Genomic Analysis of Inbreeding and Coancestry in Nordic Jersey and Holstein Dairy Cattle Populations.

In recent years, Genomic Selection (GS) has accelerated genetic gain in dairy cattle breeds worldwide. Despite the evident genetic progress, several dairy populations have also encountered challenges such as heightened inbreeding rates and reduced effective population sizes. The challenge has been to find a balance between achieving substantial genetic gain while managing genetic diversity within the population, thereby mitigating the negative effects of inbreeding depression. This study aims to elucidate the impact of GS on pedigree and genomic rates of inbreeding (ΔF) and coancestry (ΔC) in Nordic Jersey (NJ) and Holstein (NH) cattle populations. Furthermore, key genetic metrics including the generation interval (L), effective population size (Ne), and future effective population size (FNe) were assessed between 2 time periods, before and after GS, and across distinct animal cohorts in both breeds: females, bulls, and approved semen-producing bulls (AI-sires). Analysis of ΔF and ΔC revealed distinct trends across the studied periods and animal groups. Notably, there was a consistent increase in yearly ΔF for most animal groups in both breeds. An exception was observed in NH AI-sires, which demonstrated a slight decrease in yearly ΔF. Moreover, NJ displayed minimal changes in yearly ΔC between the periods, whereas NH exhibited elevated ΔC values across all animal groups. Particularly striking was the substantial increase in yearly ΔC within the NH female population, surging from 0.02% to 0.39% between the periods. Implementation of GS resulted in a reduction of the generation interval across all animal cohorts in both NJ and NH breeds. However, the extent of reduction was more pronounced in males compared with females. This reduction in generation interval influenced generational changes in ΔF and ΔC. Bulls and AI-sires of both breeds exhibited reduced generational ΔF between periods, in contrast to females that demonstrated an opposing pattern. Between the periods, NJ maintained a relatively stable Ne, 29.4 before and 30.3 after GS, while NH experienced a notable decline from 54.3 to 42.8. Female groups in both breeds displayed a negative Ne trend, while males demonstrated either neutral or positive Ne developments. Regarding FNe, NJ exhibited positive FNe development with an increase from 40.7 to 57.2. The opposite was observed in NH, where FNe decreased from 198.8 to 42.7. In summary, it was evident that the genomic methods could detect differences between the populations and changes in ΔF and ΔC more efficiently than pedigree methods. GS implementation yielded positive outcomes within the NJ population regarding the rate of coancestry but the opposite was observed with NH. Moreover, analysis of ΔC data hints at the potential to decrease future ΔF through informed mating strategies. Conversely, NH faces more pressing concerns, even though ΔF remains comparatively modest in contrast to what has been observed in other Holstein populations. These findings underscore the necessity of genomic control of inbreeding and coancestry with strategic changes in the Nordic breeding schemes for dairy to ensure long-term sustainability in the forthcoming years.

The AE4 transporter mediates kidney acid-base sensing.

The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na+-dependent Cl-/HCO3- exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl-/HCO3- exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.

[rTMS for a patient with derealisation disorder; an experimental treatment]. / rTMS bij een patiënt met een derealisatie-stoornis; een experimentele behandeling.

We describe a 70 year old patient with a history of epilepsy, who developed a derealisation disorder after discontinuing the use of valproic acid. An experimental treatment with rTMS led to a remarkable decrease of his symptoms. We determined our target, the right ventrolateral prefrontal cortex (VLPFC), with the use of neuronavigation. During treatment no complications occurred, specifically no epileptic seizures.

Design of a virtual data shelf to effectively explore a large database of 3D medical surface models in VR.

PURPOSE: Medical researchers deal with a large amount of patient data to improve future treatment decisions and come up with new hypotheses. To facilitate working with a large database containing many patients and parameters, we propose a virtual data shelf, displaying the 3D anatomical surface models in an immersive VR environment. METHODS: Thereby, different functionalities such as sorting, filtering and finding similar cases are included. To provide an appropriate layout and arrangement of 3D models that optimally supports working with the database, three layouts (flat, curved and spherical) and two distances are evaluated. A broad audience study with 61 participants was conducted to compare the different layouts based on their ease of interaction, to get an overview and to explore single cases. Medical experts additionally evaluated medical use cases. RESULTS: The study revealed that the flat layout with small distance is significantly faster in providing an overview. Applying the virtual data shelf to the medical use case intracranial aneurysms, qualitative expert feedback with two neuroradiologists and two neurosurgeons was gathered. Most of the surgeons preferred the curved and spherical layouts. CONCLUSION: Our tool combines benefits of two data management metaphors, resulting in an efficient way to work with a large database of 3D models in VR. The evaluation gives insight into benefits of layouts as well as possible use cases in medical research.

