Algorithms for early detection of silent liver fibrosis in the primary care setting - a scoping review.

INTRODUCTION: Fatty liver disease affects almost 30% of the adult population worldwide. Most patients are asymptomatic, and there is not a linear relationship between exposure to risk factors and the risk of developing fibrosis. The combination of a very large, asymptomatic risk population where only a few percent will develop life-threatening liver disease is a growing diagnostic challenge for the health services. Accurate fibrosis assessment in primary care is limited by poor correlation with liver blood tests and low availability of elastography. Non-invasive tests are promising tools, but little is known about their diagnostic accuracy in low-risk populations. AREAS COVERED: A scoping review was conducted to identify articles that focused on the current use of biomarkers and algorithms in primary care for the detection of patients with fatty liver disease in need of referral for further work-up. EXPERT OPINION: Currently available algorithms for targeted screening for liver fibrosis perform better than the individual routine liver blood tests or liver ultrasonography. However, primary care physicians urgently need algorithms with even higher diagnostic accuracies than what is available today. The main limitation of the existing widely accessible algorithms, such as the FIB-4, is the large number of false-positive tests, resulting in overdiagnosis and futile referrals to secondary care.

Genome Sequence of SN1, a Bacteriophage That Infects Sphaerotilus natans and Pseudomonas aeruginosa.

Phage SN1 infects Sphaerotilus natans and Pseudomonas aeruginosa strains. Its genome consists of 61,858 bp (64.3% GC) and 89 genes, including 32 with predicted functions. SN1 genome is very similar to Pseudomonas phage M6, which contains hypermodified thymidines. Genome analyses revealed similar base-modifying genes as those found in M6.

The pathway and characteristics of patients with non-specific symptoms of cancer: a systematic review.

BACKGROUND: Non-specific symptoms are common and often sign of a non-serious disease. Because of this, patients with non-specific symptoms of cancer (NSSC) present a challenge for general practitioners (GP). Studies describing characteristics of patients with NSSC have been done after fast-track pathways were created to diagnose and treat patients with NSSC. This study reviews characteristics of patients with NSSC and their patient pathways. MATERIALS AND METHODS: Database searches of Embase, Cochrane, PubMed, Cinahl and Web of Science were performed. Search terms used were cancer, patient pathway, and NSSC with their synonyms. The flow diagram Preferring Reporting Items for Systematic Review was applied to the systematic search. The Newcastle-Ottawa Assessment Scale (NOS) was used to compare the quality of the included studies. RESULTS: Twelve studies met the inclusion criterias. All studies were considered to be of high methodological quality. Patient Pathway: 11-35% of patients were diagnosed with cancer. Median number of days through diagnostic process was 7-10. PATIENT CHARACTERISTICS: The most prevalent cancers included hematological-(14-30%), gastrointestinal-(13-23%) and lung cancers (13%). Rheumatological, musculoskeletal and gastrointestinal diseases were among the most common non-malignant diseases diagnosed. Weight loss, fatigue, pain and loss of appetite were the most common symptoms. Cardiovascular diseases, lung diseases, diabetes and previous diagnosed cancer were the most common comorbidities. Mean age of included patients was 60-72 years. CONCLUSION: Limited number of studies were found and they lacked sufficient heterogenic data to conduct a metaanalysis. Symptoms, diagnoses, age and gender were described with some heterogenic results. Further studies should be conducted to gather broader knowledge about patients with NSSC.

Searching for the "Active Ingredients" in Physical Rehabilitation Programs Across Europe, Necessary to Improve Mobility in People With Multiple Sclerosis: A Multicenter Study.

