity due to scarring, and changes in bleb size and shape, and eye outflow facility. This study is motivated by the fact that some blebs are known to have 'successful' characteristics that are generally described by clinicians as being low, diffuse and large without the formation of a distinct sub-conjunctival encapsulation. The model predictions are shown to accord with clinical observations in a number of key ways, specifically the variation of intra-ocular pressure with bleb size and shape and the correspondence between sites of predicted maximum interstitial fluid pressure and key features observed in blebs, which gives validity to the model described here. This model should contribute to a more complete explanation of the physical processes behind successful bleb characteristics and provide a new basis for clinically grading blebs.


Obstruction of the superior vena cava after neonatal extracorporeal membrane oxygenation: association with chylothorax and outcome of transcatheter treatment.
Obstruction of the superior vena cava is one of the potential complications of neonatal extracorporeal membrane oxygenation. Chylothorax is a known complication of surgery involving the thoracic cavity in children, and of extracorporeal membrane oxygenation. The aim of this study was to evaluate the association between chylothorax and superior vena cava obstruction after neonatal extracorporeal membrane oxygenation. Twenty-two patients diagnosed with superior vena cava obstruction at ≤ 6 months of age (median 1.8 months) after neonatal extracorporeal membrane oxygenation were compared with a randomly selected cohort of 44 neonatal extracorporeal membrane oxygenation patients without superior vena cava obstruction. Among patients with superior vena cava obstruction, 18 underwent extracorporeal membrane oxygenation for respiratory disease and four for cardiac insufficiency. Chylothorax was more prevalent among patients with superior vena cava obstruction than controls (odds ratio 9.4 [2.2-40], p = .01) and was associated with extension of obstruction into the left innominate vein. Patients with superior vena cava obstruction were supported by extracorporeal membrane oxygenation for a longer duration than controls. Nineteen patients with superior vena cava obstruction (86%) underwent transcatheter balloon angioplasty and/or stent implantation (median 7 days after diagnosis), which decreased the superior vena cava pressure and superior vena cava-to-right atrium pressure gradient and increased the superior vena cava diameter (all p < 0.001). There were no serious procedural adverse events. Six study patients died within 30 days of the diagnosis of superior vena cava obstruction (including three of nine with chylothorax), which did not differ from controls. During a median follow-up of 2.7 yrs, two additional patients died and nine underwent 14 superior vena cava reinterventions. Among neonates treated with extracorporeal membrane oxygenation, superior vena cava obstruction is associated with an increased risk of chylothorax. In neonates with chylothorax after extracorporeal membrane oxygenation, evaluation for superior vena cava obstruction may be warranted. Although mortality is high in this population, transcatheter treatment can relieve superior vena cava obstruction and facilitate symptomatic improvement.


In vitro and animal studies of sodium thiosulfate as a potential chemoprotectant against carboplatin-induced ototoxicity.
When carboplatin (cis-diammine-1,1-cyclobutane-dicarboxylato-platinum) delivery to brain tumors is optimized with osmotic blood-brain barrier disruption (BBBD), high frequency hearing loss can result. Treatment with sodium thiosulfate (STS) blocked carboplatin cytotoxicity against the LX-1 human small cell lung carcinoma cell line in vitro. STS decreased carboplatin-induced ototoxicity in a guinea pig model, as determined by electrophysiological measurements and analysis of inner ear outer hair cell numbers. Protection was found when STS was administered up to 8 h subsequent to carboplatin but not 24 h after carboplatin. In a rat model of osmotic BBBD, STS was neurotoxic when given immediately after BBBD but not when given 60 min after BBBD, when the barrier is reestablished. Thus, delayed administration of STS may provide a mechanism to reduce the cochlear toxicity caused by BBBD-enhanced carboplatin delivery to the brain.


How Health Risks Are Pinpointed (or Not) on Social Media: The Portrayal of Waterpipe Smoking on Pinterest.
Waterpipe tobacco is among the most rapidly growing trends in tobacco smoking, the growing use and acceptance of which are taking place at a time when cigarette smoking is regarded in an increasingly negative manner (Martinasek, McDermott, & Martini, 2011). Given the health risks and the misperceptions associated with waterpipe smoking, this study focuses on how waterpipe smoking is portrayed and represented on the social media platform Pinterest. In total, 800 Pinterest pins were content analyzed. The vast majority of the sampled pins were primarily image based. More than half of the pins linked to a website external to Pinterest that often redirected the pinner to a commercial website. Waterpipe-focused pins portrayed waterpipe smoking more in a positive light than in a negative light, and conveyed a sense of pleasure, aesthetic, and relaxation, which tended to trigger more repins, likes, and higher levels of engagement. Overall, the risks of waterpipe smoking were not represented on Pinterest, indicating that the social media portrayal of waterpipe smoking needs improvement and could benefit from a public health perspective.


Communication about opioid versus nonopioid analgesics in the emergency department.
The Medication Communication Index (MCI) was used to compare counseling about opioids to nonopioid analgesics in the Emergency Department (ED) setting. Secondary analysis of prospectively collected audio recordings of ED patient visits. Urban, academic medical center (>85,000 annual patient visits). Patient participants aged >18 years with one of four low acuity diagnoses: ankle sprain, back pain, head injury, and laceration. ED clinician participants included resident and attending physicians, nursing staff, and ED technicians. The MCI is a five-point index that assigns points for communicating the following: medication name (1), purpose (1), duration (1), adverse effects (1), number of tablets (0.5), and frequency of use (0.5). Recording transcripts were scored with the MCI, and total scores were compared between drug classes. The 41 patients received 56 prescriptions (27 nonopioids, 29 opioids). Nonopioid median MCI score was 3 and opioid score was 4.5 (p=0.0008). Patients were counseled equally about name (nonopioid 100 percent, opioid 96.6 percent, p=0.34) and purpose (88.9 percent, 89.7 percent, p=0.93). However, patients receiving opioids were counseled more frequently about duration of use (nonopioid 40.7 percent, opioid 69.0 percent, p=0.03) and adverse effects (18.5 percent, 93.1 percent, p<0.001). In multivariable analysis, opioids (β=0.54, p=0.04), number of medications prescribed (β=-0.49, p=0.05), and time spent in the ED (β=0.007, p=0.006) were all predictors of total MCI score. The extent of counseling about analgesic medications in the ED differs by drug class. When counseling patients about all analgesic medications, providers should address not only medication name and purpose but also the less frequently covered topics of medication dosing, timing, and adverse effects.


Safety and efficacy of an add-on therapy with curcumin phytosome and piperine and/or lipoic acid in subjects with a diagnosis of peripheral neuropathy treated with dexibuprofen.
We conducted an 8-week, open, randomized controlled clinical trial on 141 subjects affected by neuropathic pain to investigate the role of an adjunctive therapy added to the administration of dexibuprofen (400 mg twice a day) and based on a multi-ingredient formula (Lipicur), consisting of lipoic acid plus curcumin phytosome and piperine, in patients with a diagnosis of lumbar sciatica, lumbar disk herniation, and/or lumbar canal stenosis (96 subjects), or with carpal tunnel syndrome (45 subjects). A total of 135 participants completed the study. Treatment with the multi-ingredient formula (Lipicur) reduced neuropathic pain by more than 66% in both conditions (subjects with lumbar sciatica and with carpal tunnel syndrome), and these reductions were statistically significant. Moreover, the treatment reduced dexibuprofen use by about 40%. An add-on therapy with only lipoic acid has not shown any significant results. On the basis of its safety and efficacy, Lipicur could be considered an effective complementary therapy to be added to conventional treatments to achieve better efficacy in reducing neuropathic pain.