Variation and genetic control of individual recombination rates in Norwegian Red dairy cattle.

Meiotic recombination is an important evolutionary mechanism that breaks up linkages between loci and creates novel haplotypes for selection to act upon. Understanding the genetic control of variation in recombination rates is therefore of great interest in both natural and domestic breeding populations. In this study, we used pedigree information and medium-density (∼50K) genotyped data in a large cattle (Bos taurus) breeding population in Norway (Norwegian Red cattle) to investigate recombination rate variation between sexes and individual animals. Sex-specific linkage mapping showed higher rates in males than in females (total genetic length of autosomes = 2,492.9 cM in males and 2,308.9 cM in females). However, distribution of recombination along the genome showed little variation between males and females compared with that in other species. The heritability of autosomal crossover count was low but significant in both sexes (h2 = 0.04 and 0.09 in males and females, respectively). We identified 2 loci associated with variation in individual crossover counts in female, one close to the candidate gene CEP55 and one close to both MLH3 and NEK9. All 3 genes have been associated with recombination rates in other cattle breeds. Our study contributes to the understanding of how recombination rates are controlled and how they may vary between closely related breeds as well as between species.

Intra- and inter-spatial variability of meiofauna in hadal trenches is linked to microbial activity and food availability.

Hadal trenches are depocenters for organic material, and host intensified benthic microbial activity. The enhanced deposition is presumed to be reflected in elevated meiofaunal standing-stock, but available studies are ambiguous. Here, we investigate the distribution of meiofauna along the Atacama Trench axis and adjacent abyssal and bathyal settings in order to relate the meiofauna densities to proxies for food availability. Meiofauna densities peaked at the sediment surface and attenuated steeply with increasing sediment depth. The distribution mirrored the vertical profile of the microbial-driven oxygen consumption rate demonstrating a close linkage between microbial activity and meiofauna density. Meiofaunal standing-stock along the trench axis varied by a factor of two, but were markedly higher than values from the abyssal site at the oceanic plate. Overall, meiofaunal densities poorly correlated with common proxies for food availability such as total organic carbon and phytopigments, but strongly correlated with the microbial benthic O2 consumption rate. We argue that microbial biomass likely represents an important meiofaunal food source for hadal meiofauna. Observations from three trench systems underlying surface water of highly different productivity confirmed elevated meiofaunal densities at the trench axis as compared to abyssal sites on oceanic plates. Food availability appear to drive elevated abundance and variations in meiofauna densities in hadal sediments.

Single pharmacy governed denosumab home administration: optimal adherence by means of a fracture liaison service (FLS) and home care collaboration.

Low adherence for denosumab (Dmab, Prolia®) is of major concern. Dutch pharmacies deliveries were calculated recently being 76.5% for a total of 3 injections. INTRODUCTION: Comparing a model where the prescriber maintains responsibility for adherence (model HC1) (Dmab is purchased and dispensed by patient's own community pharmacy and administered through a home care service (HC)) or an all-in-one model where the pharmacist maintains responsibility for the adherence (Dmab is purchased, dispensed, and administered by a pharmacist's HC) (HC2). METHODS: We counted the number of Dmab injections, follow-up appointments on time, Dmab administrations delayed to a maximum of 60 days, the number of Dmab discontinuations, and all causes legally traceable under EU privacy act (EDPR). RESULTS: Home care started by 2014 (study closure in 2021) and included 711 Dmab injections to 256 unique patients: HC1: 536 and HC2: 175 orders. The whole group received on average 2.8 Dmab injections by consistent intervals of about 182 days. Average administration after the latest Dmab injection: 272.8 days (HC1: 362.0 and HC2: 124.0 days). Administration of a subsequent injection > 60 days occurred in 26.6% (HC1: 38.8% and HC2: 6.2%; OR = 9.49). After adjustment for no more than three Dmab injections administered per patient, it occurred in 27.3% (HC1: 51.8% and HC2 4.4%; OR = 23.34). CONCLUSION: It was possible to achieve 94% adherence for Dmab injections treatment just by transferring the complete supply chain to one pharmacy-initiated home care provider after treatment initiation by either a physician or FLS health care professional.

Improved dairy cattle mating plans at herd level using genomic information.