BACKGROUND: Physical rehabilitation programs can lead to improvements in mobility in people with multiple sclerosis (PwMS). OBJECTIVE: To identify which rehabilitation program elements are employed in real life and how they might affect mobility improvement in PwMS. METHODS: Participants were divided into improved and nonimproved mobility groups based on changes observed in the Multiple Sclerosis Walking Scale-12 following multimodal physical rehabilitation programs. Analyses were performed at group and subgroup (mild and moderate-severe disability) levels. Rehabilitation program elements included setting, number of weeks, number of sessions, total duration, therapy format (individual, group, autonomous), therapy goals, and therapeutic approaches. RESULTS: The study comprised 279 PwMS from 17 European centers. PwMS in the improved group received more sessions of individual therapy in both subgroups. In the mildly disabled group, 60.9% of the improved received resistance training, whereas, 68.5% of the nonimproved received self-stretching. In the moderately-severely disabled group, 31.4% of the improved, received aerobic training, while 50.4% of the nonimproved received passive mobilization/stretching. CONCLUSIONS: We believe that our findings are an important step in opening the black-box of physical rehabilitation, imparting guidance, and assisting future research in defining characteristics of effective physical rehabilitation.

Atmospheric chemistry of iodine anions: elementary reactions of I-, IO-, and IO2- with ozone studied in the gas-phase at 300 K using an ion trap.

Using a radio-frequency ion trap to study ion-molecule reactions under isolated conditions, we report a direct experimental determination of reaction rate constants for the sequential oxidation of iodine anions by ozone at room temperature (300 K). The results are R1: I- + O3 → IO- + O2, k1 = (7 ± 2) × 10-12 cm3 s-1; R2: IO- + O3 → IO2- + O2, k2 = (10 ± 2) × 10-9 cm3 s-1; R3: IO2- + O3 → IO3- + O2, k3 = (16 ± 2) × 10-9 cm3 s-1. More oxidized forms such as IO4- and IO5- were not observed. Additionally, we performed quantum chemical calculations to elucidate the energetics of these oxidation reactions.

[Mycobacterium abscessus infection after cosmetic breast surgery in India].

A 36-year-old Danish woman underwent cosmetic breast surgery in India. Post-operatively, she presented with infection and ulcers under the breasts, and dicloxacillin was administered. The patient did not return for follow-up. Two years later the ulcer under the right breast had not healed, and the patient returned to hospital, where a wound culture was done. The result showed Mycobacterium abscessus. Hence, cephalexin administration was instituted, but the ulcer did not heal, and it was excised. The subsequent healing was rapid. Mycobacterial infections in Denmark are rare, serious, and often resistant to antibiotics.

Prevalence of Walking-Related Motor Fatigue in Persons With Multiple Sclerosis: Decline in Walking Distance Induced by the 6-Minute Walk Test.

OBJECTIVE: To investigate the individual occurrence of walking-related motor fatigue in persons with multiple sclerosis (PwMS), according to disability level and disease phenotype.Study design This was a cross-sectional, multinational study.Participants They were 208 PwMS from 11 centers with Expanded Disability Status Scale (EDSS) scores up to 6.5. METHODS: The percentage change in distance walked (distance walked index, DWI) was calculated between minute 6 and 1 (DWI(6-1)) of the 6-Minute Walk Test (6MWT). Its magnitude was used to classify participants into 4 subgroups: (1) DWI(6-1)[≥5%], (2) DWI(6-1)[5%; -5%], (3) DWI(6-1)[-5%; > -15%], and (4) DWI(6-1)[≤-15%]. The latter group was labeled as having walking-related motor fatigue. PwMS were stratified into 5 subgroups based on the EDSS (0-2.5, 3-4, 4.5-5.5, 6, 6.5) and 3 subgroups based on MS phenotype (relapsing remitting [RR], primary progressive [PP], and secondary progressive [SP]). RESULTS: The DWI6-1was ≥5% in 16 PwMS (7.7%), between 5% and -5% in 70 PwMS (33.6%), between -5% and -15% in 58 PwMS (24%), and ≤-15% in 64 PwMS (30.8%). The prevalence of walking-related motor fatigue (DWI(6-1)[≤-15%]) was significantly higher among the progressive phenotype (PP = 50% and SP = 39%; RR = 15.6%) and PwMS with higher disability level (EDSS 4.5-5.5 = 48.3%, 6 = 46.3% and 6.5 = 51.5%, compared with EDSS 0-2.5 = 7.8% and 3-4 = 16.7%;P< .05). Stepwise multiple regression analysis indicated that EDSS, but not MS phenotype, explained a significant part of the variance in DWI(6-1)(R(2)= 0.086;P< .001). CONCLUSION: More than one-third of PwMS showed walking-related motor fatigue during the 6MWT, with its prevalence greatest in more disabled persons (up to 51%) and in those with progressive MS phenotype (up to 50%). Identification of walking-related motor fatigue may lead to better-tailored interventions.