Methods for recovering poliovirus and rotavirus from oysters.
Polioviruses and rotaviruses are potential indicators of sewage pollution of water and shellfish. Several methods for detecting these viruses in oysters were assessed. Elution-precipitation involving Catfloc for clarification and skim milk for subsequent flocculation resulted in the recovery of an average of 79% of poliovirus type 1 and 37% of rotavirus SA-11 from oyster homogenates inoculated with low numbers of these viruses. Adsorption-elution-precipitation did not improve the recovery of poliovirus and was detrimental to the recovery of rotavirus. Ultrafiltration or ultracentrifugation resulted in improved recovery of rotavirus but also in higher toxicity of oyster extracts to cell cultures. We recommend the use of the described elution-precipitation method for detecting viral pollutants in sample of oysters.


Mechanism of ghrelin-induced gastric contractions in Suncus murinus (house musk shrew): involvement of intrinsic primary afferent neurons.
Here, we have reported that motilin can induce contractions in a dose-dependent manner in isolated Suncus murinus (house musk shrew) stomach. We have also shown that after pretreatment with a low dose of motilin (10(-10) M), ghrelin also induces gastric contractions at levels of 10(-10) M to 10(-7) M. However, the neural mechanism of ghrelin action in the stomach has not been fully revealed. In the present study, we studied the mechanism of ghrelin-induced contraction in vitro using a pharmacological method. The responses to ghrelin in the stomach were almost completely abolished by hexamethonium and were significantly suppressed by the administration of phentolamine, prazosin, ondansetron, and naloxone. Additionally, N-nitro-l-arginine methylester significantly potentiated the contractions. Importantly, the mucosa is essential for ghrelin-induced, but not motilin-induced, gastric contractions. To evaluate the involvement of intrinsic primary afferent neurons (IPANs), which are multiaxonal neurons that pass signals from the mucosa to the myenteric plexus, we examined the effect of the IPAN-related pathway on ghrelin-induced contractions and found that pretreatment with adenosine and tachykinergic receptor 3 antagonists (SR142801) significantly eliminated the contractions and GR113808 (5-hydroxytryptamine receptor 4 antagonist) almost completely eliminated it. The results indicate that ghrelin stimulates and modulates suncus gastric contractions through cholinergic, adrenergic, serotonergic, opioidergic neurons and nitric oxide synthases in the myenteric plexus. The mucosa is also important for ghrelin-induced gastric contractions, and IPANs may be the important interneurons that pass the signal from the mucosa to the myenteric plexus.


Infrared thermal imaging for automated detection of diabetic foot complications.
Although thermal imaging can be a valuable technology in the prevention and management of diabetic foot disease, it is not yet widely used in clinical practice. Technological advancement in infrared imaging increases its application range. The aim was to explore the first steps in the applicability of high-resolution infrared thermal imaging for noninvasive automated detection of signs of diabetic foot disease. The plantar foot surfaces of 15 diabetes patients were imaged with an infrared camera (resolution, 1.2 mm/pixel): 5 patients had no visible signs of foot complications, 5 patients had local complications (e.g., abundant callus or neuropathic ulcer), and 5 patients had diffuse complications (e.g., Charcot foot, infected ulcer, or critical ischemia). Foot temperature was calculated as mean temperature across pixels for the whole foot and for specified regions of interest (ROIs). No differences in mean temperature >1.5 °C between the ipsilateral and the contralateral foot were found in patients without complications. In patients with local complications, mean temperatures of the ipsilateral and the contralateral foot were similar, but temperature at the ROI was >2 °C higher compared with the corresponding region in the contralateral foot and to the mean of the whole ipsilateral foot. In patients with diffuse complications, mean temperature differences of >3 °C between ipsilateral and contralateral foot were found. With an algorithm based on parameters that can be captured and analyzed with a high-resolution infrared camera and a computer, it is possible to detect signs of diabetic foot disease and to discriminate between no, local, or diffuse diabetic foot complications. As such, an intelligent telemedicine monitoring system for noninvasive automated detection of signs of diabetic foot disease is one step closer. Future studies are essential to confirm and extend these promising early findings.


Bioinformatics analysis of the gene expression profiles in human intervertebral disc degeneration associated with inflammatory cytokines.
To investigate the microarray data on the gene expression profiles of intervertebral disc degeneration related to cytokine exposure. The purpose of the study was to identify the key genes that were differentially expressed in these disc cells compared to cells without inflammatory cytokine treatment, using bioinformatics analyses, and to explore the related signaling pathways and interaction networks, providing clues to the molecular mechanisms of disc degeneration for future experimental studies. The gene expression profiles data were obtained using the same microarray platform for two groups of patients suffering from degenerative disc diseases: GSE41883 (Human annulus disc cells exposed to TNF-a; 4 samples) and GSE27494 (Human annulus disc cells exposed to IL-1β; 4 samples). The genes that were differentially expressed in these two datasets compared to control disc cells (without cytokine exposure; 4 samples each) were identified using the R language, and were pooled using the Excel software program to select the common differentially expressed genes in the two datasets. The initial functional clustering, signaling pathways and protein-protein interaction relationship analyses were conducted using the DAVID and STRING software programs. Of the 255 concomitantly and differentially expressed genes identified after respective treatment with TNF-α and IL-1β, 141 were up-regulated and 114 were down-regulated. The gene ontology annotation analysis showed that these differentially expressed genes were primarily associated with cytokine activity, growth factor activity, the inflammatory reaction and the response to injury. The signaling pathway analysis showed that these differentially expressed genes were mainly related to the interactions of cytokines, apoptosis and NOD-like receptor signaling pathways. The interaction network analysis indicated that PTGS2, ICAM1, NOV and other genes may play a role in disc degeneration. We found that ICAM1 and other genes may play a role in the development of disc degeneration induced by inflammatory reactions using a bioinformatics analysis of the gene expression profiles of degenerative intervertebral disc cells stimulated with inflammatory factors, suggesting that bioinformatics methods can be used to identify potential target for intervertebral disc degeneration.


Gastroduodenal peptic ulcer and Helicobacter pylori infection in children and adolescents.
To show important aspects of gastroduodenal peptic ulcer and of Helicobacter pylori infection in children and adolescents. Technical textbooks and MEDLINE and LILACS databases including publications between 1966 and 2006. The etiology of peptic ulcer in children and adolescents may be primary, associated with H. pylori infection, or secondary, in which etiopathogenic mechanisms rely upon the underlying disease. The infection is acquired predominantly in childhood, with prevalence rates between 56.8 and 83.1% in children who live in the poorest Brazilian regions, amounting to nearly 10% in children aged less than 10 years in industrialized countries. The infection can be diagnosed by invasive methods, which investigate the presence of the bacterium, or of DNA, RNA or bacterial products in biopsy fragments of the gastric mucosa obtained at endoscopic examination; it can also be diagnosed through noninvasive methods, which include the detection of anti-H. pylori antibodies in serum, urine or saliva samples, detection of bacterial antigens in stool samples, and the carbon 13-labeled urea breath test. However, upper gastrointestinal endoscopy is the method of choice for the diagnosis of peptic ulcer, as it allows collecting fragments from the gastric mucosa during the procedure for the diagnosis of infection and for histopathological analysis. H. pylori infection is the major cause of peptic ulcer among children. Eradication of the bacterium with antimicrobial therapy results in the cure of the disease, and is therefore indicated for all children with H. pylori infection with an active, recurrent, healed, or complicated peptic ulcer.