From 2012 to 2018, 223 180 Montbéliarde females were genotyped in France and the number of newly genotyped females increased at a rate of about 33% each year. With female genotyping information, farmers have access to the genomic estimated breeding values of the females in their herd and to their carrier status for genetic defects or major genes segregating in the breed. This information, combined with genomic coancestry, can be used when planning matings in order to maximize the expected on-farm profit of future female offspring. We compared different mating allocation approaches for their capacity to maximize the expected genetic gain while limiting expected progeny inbreeding and the probability to conceive an offspring homozygous for a lethal recessive allele. Three mate allocation strategies (random mating (RAND), sequential mating (gSEQ€) and linear programing mating (gLP€)) were compared on 160 actual Montbéliarde herds using male and female genomic information. Then, we assessed the benefit of using female genomic information by comparing matings planned using only female pedigree information with the equivalent strategy using genomic information. We measured the benefit of adding genomic expected inbreeding and risk of conception of an offspring homozygous for a lethal recessive allele to Net merit in mating plans. The influence of three constraints was tested: by relaxing the constraint on availability of a particular semen type (sexed or conventional) for bulls, by adding an upper limit of 8.5% coancestry between mate pairs or by using a more stringent maximum use of a bull in a herd (5% vs 10%). The use of genomic information instead of pedigree information improved the mate allocation method in terms of progeny expected genetic merit, genetic diversity and risk to conceive an offspring homozygous for a lethal recessive allele. Optimizing mate allocation using linear programming and constraining coancestry to a maximum of 8.5% per mate pair reduced the average coancestry with a small impact on expected Net Merit. In summary, for male and female selection pathways, using genomic information is more efficient than using pedigree information to maximize genetic gain while constraining the expected inbreeding of the progeny and the risk to conceive an offspring homozygous for a lethal recessive allele. This study also underlines the key role of semen type (sexed vs conventional) and the associated constraints on the mate allocation algorithm to maximize genetic gain while maintaining genetic diversity and limiting the risk to conceive an offspring homozygous for a lethal recessive allele.

A rectal metastasis of an unknown lobular breast carcinoma and its management.

Breast cancer is the most common cancer in women but gastro- intestinal metastases of breast cancer are rare. They can occur years after the diagnosis or at the diagnosis of breast cancer. We report the case of a patient complaining of dyschesia, tenesmus and anal incontinence leading to the discovery of a rectal metastasis of an unknown breast neoplasia. Given the oligo-metastatic condition, multidisciplinary and aggressive management was the chosen therapy.

Characterization of fracture liaison service non-responders after invitation by home visits and questionnaires.

This study aimed to gain insight in specific characteristics and beliefs of FLS non-responders. INTRODUCTION: The proportion of non-responding fracture liaison service (FLS) invitees is high but characteristics of FLS non-responders are unknown. METHODS: We contacted FLS non-responders by telephone to consent with home visit (HV) and to fill in a questionnaire or, if HV was refused, to receive a questionnaire by post (Q), to gain insight in beliefs on fracture cause and subsequent fracture risk. RESULTS: Out of 716 FLS invitees, 510 attended, nine declined, and 197 did not respond. Of these non-responders, 181 patients were consecutively traced and phoned until 50 consented with HV. Forty-two declined HV but consented with Q. Excluded were eight Q-consenters in whom no choice was offered (either HV or Q) and 81 patients who declined any proposition (non-HV|Q). 62% HV and Q could recall the FLS invitation letter. The fracture cause was differently believed between HV and Q; the fall (96% versus 79%, p = .02), bad physical condition (36% versus 2%, p = .0001), dizziness or imbalance (24% versus Q 7%, p = .03), osteoporosis (16% versus 2%, p = .02), and increased fracture risk (26% versus 17%, NS). Age ≥ 70, woman, and major fracture were significantly associated with HV consent compared to Q (OR 2.7, 2.5, and 2.4, respectively) and HV compared to non-HV|Q (OR 16.8, 5.3, and 6.1). CONCLUSION: FLS non-responders consider fracture risk as low. Note, 50 patients (about 25%) consented with a home visit after one telephone call, mainly older women with a major fracture. This non-responder subgroup with high subsequent fracture risk is therefore approachable for secondary fracture prevention.

Multi-kingdom characterization of the core equine fecal microbiota based on multiple equine (sub)species.