Technical review: types of imaging-direct STORM.

In the 1990s, new concepts of microscopy revolutionized the imaging field by breaking the lateral resolution diffraction limit for the first time, even with propagating light and regular lenses (i.e., far-field). In 2006, several research groups independently showed super-resolution microscopy using high-precision localization of single fluorophores. These new developments in single-molecule spectroscopy enabled a different approach to achieving nanometer-scale optical microscopy. Direct stochastic optical reconstruction microscopy (dSTORM) is a technique of single-molecule super-resolution imaging that does not require an activator fluorophore. This technique is used to visualize cellular structures with a resolution of approximately 20 nm. dSTORM is compatible with many conventionally used fluorophores. This article provides an overview of the principles and uses of dSTORM. Advantages and disadvantages of dSTORM are also discussed.

Technical review: In situ hybridization.

In situ hybridization is a technique that is used to detect nucleotide sequences in cells, tissue sections, and even whole tissue. This method is based on the complementary binding of a nucleotide probe to a specific target sequence of DNA or RNA. These probes can be labeled with either radio-, fluorescent-, or antigen-labeled bases. Depending on the probe used, autoradiography, fluorescence microscopy, or immunohistochemistry, respectively, are used for visualization. In situ hybridization is extensively used in research, as well as clinical applications, especially for diagnostic purposes. This review discusses the basic technique of in situ hybridization. The standard in situ hybridization process is reviewed, and different types of in situ hybridization, their applications, and advantages and disadvantages are discussed.

Sustained sympathetic nervous system support of arterial blood pressure during repeated brief umbilical cord occlusions in near-term fetal sheep.

Sympathetic nervous system (SNS)-mediated peripheral vasoconstriction plays a key role in initial maintenance of blood pressure during rapid-onset asphyxia in the mammalian fetus, but it is attenuated after the first few minutes. It is unclear whether the SNS response is sustained during the brief, but frequently repeated, episodes of asphyxia characteristic of labor. In the present study, 14 fetal sheep at 0.85 of gestation received either chemical sympathectomy with 6-hydroxydopamine (6-OHDA; n = 7) or sham injection (control; n = 7), followed 4-5 days later by repeated 2-min episodes of complete umbilical cord occlusion every 5 min for up to 4 h or until mean arterial blood pressure (MAP) fell to <20 mmHg for two successive occlusions. In controls, umbilical cord occlusions were associated with a rapid initial fall in fetal heart rate (FHR) and femoral blood flow (FBF), with initial hypertension, followed by progressive development of hypotension during ongoing occlusions. Sympathectomy was associated with attenuation of the initial rise in MAP during umbilical cord occlusion, and after the onset of hypotension, a markedly more rapid fall of MAP to the nadir, with a correspondingly slower fall in FBF (P < 0.05). In contrast, MAP and FHR between successive occlusions were higher after sympathectomy (P < 0.05). There was no significant difference in the number of occlusions before terminal hypotension (6-OHDA; 16.1 ± 2.2 vs. control; 18.7 ± 2.3). These data show that SNS activity provides ongoing support for fetal MAP during prolonged exposure to brief repeated asphyxia.