The WHO Health Promoting School framework for improving the health and well-being of students and their academic achievement.
The World Health Organization's (WHO's) Health Promoting Schools (HPS) framework is an holistic, settings-based approach to promoting health and educational attainment in school. The effectiveness of this approach has not been previously rigorously reviewed. To assess the effectiveness of the Health Promoting Schools (HPS) framework in improving the health and well-being of students and their academic achievement. We searched the following electronic databases in January 2011 and again in March and April 2013: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, Campbell Library, ASSIA, BiblioMap, CAB Abstracts, IBSS, Social Science Citation Index, Sociological Abstracts, TRoPHI, Global Health Database, SIGLE, Australian Education Index, British Education Index, Education Resources Information Centre, Database of Education Research, Dissertation Express, Index to Theses in Great Britain and Ireland, ClinicalTrials.gov, Current controlled trials, and WHO International Clinical Trials Registry Platform. We also searched relevant websites, handsearched reference lists, and used citation tracking to identify other relevant articles. We included cluster-randomised controlled trials where randomisation took place at the level of school, district or other geographical area. Participants were children and young people aged four to 18 years, attending schools or colleges. In this review, we define HPS interventions as comprising the following three elements: input to the curriculum; changes to the school's ethos or environment or both; and engagement with families or communities, or both. We compared this intervention against schools that implemented either no intervention or continued with their usual practice, or any programme that included just one or two of the above mentioned HPS elements. At least two review authors identified relevant trials, extracted data, and assessed risk of bias in the trials. We grouped different types of interventions according to the health topic targeted or the approach used, or both. Where data permitted, we performed random-effects meta-analyses to provide a summary of results across studies. We included 67 eligible cluster trials, randomising 1443 schools or districts. This is made up of 1345 schools and 98 districts. The studies tackled a range of health issues: physical activity (4), nutrition (12), physical activity and nutrition combined (18), bullying (7), tobacco (5), alcohol (2), sexual health (2), violence (2), mental health (2), hand-washing (2), multiple risk behaviours (7), cycle-helmet use (1), eating disorders (1), sun protection (1), and oral health (1). The quality of evidence overall was low to moderate as determined by the GRADE approach. 'Risk of bias' assessments identified methodological limitations, including heavy reliance on self-reported data and high attrition rates for some studies. In addition, there was a lack of long-term follow-up data for most studies.We found positive effects for some interventions for: body mass index (BMI), physical activity, physical fitness, fruit and vegetable intake, tobacco use, and being bullied. Intervention effects were generally small but have the potential to produce public health benefits at the population level. We found little evidence of effectiveness for standardised body mass index (zBMI) and no evidence of effectiveness for fat intake, alcohol use, drug use, mental health, violence and bullying others; however, only a small number of studies focused on these latter outcomes. It was not possible to meta-analyse data on other health outcomes due to lack of data. Few studies provided details on adverse events or outcomes related to the interventions. In addition, few studies included any academic, attendance or school-related outcomes. We therefore cannot draw any clear conclusions as to the effectiveness of this approach for improving academic achievement. The results of this review provide evidence for the effectiveness of some interventions based on the HPS framework for improving certain health outcomes but not others. More well-designed research is required to establish the effectiveness of this approach for other health topics and academic achievement.


Comparison of microdilution and disc diffusion methods in assessing the in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil against vaginal Candida isolates.
The in vitro activity of fluconazole and Melaleuca alternifolia (tea tree) oil was evaluated against 99 vaginal Candida strains by the broth microdilution and disc diffusion methods. The microdilution method was performed in accordance with NCCLS-M27A guidelines. An investigational method was used for the disc diffusion test. Fluconazole and tea tree oil minimum inhibitory concentrations (MICs) obtained at 48 h tended to increase 1- to 2-fold or remain the same compared to 24 h readings for most of the isolates tested. C. krusei and C. norvegensis had significantly higher MICs and smaller inhibition zones for fluconazole compared to other species. Tea tree oil MICs were found to be similar, in general, for all Candida spp. tested. The geometric mean MIC of tea tree oil for all isolates was 2.2% (range, 0.25-4%) at 24 h and 3.0% (range, 1-8%) at 48 h. Tea tree oil mean inhibition zone diameter was 24 mm (range, 14-42 mm) at 24 h and 15.8 mm (range, 10-35 mm) at 48 h. In vitro activity of tea tree oil against fluconazole-resistant Candida strains was of particular interest. The isolates had similar tea tree oil MICs and inhibition zone diameters regardless of their fluconazole susceptibility profile. Tea tree oil MIC ranges (inhibition zone diameter ranges) were 2-4% (12-21 mm) and 2% (35 mm) at 48 h for C. krusei and C. norvegensis, respectively. These results suggest that tea tree oil MICs of the fluconazole-resistant isolates are comparable to those of fluconazole-susceptible isolates. This in vitro finding is promising for potential use of topical tea tree oil formulations in the treatment of candidiasis due to fluconazole-resistant strains.


Intracellular crystalline ergosterol in Neurospora.
In the fungus Neurospora crassa, hexagonal crystalline inclusions have been observed with both the light and electron microscopes. These crystals have been enriched by differential centrifugation and found to be identical with ergosterol by the criteria of ultraviolet spectral analysis and cytochemical analysis. Observations have been made on the distribution and fine structure of the crystalline bodies in various wild type and mutant strains of N. crassa.


Surgical technique: Tscherne-Johnson extensile approach for tibial plateau fractures.
The standard approach to lateral tibial plateau fractures involves elevation of the iliotibial band (IT) and anterior tibialis origin in continuity from Gerdy's tubercle and metaphyseal flare. We describe an alternative approach to increase lateral plateau joint exposure and maintain iliotibial band insertion to Gerdy's tubercle. The approach entails a partial tenotomy of the anterior half of the IT band leaving the posterior IT band insertion attached to Gerdy's tubercle. Fracture lines around Gerdy's tubercle are completed or the tubercle was osteotomized and externally rotated and the joint overdistracted, allowing direct visualization of the joint depression. Joint elevation, grafting, and internal fixation are performed through this window. We retrospectively reviewed 76 patients (two groups), Schatzker Types I to II and IV to VI fractures (66 patients), between 1989 and 2005, and 10 patients, with 10 bicondylar posterior plateau fractures, from 2002 to 2010. All patients were followed a minimum of 12 months (average, 3.9 years; range, 12 months to 10 years). Ten patients, with posterior plateau fractures, received anterolateral plateau intraarticular osteotomy for exposure of centroposterior and posterolateral articular depression. Average knee ROM was 2° of flexion (range, -3° to 5°) to greater than 120° of flexion (range, 100°-145°). In 66 patients, average articular depression improved from 7.4 mm to 1 mm (range, 0-5 mm) and, in 10 posterior fractures, from 18 mm to 1 mm (range, 0-4.5 mm). Infection occurred in one of the 76 patients; acute débridement and intravenous antibiotics resulted in control of the infection. This approach reliably increases direct visualization of the lateral plateau articular fractures and maintains IT band insertion. Articular osteotomy of the anterolateral plateau provides access to extensive posterior plateau fractures.


A lipopolysaccharide-induced DNA-binding protein for a class II gene in B cells is distinct from NF-kappa B.
Class II (Ia) major histocompatibility complex molecules are cell surface proteins normally expressed by a limited subset of cells of the immune system. These molecules regulate the activation of T cells and are required for the presentation of antigens and the initiation of immune responses. The expression of Ia in B cells is determined by both the developmental stage of the B cell and by certain external stimuli. It has been demonstrated previously that treatment of B cells with lipopolysaccharide (LPS) results in increased surface expression of Ia protein. However, we have confirmed that LPS treatment results in a significant decrease in mRNA encoding the Ia proteins which persists for at least 18 h. Within the upstream regulatory region of A alpha k, an NF-kappa B-like binding site is present. We have identified an LPS-induced DNA-binding protein in extracts from athymic mice whose spleens consist predominantly of B cells. Binding activity is present in low levels in unstimulated spleen cells and is increased by LPS treatment. This protein binds to two sites in a regulatory region of the Ia A alpha k gene, one of which contains the NF-kappa B-like binding site. DNA fragments containing these sites cross-compete for protein binding. Analysis by DNase I footprinting identified a target binding sequence, named the LPS-responsive element. Although this target sequence contains an NF-kappa B-like binding site, competition with a mutant oligonucleotide demonstrated that bases critical for NF-kappa B binding are not required for binding of the LPS-inducible protein. Therefore, we hypothesized that this inducible protein represents a new mediator of LPS action, distinct from NF-kappa B, and may be one mechanism to account for the decrease in mRNA encoding the Ia proteins.


Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy.
Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.


Long-distance pulse propagation in nonlinear optical fibers by using periodically spaced parametric amplifiers.
We analyze pulse propagation in a nonlinear optical fiber in which linear loss in the fiber is balanced by a chain of periodically spaced, phase-sensitive, degenerate parametric amplifiers. Our analysis shows that no pulse evolution occurs over a soliton period owing to attenuation in the quadrature orthogonal to the amplified quadrature. Evidence is presented that indicates that stable pulse solutions exist on length scales much longer than the soliton period. These pulses are governed by a nonlinear fourth-order evolution equation, which describes the exponential decay of arbitrary initial pulses (within the stability regime) onto stable, steady-state, solitonlike pulses.


Family-based interventions to increase physical activity in children: a systematic review, meta-analysis and realist synthesis.
Family-based interventions represent a potentially valuable route to increasing child physical activity (PA) in children. A dual meta-analysis and realist synthesis approach examined existing interventions to assist those developing programmes to encourage uptake and maintenance of PA in children. Studies were screened for inclusion based on including participants aged 5-12 years, having a substantive aim of increasing PA by engaging the family and reporting on PA outcome. Duplicate data extraction and quality assessment were conducted. Meta-analysis was conducted in STATA. Realist synthesis included theory development and evidence mapping. Forty-seven studies were included, of which three received a 'strong' quality rating, 21 'moderate' and 23 'weak'. The meta-analysis (19 studies) demonstrated a significant small effect in favour of the experimental group (standardized mean difference: 0.41; 95%CI 0.15-0.67). Sensitivity analysis, removing one outlier, reduced this to 0.29 (95%CI 0.14-0.45). Realist synthesis (28 studies) provided insight into intervention context (particularly, family constraints, ethnicity and parental motivation), and strategies to change PA (notably, goal-setting and reinforcement combined). This review provides key recommendations to inform policy makers and other practitioners in developing evidence-based interventions aimed at engaging the family to increase PA in children, and identifies avenues for future research.


Sulforaphane Bioavailability and Chemopreventive Activity in Women Scheduled for Breast Biopsy.
Epidemiologic studies suggest a protective effect of cruciferous vegetables on breast cancer. Sulforaphane (SFN), an active food component derived from crucifers, has been shown to be effective in breast cancer chemoprevention. This study evaluated the chemopreventive effect of SFN on selective biomarkers from blood and breast tissues. In a 2- to 8-week double-blinded, randomized controlled trial, 54 women with abnormal mammograms and scheduled for breast biopsy were randomized to consume a placebo or a glucoraphanin (GFN) supplement providing SFN (n = 27). Plasma and urinary SFN metabolites, peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity, and tissue biomarkers (H3K18ac, H3K9ac, HDAC3, HDAC6, Ki-67, p21) were measured before and after the intervention in benign, ductal carcinoma in situ, or invasive ductal carcinoma breast tissues. Within the supplement group, Ki-67 (P = 0.003) and HDAC3 (P = 0.044) levels significantly decreased in benign tissue. Pre-to-postintervention changes in these biomarkers were not significantly different between treatment groups after multiple comparison adjustment. GFN supplementation was associated with a significant decrease in PBMC HDAC activity (P = 0.04). No significant associations were observed between SFN and examined tissue biomarkers when comparing treatment groups. This study provides evidence that GFN supplementation for a few weeks is safe but may not be sufficient for producing changes in breast tissue tumor biomarkers. Future studies employing larger sample sizes should evaluate alternative dosing and duration regimens to inform dietary SFN strategies in breast cancer chemoprevention.


Plasmodium falciparum malaria elicits inflammatory responses that dysregulate placental amino acid transport.
Placental malaria (PM) can lead to poor neonatal outcomes, including low birthweight due to fetal growth restriction (FGR), especially when associated with local inflammation (intervillositis or IV). The pathogenesis of PM-associated FGR is largely unknown, but in idiopathic FGR, impaired transplacental amino acid transport, especially through the system A group of amino acid transporters, has been implicated. We hypothesized that PM-associated FGR could result from impairment of transplacental amino acid transport triggered by IV. In a cohort of Malawian women and their infants, the expression and activity of system A (measured by Na⁺-dependent ¹⁴C-MeAIB uptake) were reduced in PM, especially when associated with IV, compared to uninfected placentas. In an in vitro model of PM with IV, placental cells exposed to monocyte/infected erythrocytes conditioned medium showed decreased system A activity. Amino acid concentrations analyzed by reversed phase ultra performance liquid chromatography in paired maternal and cord plasmas revealed specific alterations of amino acid transport by PM, especially with IV. Overall, our data suggest that the fetoplacental unit responds to PM by altering its placental amino acid transport to maintain adequate fetal growth. However, IV more profoundly compromises placental amino acid transport function, leading to FGR. Our study offers the first pathogenetic explanation for FGR in PM.


A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2.
The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients' demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63+ intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies.


Impact of selection, mutation rate and genetic drift on human genetic variation.
The accumulation of genome-wide information on single nucleotide polymorphisms in humans provides an unprecedented opportunity to detect the evolutionary forces responsible for heterogeneity of the level of genetic variability across loci. Previous studies have shown that history of recombination events has produced long haplotype blocks in the human genome, which contribute to this heterogeneity. Other factors, however, such as natural selection or the heterogeneity of mutation rates across loci, may also lead to heterogeneity of genetic variability. We compared synonymous and non-synonymous variability within human genes with their divergence from murine orthologs. We separately analyzed the non-synonymous variants predicted to damage protein structure or function and the variants predicted to be functionally benign. The predictions were based on comparative sequence analysis and, in some cases, on the analysis of protein structure. A strong correlation between non-synonymous, benign variability and non-synonymous human-mouse divergence suggests that selection played an important role in shaping the pattern of variability in coding regions of human genes. However, the lack of correlation between deleterious variability and evolutionary divergence shows that a substantial proportion of the observed non-synonymous single-nucleotide polymorphisms reduces fitness and never reaches fixation. Evolutionary and medical implications of the impact of selection on human polymorphisms are discussed.