Responsiveness and clinically meaningful improvement, according to disability level, of five walking measures after rehabilitation in multiple sclerosis: a European multicenter study.

BACKGROUND: Evaluation of treatment effects on walking requires appropriate and responsive outcome measures. OBJECTIVES: To determine responsiveness of 5 walking measures and provide reference values for clinically meaningful improvements, according to disability level, in persons with multiple sclerosis (pwMS). METHODS: Walking tests were measured pre- and postrehabilitation in 290 pwMS from 17 European centers. Combined anchor- and distribution-based methods determined responsiveness of objective short and long walking capacity tests (Timed 25-Foot Walk [T25FW] and 2- and 6-Minute Walk Tests [2MWT and 6MWT] and of the patient-reported Multiple Sclerosis Walking Scale-12 [MSWS-12]). A global rating of change scale, from patients' and therapists' perspective, was used as external criteria to determine the area under the receiver operating characteristic curve (AUC), minimally important change (MIC), and smallest real change (SRC). Patients were stratified into disability subgroups (Expanded Disability Status Scale score ≤4 [n = 98], >4 [n = 186]). RESULTS: MSWS-12, 2MWT, and 6MWT were more responsive (AUC 0.64-0.73) than T25FW (0.50-0.63), especially in moderate to severely disabled pwMS. Clinically meaningful changes (MICs) from patient and therapist perspective were -10.4 and -11.4 for MSWS-12 (P < .01), 9.6 m and 6.8 m for 2MWT (P < .05), and 21.6 m (P < .05) and 9.1 m (P = .3) for 6MWT. In subgroups, MIC was significant from patient perspective for 2MWT (10.8 m) and from therapist perspective for MSWS-12 (-10.7) in mildly disabled pwMS. In moderate to severely disabled pwMS, MIC was significant for MSWS-12 (-14.1 and -11.9). CONCLUSIONS: Long walking tests and patient-reported MSWS-12 were more appropriate than short walking tests in detecting clinically meaningful improvement after physical rehabilitation, particularly the MSWS-12 for moderate to severely disabled pwMS.

Within-day variability on short and long walking tests in persons with multiple sclerosis.

OBJECTIVE: To compare within-day variability of short (10 m walking test at usual and fastest speed; 10MWT) and long (2 and 6-minute walking test; 2MWT/6MWT) tests in persons with multiple sclerosis. DESIGN: Observational study. SETTING: MS rehabilitation and research centers in Europe and US within RIMS (European network for best practice and research in MS rehabilitation). SUBJECTS: Ambulatory persons with MS (Expanded Disability Status Scale 0-6.5). INTERVENTION: Subjects of different centers performed walking tests at 3 time points during a single day. MAIN MEASURES: 10MWT, 2MWT and 6MWT at fastest speed and 10MWT at usual speed. Ninety-five percent limits of agreement were computed using a random effects model with individual pwMS as random effect. Following this model, retest scores are with 95% certainty within these limits of baseline scores. RESULTS: In 102 subjects, within-day variability was constant in absolute units for the 10MWT, 2MWT and 6MWT at fastest speed (+/-0.26, 0.16 and 0.15m/s respectively, corresponding to +/-19.2m and +/-54 m for the 2MWT and 6MWT) independent on the severity of ambulatory dysfunction. This implies a greater relative variability with increasing disability level, often above 20% depending on the applied test. The relative within-day variability of the 10MWT at usual speed was +/-31% independent of ambulatory function. CONCLUSIONS: Absolute values of within-day variability on walking tests at fastest speed were independent of disability level and greater with short compared to long walking tests. Relative within-day variability remained overall constant when measured at usual speed.

Copper doped TiO2 nanoparticles characterized by X-ray absorption spectroscopy, total scattering, and powder diffraction--a benchmark structure-property study.