Biomechanical analysis of occipitocervical stabilization techniques: emphasis on integrity of osseous structures at the occipital implantation sites.
The objective of the current study was to quantify and compare the multidirectional flexibility properties of occipital anchor fixation with conventional methods of occipitocervical screw fixation using nondestructive and destructive investigative methods. Fourteen cadaveric occipitocervical specimens (Oc-T2) were randomized to reconstruction with occipital anchors or an occipital plate and screws. Using a 6-degree-of-freedom spine simulator with moments of ± 2.0 Nm, initial multidirectional flexibility analysis of the intact and reconstructed conditions was performed followed by fatigue loading of 25,000 cycles of flexion-extension (x-axis, ± 2.0 Nm), 15,000 cycles of lateral bending (z-axis, ± 2.0 Nm), and 10,000 cycles of axial rotation (y-axis, ± 2.0 Nm). Fluoroscopic images of the implantation sites were obtained before and after fatigue testing and placed on an x-y coordinate system to quantify positional stability of the anchors and screws used for reconstruction and effect, if any, of the fatigue component. Destructive testing included an anterior flexural load to construct failure. Quantification of implant, occipitocervical, and atlantoaxial junction range of motion is reported as absolute values, and peak flexural failure moment in Newton-meters (Nm). Absolute value comparisons between the intact condition and 2 reconstruction groups demonstrated significant reductions in segmental flexion-extension, lateral bending, and axial rotation motion at the Oc-C1 and C1-2 junctions (p < 0.05). The average bone mineral density at the midline keel (1.422 g/cm3) was significantly higher compared with the lateral occipital region at 0.671 g/cm3 (p < 0.05). There were no significant differences between the occipital anchor and plate treatments in terms of angular rotation (degrees; p = 0.150) or x-axis displacement (mm; p = 0.572), but there was a statistically significant difference in y-axis displacement (p = 0.031) based on quantitative analysis of the pre- and postfatigue fluoroscopic images (p > 0.05). Under destructive anterior flexural loading, the occipital anchor group failed at 90 ± 31 Nm, and the occipital plate group failed at 79 ± 25 Nm (p > 0.05). Both reconstructions reduced flexion-extension, lateral bending, and axial rotation at the occipitocervical and atlantoaxial junctions, as expected. Flexural load to failure did not differ significantly between the 2 treatment groups despite occipital anchors using a compression-fit mechanism to provide fixation in less dense bone. These data suggest that an occipital anchor technique serves as a biomechanically viable clinical alternative to occipital plate fixation.


Phthalate exposure and pubertal development in a longitudinal study of US girls.
Does phthalate exposure during early childhood alter the timing of pubertal development in girls? Urinary concentrations of high-molecular weight phthalate (high-MWP) metabolites are associated with later pubarche. Phthalates are anti-androgenic environmental agents known to alter early development, with possible effects on pubertal onset. This multi-ethnic study included 1239 girls from New York City, greater Cincinnati, and the San Francisco Bay Area who were 6-8 years old at enrollment (2004-2007) and who were followed until 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS Phthalate metabolites were measured in urine collected at enrollment from 1170 girls; concentrations ranged from <1 to >10,000 µg/l. Breast and pubic hair stages and body size were assessed one to two times annually to determine the age at transition from stage 1 to 2 for breast and pubic hair development. Associations between exposures and pubertal ages were estimated using Cox proportional hazard ratios (HR) with 95% confidence intervals (CI) and survival analyses. Associations were examined with respect to age-specific body mass-index percentile, one of the strongest predictors of pubertal onset. Urinary concentrations of high-MWP including di(2-ethylhexyl) phthalate (ΣDEHP) metabolites were associated with later pubic hair development during 7 years of observation. The relationship was linear and was stronger among normal-weight girls. Among normal-weight girls, age at pubic hair stage 2 (PH2) was 9.5 months older for girls in the fifth compared with the first quintile of urinary ΣDEHP (medians: 510 and 59 µg/g creatinine, respectively; adjusted HR 0.70, CI 0.53-0.93, P-trend 0.005. Age at first breast development was older for fifth quintile of mono-benzyl phthalate versus first (HR 0.83, CI 0.68-1.02; P-trend 0.018). No associations were observed between low-molecular weight phthalate urinary metabolite concentrations and age at pubertal transition in adjusted analyses. While there is evidence that phthalate exposures are fairly consistent over time, the exposure measure in this study may not reflect an earlier, more susceptible window of exposure. We investigated alternative explanations that might arise from exposure misclassification or confounding. Phthalates are widespread, hormonally active pollutants that may alter pubertal timing. Whether exposures delay or accelerate pubertal development may depend on age at exposure as well as other factors such as obesity and exposures earlier in life. Whether exposures act independently or as part of real life mixtures may also change their effects on maturation from birth through childhood. This project was supported by the US National Institutes of Health, Environmental Protection Agency, New York State Empire Clinical Research Investigator Program and the Avon Foundation. L.H.K. is employed by Kaiser Permanente. The remaining authors declare they have no actual or potential competing financial interests.


Surgical management of bronchiectasis in childhood.
Though there is a gradual decrease in the prevalence of bronchiectasis, it is still a cause of mortality and morbidity among children in developing countries such as Turkey. We reviewed the morbidity and mortality rates and the outcome of surgical treatment for childhood bronchiectasis. Age, sex, etiological factors, symptoms, radiological examinations, surgical procedures, postoperative morbidity and mortality in patients aged 16 years and younger, operated for bronchiectasis between January 1991 and April 2006 in the Thoracic Surgery Clinic of Atatürk Training and Research Hospital for Chest Disease and Chest Surgery were reviewed retrospectively. Between January 1991 and April 2006, 176 cases aged 16 and younger were operated for bronchiectasis. There were 95 females (54%) and 81 males (46%), with a mean age of 12.3 years (range: 3.4-16 years). The most common cause of bronchiectasis was lung infection (n: 87, 49.4%). Main symptoms were coughing (n: 167, 94.9%), sputum (n: 139, 79%), hemoptysis (n: 78, 44.3%), and fever (n: 77, 43.7%). Mean duration of the symptoms in patients who were operated was 3.8 years (range: 0-7.6 years). Cases underwent a total of 201 operations: 19 cases had bilateral surgical resection and 6 cases had completion pneumonectomy. Majority of cases had complete resection (n: 165, 93.75%) while only 11 cases (6.25%) had incomplete resection. Mean duration of hospitalization was 8.9 days (range: 5-39 days). The outcome, based on the responses of patients postoperatively, was 'perfect' in 129 cases (73.3%), 'improved' in 41 cases (23.3%), and 'no changes' in 6 cases (3.4%). The mean follow-up after surgery was 4.3 years (range: 14 months to 7.2 years), mortality was 0% and morbidity was 13% (n: 23). With acceptable mortality and morbidity rates and high chance of cure after complete resection, surgical treatment is a successful and reliable method of treatment in childhood bronchiectasis that yields marked improvement in the quality of life.


Can preschool improve child health outcomes? A systematic review.
Early childhood development interventions (ECDIs) have the potential to bring about wide ranging human capital benefits for children through to adulthood. Less is known, however, about the potential for such interventions to improve population health. The aim of this study was to examine the evidence for child health effects of centre-based preschool intervention programs for healthy 4 year olds, beyond the preschool years. Medline, Embase, ERIC, Psych Info, Sociological Abstracts, the Cochrane Library, C2-SPECTR and the Head Start database were searched using terms relating to preschool and health from 1980 to July 2008, limited to English language publications. Reference lists and the journal Child Development were hand searched for eligible articles missed by the electronic search. There were 37 eligible studies identified. The reviewed studies examined a range of interventions from centre-based preschool alone, to interventions also including parenting programs and/or health services. The study populations were mostly sampled from populations at risk of school failure (76%). Only eight of the 37 studies had a strong methodological rating, 15 were evaluated as at moderate potential risk of bias and 14 as at high potential risk of bias. The review found generally null effects of preschool interventions across a range of health outcomes, however there was some evidence for obesity reduction, greater social competence, improved mental health and crime prevention. We conclude that the great potential for early childhood interventions to improve population health across a range of health outcomes, as anticipated by policy makers worldwide, currently rests on a rather flimsy evidence base. Given the potential and the increasingly large public investment in these interventions, it is imperative that population health researchers, practitioners and policy makers worldwide collaborate to advance this research agenda.


Ultrasound for fracture healing: current evidence.
Low-intensity pulsed ultrasound (LIPUS) is a relatively new technique for the acceleration of fracture healing in fresh fractures and nonunions. It has a frequency of 1.5 MHz, a signal burst width of 200 micros, a signal repetition frequency of 1 kHz, and an intensity of 30 mW/cm2. In 1994 and 1997, two milestone double-blind randomized controlled trials revealed the benefits of LIPUS for the acceleration of fracture healing in the tibia and radius. They showed that LIPUS accelerated the fracture healing rate from 24% to 42% for fresh fractures. Some literature, however, has shown no positive effects. The beneficial effect of acceleration of fracture healing by LIPUS is considered to be larger in the group of patients or fractures with potentially negative factors for fracture healing. The incidence of delayed union and nonunion is 5% to 10% of all fractures. For delayed union and nonunion, the overall success rate of LIPUS therapy is approximately 67% (humerus), 90% (radius/radius-ulna), 82% (femur), and 87% (tibia/tibia-fibula). LIPUS likely has the ability to enhance maturation of the callus in distraction osteogenesis and reduce the healing index. The critical role of LIPUS for fracture healing is still unknown because of the heterogeneity of results in clinical trials for fresh fractures and the lack of controlled trials for delayed unions and nonunions.


Genetic predispositions moderate the effectiveness of tobacco excise taxes.
Tobacco consumption is one of the leading causes of preventable death. In this study, we analyze whether someone's genetic predisposition to smoking moderates the response to tobacco excise taxes. We interact polygenic scores for smoking behavior with state-level tobacco excise taxes in longitudinal data (1992-2016) from the US Health and Retirement Study (N = 12,058). Someone's genetic propensity to smoking moderates the effect of tobacco excise taxes on smoking behavior along the extensive margin (smoking vs. not smoking) and the intensive margin (the amount of tobacco consumed). In our analysis sample, we do not find a significant gene-environment interaction effect on smoking cessation. When tobacco excise taxes are relatively high, those with a high genetic predisposition to smoking are less likely (i) to smoke, and (ii) to smoke heavily. While tobacco excise taxes have been effective in reducing smoking, the gene-environment interaction effects we observe in our sample suggest that policy makers could benefit from taking into account the moderating role of genes in the design of future tobacco control policies.


Vitamin E (Alpha-Tocopherol) Metabolism and Nutrition in Chronic Kidney Disease.
Vitamin E (alpha-tocopherol) is an essential micronutrient and fat-soluble antioxidant with proposed role in protecting tissues from uncontrolled lipid peroxidation. This vitamin has also important protein function and gene modulation effects. The metabolism of vitamin E depends on hepatic binding proteins that selectively retain food alpha-tocopherol for incorporation into nascent VLDL and tissue distribution together with esterified cholesterol and triglycerides. Chronic kidney disease (CKD) is a condition of oxidative stress and increased lipid peroxidation, that are associated with alterations of alpha-tocopherol metabolism and function. Specific changes have been reported for the levels of its enzymatic metabolites, including both short-chain and long-chain metabolites, the latter being endowed with regulatory functions on enzymatic and gene expression processes important for the metabolism of lipids and xenobiotics detoxification, as well as for the control of immune and inflammatory processes. Vitamin E therapy has been investigated in CKD using both oral vitamin E protocols and vitamin E-coated hemodialyzers, showing promising results in the secondary prevention of cardiovascular disease, as well as of immune and hematological complications. These therapeutic approaches are reviewed in the present article, together with a narrative excursus on the main findings indicating CKD as a condition of relative deficiency and impaired metabolism of vitamin E.


Pilot study of etanercept in patients with refractory juvenile dermatomyositis.
To evaluate the efficacy of etanercept in patients with juvenile dermatomyositis (DM) refractory to standard treatment. Nine patients with juvenile DM prospectively received etanercept 0.4 mg/kg subcutaneous twice weekly concurrently with baseline medications for 12 weeks. Patients were reevaluated 12 weeks (week 24) after stopping etanercept. Outcome measures included a validated Disease Activity Score (DAS), serum muscle enzymes, Childhood Myositis Assessment Scale (CMAS), and nailfold capillaroscopy (NFC). Six patients completed all visits; 2 patients completed through week 12 and 1 patient stopped after the fifth etanercept dose due to marked worsening of a rash. At week 12, 7 patients had a mild decrease in DAS and 1 patient noted worsening of the DAS. At week 24, 1 patient remained stable, 2 patients had worsening of the DAS, and 3 patients had improvement of the DAS (1 patient with inactive disease), including the patient who worsened while receiving etanercept. This patient and the patient who stopped (worsening rash) both had the tumor necrosis factor α (TNFα) 308A allele. There was a trend of worsening NFC at week 12, while at week 24 improvement of NFC was noted. There was no appreciable change in serum muscle enzymes or CMAS throughout the study. In this trial of patients with refractory juvenile DM, etanercept did not demonstrate appreciable improvement and some patients noted worsening of disease. Caution should be taken when recommending TNF receptor inhibitors to patients with active symptoms of juvenile DM, and close followup is warranted. Further investigation of the interaction of the TNFα-308A polymorphism and type I interferon is needed to define the mechanism of TNF blockade in juvenile DM.


Incremental Trainable Parameter Selection in Deep Neural Networks.
This article explores the utilization of the effective degree-of-freedom (DoF) of a deep learning model to regularize its stochastic gradient descent (SGD)-based training. The effective DoF of a deep learning model is defined only by a subset of its total parameters. This subset is highly responsive or sensitive toward the training loss, and its cardinality can be used to govern the effective DoF of a model during training. To this aim, the incremental trainable parameter selection (ITPS) algorithm is introduced in this article. The proposed ITPS algorithm acts as a wrapper over SGD and incrementally selects the parameters for updation that exhibit the maximum sensitivity toward the training loss. Hence, it gradually increases the DoF of the model during training. In ideal cases, the proposed algorithm arrives at a model configuration (i.e., DoF) optimum for the task at hand. This whole process results in a regularization-like behavior induced by a gradual increment of the DoF. Since the selection and updation of parameters is a function of the training loss, the proposed algorithm can be seen as a task and data-dependent regularization mechanism. This article exhibits the general utility of ITPS by evaluating it on various prominent neural network architectures such as CNNs, transformers, recurrent neural networks (RNNs), and multilayer perceptrons. These models are trained for image classification and healthcare tasks using the publicly available CIFAR-10, SLT-10, and MIMIC-III datasets.