Metal functionalized nanoparticles potentially have improved properties e.g. in catalytic applications, but their precise structures are often very challenging to determine. Here we report a structural benchmark study based on tetragonal anatase TiO2 nanoparticles containing 0-2 wt% copper. The particles were synthesized by continuous flow synthesis under supercritical water-isopropanol conditions. Size determination using synchrotron PXRD, TEM, and X-ray total scattering reveals 5-7 nm monodisperse particles. The precise dopant structure and thermal stability of the highly crystalline powders were characterized by X-ray absorption spectroscopy and multi-temperature synchrotron PXRD (300-1000 K). The combined evidence reveals that copper is present as a dopant on the particle surfaces, most likely in an amorphous oxide or hydroxide shell. UV-VIS spectroscopy shows that copper presence at concentrations higher than 0.3 wt% lowers the band gap energy. The particles are unaffected by heating to 600 K, while growth and partial transformation to rutile TiO2 occur at higher temperatures. Anisotropic unit cell behavior of anatase is observed as a consequence of the particle growth (a decreases and c increases).

Acute on chronic exposure to endotoxin is associated with enhanced chemoreflex responses in preterm fetal sheep.

There is increasing evidence that exposure to infection can sensitize the fetus to subsequent hypoxic injury. However, it is unclear whether this involves compromise of the fetal cardiovascular adaptation to acute asphyxia. Chronically instrumented 103-day-old (0.7 gestational age, term is 147 days) fetal sheep in utero were randomized to receive either gram-negative lipopolysaccharide (LPS) as a continuous low-dose infusion for 120 h plus boluses of 1 µg LPS at 48, 72, and 96 h with asphyxia at 102 h (i.e., 6 h after the final LPS bolus) induced by umbilical cord occlusion for 15 min (LPS treated, n = 8), or the same volume of saline plus occlusion (saline treated, n = 7). Fetuses were killed 5 days after occlusion. LPS was associated with a more rapid fall in fetal heart rate at the onset of occlusion (P < 0.05) and with minimally lower values during occlusion (P < 0.05). The LPS-treated fetuses had lower fetal mean arterial blood pressure (BP) and greater carotid artery blood flow (CaBF) before occlusion (P < 0.05) but showed an increase in BP and fall in CaBF to similar values as saline controls during occlusion. There were no differences between the groups in femoral blood flow before or during occlusion. Contrary to our initial hypothesis, acute on chronic exposure to LPS was associated with more rapid cardiovascular adaptation to umbilical cord occlusion.

Acute on chronic exposure to endotoxin in preterm fetal sheep.

Acute, high-dose exposure to endotoxin lipopolysaccharide (LPS) in preterm fetal sheep can trigger periventricular white matter lesions (PVL), in association with severe hypotension/hypoxemia and significant mortality. Intriguingly, however, chronic or repeated exposure to LPS can induce tachyphylaxis. We therefore tested the hypothesis that progressive, acute on chronic fetal infection would be associated with white matter injury with little fetal mortality. Chronically instrumented preterm (0.7 gestational age) fetal sheep were exposed to a continuous low-dose LPS infusion (100 ng over 24 h, followed by 250 ng/24 h for 96 h) or saline. Boluses of 1 µg LPS or saline were given at 48, 72, and 96 h; sheep were killed at day 10. Six of 11 fetal sheep exposed to saline infusion + LPS boluses died 4-7 h after the first bolus. In contrast, there was no fetal mortality after saline infusions alone (n = 9), low-dose LPS infusion + saline boluses (n = 5), or low-dose LPS + LPS boluses (n = 9). Low-dose LPS infusion + LPS boluses was associated with greater microglial induction than low-dose LPS + saline boluses but a similar area of periventricular white matter inflammation. One fetus developed severe focal white matter necrosis after LPS infusion + boluses. The acute cardiovascular compromise associated with high-dose, acute exposure to LPS is markedly attenuated by previous low-dose infusions, with limited apparent exacerbation of periventricular white matter injury compared with low-dose infusion alone.