Autografts commonly used in anterior cruciate ligament reconstruction.
Anterior cruciate ligament reconstruction is among the most common orthopaedic procedures in the United States, with >200,000 performed annually. Much has been published regarding the use of autograft versus allograft. Bone-patellar tendon-bone is the most frequently used autograft, but hamstring and quadriceps tendon grafts are common alternatives. Each graft has distinct advantages and disadvantages, and selection is individualized. Fixation methods vary by graft type. Fixation resulting in a construct that is too rigid may restrict knee range of motion. Donor site morbidity must be considered, as well. Autograft harvest may result in anterior knee pain, kneeling pain, anterior knee numbness, muscle weakness, and patellar fracture. Appropriate graft selection is essential to optimize outcomes.


Research on workplace health promotion in the Nordic countries: a literature review, 1986-2008.
Workplace health promotion may include approaches focusing on behavioral change among employees and approaches with a holistic system-oriented thinking aiming at changing the physical, social and organizational factors of a setting. This literature review aimed to identify studies on workplace health promotion in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), to describe when, where and how the studies were performed and to further analyze the use of settings approaches and empowerment processes. Using scientific literature databases, we found 1809 hits when searching for Nordic studies published from 1986 to 2008 with the search term health promotion. Of these, 116 studies were related to workplace health promotion and 33 included interventions. We used content analysis to analyze the abstracts of all articles and the full articles of the intervention studies. Most studies were performed in Sweden and Finland. The focus was mainly on behavioral change rather than on holistic health promotion as defined by the Ottawa Charter for Health Promotion. This was especially obvious for the intervention studies. In addition to the intervention studies using non-settings approaches with top-down driven behavioral change, we identified studies with participatory settings approaches aimed at changing the setting. We categorized relatively few studies as having a non-participatory settings approach. The studies aiming specifically at improving employees' empowerment were evenly distributed between the categories market-oriented persuasion of empowerment, therapeutic empowerment and empowerment as a liberal management strategy. More studies on workplace health promotion using empowering and participatory settings approaches are needed in the Nordic countries, and a more theory-based approach towards this research field is needed.


Whey protein concentrate enhances intestinal integrity and influences transforming growth factor-β1 and mitogen-activated protein kinase signalling pathways in piglets after lipopolysaccharide challenge.
Whey protein concentrate (WPC) has been reported to have protective effects on the intestinal barrier. However, the molecular mechanisms involved are not fully elucidated. Transforming growth factor-β1 (TGF-β1) is an important component in the WPC, but whether TGF-β1 plays a role in these processes is not clear. The aim of this study was to investigate the protective effects of WPC on the intestinal epithelial barrier as well as whether TGF-β1 is involved in these protection processes in a piglet model after lipopolysaccharide (LPS) challenge. In total, eighteen weanling pigs were randomly allocated to one of the following three treatment groups: (1) non-challenged control and control diet; (2) LPS-challenged control and control diet; (3) LPS+5 %WPC diet. After 19 d of feeding with control or 5 %WPC diets, pigs were injected with LPS or saline. At 4 h after injection, pigs were killed to harvest jejunal samples. The results showed that WPC improved (P<0·05) intestinal morphology, as indicated by greater villus height and villus height:crypt depth ratio, and intestinal barrier function, which was reflected by increased transepithelial electrical resistance and decreased mucosal-to-serosal paracellular flux of dextran (4 kDa), compared with the LPS group. Moreover, WPC prevented the LPS-induced decrease (P<0·05) in claudin-1, occludin and zonula occludens-1 expressions in the jejunal mucosae. WPC also attenuated intestinal inflammation, indicated by decreased (P<0·05) mRNA expressions of TNF-α, IL-6, IL-8 and IL-1β. Supplementation with WPC also increased (P<0·05) TGF-β1 protein, phosphorylated-Smad2 expression and Smad4 and Smad7 mRNA expressions and decreased (P<0·05) the ratios of the phosphorylated to total c-jun N-terminal kinase (JNK) and p38 (phospho-JNK:JNK and p-p38:p38), whereas it increased (P<0·05) the ratio of extracellular signal-regulated kinase (ERK) (phospho-ERK:ERK). Collectively, these results suggest that dietary inclusion of WPC attenuates the LPS-induced intestinal injury by improving mucosal barrier function, alleviating intestinal inflammation and influencing TGF-β1 canonical Smad and mitogen-activated protein kinase signalling pathways.


Nuclear spin hyperpolarization of the solvent using signal amplification by reversible exchange (SABRE).
Here we report the polarization of the solvent OH protons by SABRE using standard iridium-based catalysts under slightly acidic conditions. Solvent polarization was observed in the presence of a variety of structurally similar N-donor substrates while no solvent enhancement was observed in the absence of substrate or para-hydrogen (p-H2). Solvent polarization was sensitive to the polarizing field and catalyst:substrate ratio in a manner similar to that of substrate protons. SABRE experiments with pyridine-d5 suggest a mechanism where hyperpolarization is transferred from the free substrate to the solvent by chemical exchange while measured hyperpolarization decay times suggest a complimentary mechanism which occurs by direct coordination of the solvent to the catalytic complex. We found the solvent hyperpolarization to decay nearly 3 times more slowly than its characteristic spin-lattice relaxation time suggesting that the hyperpolarized state of the solvent may be sufficiently long lived (∼20s) to hyperpolarize biomolecules having exchangeable protons. This route may offer future opportunities for SABRE to impact metabolic imaging.


In vitro studies of a novel antimicrobial luer-activated needleless connector for prevention of catheter-related bloodstream infection.
We report in vitro studies of a commercially available novel antimicrobial Luer-activated connector with the inner surface coated with nanoparticle-silver to prevent contaminants from forming biofilm and causing catheter-related bloodstream infection. Sterile control nonmedicated connectors and antimicrobial connectors were filled with approximately 1 x 10(5) cfu/mL of Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, Enterobacter cloacae, Pseudomonas aeruginosa, or Candida albicans; after 24 h of incubation, the numbers of remaining viable microorganisms were quantified and compared with the concentration in control connectors ( approximately 1 x 10(7) cfu/mL). In trials simulating clinical use, septal membranes of connectors were inoculated with E. cloacae, were allowed to dry, and were then actuated and infused with lactated ringer's solution for 72 h, with sampling for microorganisms in downstream efferent fluid and for biofilm in the connector. Microorganisms suspended in the intraluminal fluid path of antimicrobial connectors were rapidly killed. For 5 species, there was a 5.23-6.80 mean log(10) reduction (>99.999%), and with C. albicans, there was a 99.9% reduction. In clinical simulation trials, heavy contamination of downstream fluid was detected at all time points with control connectors, reaching approximately 1 x 10(5) cfu/mL at 72 h, and heavy biofilm was uniformly present; with the antimicrobial connectors, there was complete prevention of downstream fluid contamination and total absence of biofilm formation. These simulation experiments show that needleless connectors readily acquire an internal biofilm when microorganisms gain access to the internal fluid path and that biofilm formation allows an exponential buildup of internal contamination, with shedding back into the fluid path and downstream sufficient to cause bacteremia. Incorporation of nanoparticle silver into the lining surfaces of the novel connector kills microorganisms in the fluid pathway and prevents internal biofilm formation, even with high levels of introduced contamination and continuous fluid flow. This technology deserves to be evaluated in a prospective, randomized clinical trial to determine its capacity to prevent catheter-associated bloodstream infection.


Dynamic mapping of human cortical development during childhood through early adulthood.
We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4-21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8-10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse "movies" reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism.


Role of the JIP4 scaffold protein in the regulation of mitogen-activated protein kinase signaling pathways.
The c-Jun NH2-terminal kinase (JNK)-interacting protein (JIP) group of scaffold proteins (JIP1, JIP2, and JIP3) can interact with components of the JNK signaling pathway and potently activate JNK. Here we describe the identification of a fourth member of the JIP family. The primary sequence of JIP4 is most closely related to that of JIP3. Like other members of the JIP family of scaffold proteins, JIP4 binds JNK and also the light chain of the microtubule motor protein kinesin-1. However, the function of JIP4 appears to be markedly different from other JIP proteins. Specifically, JIP4 does not activate JNK signaling. In contrast, JIP4 serves as an activator of the p38 mitogen-activated protein (MAP) kinase pathway by a mechanism that requires the MAP kinase kinases MKK3 and MKK6. The JIP4 scaffold protein therefore appears to be a new component of the p38 MAP kinase signaling pathway.


Autoimmune polyglandular syndrome type 2 manifested as Hashimoto's thyroiditis and adrenocortical insufficiency, in Turner syndrome woman, with onset following introduction of treatment with recombinant human growth hormone.
Autoimmune polyglandular syndrome is a constellation of signs and symptoms of simultaneous insufficiencies of several endocrine glands. Autoimmune polyglandular syndrome type 2 (APS 2) may be diagnosed when the adrenocortical insufficiency is associated with an autoimmune thyroid disease (Hashimoto's thyroiditis or Graves' disease), and/or insulin-dependent diabetes mellitus. Turner syndrome is the most common chromosomal disorder in females, caused by complete or partial X chromosome monosomy. We present the case of a 20-year-old woman with Turner syndrome, in whom APS 2 (Hashimoto's thyroiditis and adrenocortical insufficiency) has been diagnosed after introduction of recombinant human growth hormone (rhGH) therapy. In Turner syndrome, examination of the patient must regularly be conducted in order to diagnose a possible onset of autoimmune diseases; respective treatment must be applied as soon as the diagnosis is established. In particular, therapy of rhGH, used for short stature treatment, may be a trigger factor of adrenal insufficiency. The cortisol level in blood should be assessed before rhGH administration and carefully monitored during the therapy, especially in case of autoimmune thyroid disease coexistence.


Improving delivery room management for very preterm infants.
Events in the delivery room significantly impact the outcomes of preterm infants. We developed evidence-based guidelines to prevent heat loss, reduce exposure to supplemental oxygen, and increase use of noninvasive respiratory support to improve the care and outcomes of infants with birth weight ≤1250 g at our institution. The guidelines were implemented through multidisciplinary conferences, routine use of a checklist, appointment of a dedicated resuscitation nurse, and frequent feedback to clinicians. This cohort study compares a historical group (n = 80) to a prospective group (n = 80, after guidelines were implemented). Primary outcome was axillary temperature at admission to the intensive care nursery. Secondary outcomes measured adherence to the guidelines and changes in clinically relevant patient outcomes. Baseline characteristics of the groups were similar. After introduction of the guidelines, average admission temperatures increased (36.4°C vs 36.7°C, P < .001) and the proportion of infants admitted with moderate/severe hypothermia fell (14% vs 1%, P = .003). Infants were exposed to less oxygen during the first 10 minutes (P < .001), with similar oxygen saturations. Although more patients were tried on continuous positive airway pressure (40% vs 61%, P = .007), the intubation rate was not significantly different (64% vs 54%, P = .20). Median durations of invasive ventilation and hospitalization decreased after the quality initiative (5 vs 1 days [P = .008] and 80 vs 60 days [P = .02], respectively). We have demonstrated significantly improved quality of delivery room care for very preterm infants after introduction of evidence-based delivery room guidelines. Multidisciplinary involvement and continuous education and reinforcement of the guidelines permitted sustained change.


Novel penta-graphene nanotubes: strain-induced structural and semiconductor-metal transitions.
Research into novel one-dimensional (1D) materials and associated structural transitions is of significant scientific interest. It is widely accepted that a 1D system with a short-range interaction cannot have 1D phase transition at finite temperature. Herein, we propose a series of new stable carbon nanotubes by rolling up penta-graphene sheets, which exhibit fascinating well-defined 1D phase transitions triggered by axial strain. Our first-principles calculations show that such penta-graphene nanotubes (PGNTs) are dynamically stable by phonon calculations, but transform from a tri-layer structure to a highly defective single-walled nanotube at low temperature in molecular dynamics simulations. We show that moderate compressive strains can drive structural transitions of (4,4), (5,5), and (6,6) PGNTs, during which the distances of neighboring carbon dimers in the inner shell have a sudden drop, corresponding to dimer-dimer nonbonding to bonding transitions. After such transition, the tubes become much more thermally stable and undergo semiconductor-metal transitions under increasing strain. The band gaps of PGNTs are not sensitive to chirality whereas they can be tuned effectively from visible to short-wavelength infrared by appropriate strain, making them appealing materials for flexible nano-optoelectronics. These findings provide useful insight into unusual phase transitions in low-dimensional systems.


Neuroprediction and A.I. in Forensic Psychiatry and Criminal Justice: A Neurolaw Perspective.
Advances in the use of neuroimaging in combination with A.I., and specifically the use of machine learning techniques, have led to the development of brain-reading technologies which, in the nearby future, could have many applications, such as lie detection, neuromarketing or brain-computer interfaces. Some of these could, in principle, also be used in forensic psychiatry. The application of these methods in forensic psychiatry could, for instance, be helpful to increase the accuracy of risk assessment and to identify possible interventions. This technique could be referred to as 'A.I. neuroprediction,' and involves identifying potential neurocognitive markers for the prediction of recidivism. However, the future implications of this technique and the role of neuroscience and A.I. in violence risk assessment remain to be established. In this paper, we review and analyze the literature concerning the use of brain-reading A.I. for neuroprediction of violence and rearrest to identify possibilities and challenges in the future use of these techniques in the fields of forensic psychiatry and criminal justice, considering legal implications and ethical issues. The analysis suggests that additional research is required on A.I. neuroprediction techniques, and there is still a great need to understand how they can be implemented in risk assessment in the field of forensic psychiatry. Besides the alluring potential of A.I. neuroprediction, we argue that its use in criminal justice and forensic psychiatry should be subjected to thorough harms/benefits analyses not only when these technologies will be fully available, but also while they are being researched and developed.


Information-seeking behaviors of dental practitioners in three practice-based research networks.
Research on the information-seeking behaviors of dental practitioners is scarce. Knowledge of dentists' informationseeking behaviors should advance the translational gap between clinical dental research and dental practice. A cross-sectional survey was conducted to examine the self-reported information-seeking behaviors of dentists in three dental practice-based research networks (PBRNs). A total of 950 dentists (65 percent response rate) completed the survey. Dental journals and continuing dental education (CDE) sources used and their influence on practice guidance were assessed. PBRN participation level and years since dental degree were measured. Full-participant dentists reported reading the Journal of the American Dental Association and General Dentistry more frequently than did their reference counterparts. Printed journals were preferred by most dentists. A lower proportion of full participants obtained their CDE credits at dental meetings compared to partial participants. Experienced dentists read other dental information sources more frequently than did less experienced dentists. Practitioners involved in a PBRN differed in their approaches to accessing information sources. Peer-reviewed sources were more frequently used by full participants and dentists with fifteen years of experience or more. Dental PBRNs potentially play a significant role in the dissemination of evidence-based information. This study found that specific educational sources might increase and disseminate knowledge among dentists.