BACKGROUND: Equine gut microbiology studies to date have primarily focused on horses and ponies, which represent only one of the eight extant equine species. This is despite asses and mules comprising almost half of the world's domesticated equines, and donkeys being superior to horses/ponies in their ability to degrade dietary fiber. Limited attention has also been given to commensal anaerobic fungi and archaea even though anaerobic fungi are potent fiber degrading organisms, the activity of which is enhanced by methanogenic archaea. Therefore, the objective of this study was to broaden the current knowledge of bacterial, anaerobic fungal and archaeal diversity of the equine fecal microbiota to multiple species of equines. Core taxa shared by all the equine fecal samples (n = 70) were determined and an overview given of the microbiota across different equine types (horse, donkey, horse × donkey and zebra). RESULTS: Equine type was associated with differences in both fecal microbial concentrations and community composition. Donkey was generally most distinct from the other equine types, with horse and zebra not differing. Despite this, a common bacterial core of eight OTUs (out of 2070) and 16 genus level groupings (out of 231) was found in all the fecal samples. This bacterial core represented a much larger proportion of the equine fecal microbiota than previously reported, primarily due to the detection of predominant core taxa belonging to the phyla Kiritimatiellaeota (formerly Verrucomicrobia subdivision 5) and Spirochaetes. The majority of the core bacterial taxa lack cultured representation. Archaea and anaerobic fungi were present in all animals, however, no core taxon was detected for either despite several taxa being prevalent and predominant. CONCLUSIONS: Whilst differences were observed between equine types, a core fecal microbiota existed across all the equines. This core was composed primarily of a few predominant bacterial taxa, the majority of which are novel and lack cultured representation. The lack of microbial cultures representing the predominant taxa needs to be addressed, as their availability is essential to gain fundamental knowledge of the microbial functions that underpin the equine hindgut ecosystem.

Challenges and opportunities to improve fracture liaison service attendance: fracture registration and patient characteristics and motivations.

This questionnaire-based study evaluated the reasons for attendance or non-attendance at the fracture liaison service in patients with a recent fracture. Frailty, male sex, living alone, and low education were associated with non-attendance, and the information perceived by the patient was associated with attendance. INTRODUCTION: The purpose of this study was to evaluate hospital registration- and patient-related factors associated with attendance or non-attendance to the Fracture Liaison Service (FLS). METHODS: Out of 1728 consecutive patients registered with a recent fracture at hospital entry, and after exclusion of 440 patients because of death, residence in a nursing home, already on osteoporosis treatment, or recent DXA, 1288 received an FLS invitation. We evaluated the hospital registration of fractures at entry and exit of the hospital. A questionnaire was sent to all invited patients to evaluate factors related to non-attendance (including age, gender, frailty, living alone, income, education, extrinsic motivations (impact of perceived information) and intrinsic motivations (patient's own perceived views and opinions) and to attendance (personal impact of clinical professionals' advice). RESULTS: There were 278 more hospital exit codes than entry codes. Of the 1288 invited patients, 745 returned analyzable questionnaires (537 attenders and 208 non-attenders). Non-attendance was associated with male gender (OR: 2.08, 95% CI: 1.35, 3.21), frailty (OR: 1.62, CI: 1.08, 2.45), living alone (OR:2.05, CI: 1.48, 2.85), low education (OR: 1.82, CI: 1.27, 2.63), not interested in bone strength (OR: 1.85, CI: 1.33, 2.63), and being unaware of increased subsequent fracture risk (OR: 1.75, CI: 1.08, 2.86). Information perceived by the patient was significantly associated with attendance (OR: 3.32, CI: 1.75, 6.27). CONCLUSION: Fracture entry registration inaccuracies, male gender, frailty, living alone, having low general education, or low interest in bone health and subsequent fracture risk were independently associated with FLS non-attendance. Adequately perceived advice (to have a bone densitometry and attend the FLS) was strongly associated with FLS attendance.

Rapid onset of action of calcipotriol/betamethasone dipropionate cutaneous foam in psoriasis, even in patients with more severe disease.

BACKGROUND: The effectiveness of topical therapies in psoriasis is dependent on, amongst other factors, patient adherence. Together with treatment effectiveness and reduction of symptoms, speed of onset and health-related quality of life (HRQoL) are important influencers of adherence. METHODS: This pooled analysis of three Phase II/III trials evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) vs. foam vehicle at early timepoints in mild-to-severe psoriasis using clinically meaningful modified Psoriasis Area and Severity Index (mPASI) and Dermatology Life Quality Index (DLQI) targets. RESULTS: A greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved absolute mPASI targets 0 (15.1% vs. 1.0%), ≤1 (41.4% vs. 5.2%), ≤3 (78.5% vs. 29.2%) and ≤5 (90.2% vs. 62.5%) at week 4 (P < 0.001; all targets). Significant differences between Cal/BD-foam- vs. foam-vehicle-treated patients were observed as early as week 1 in those achieving mPASI ≤1 (6.8% vs. 1.5%; P < 0.01), ≤3 (40.4% vs. 22.8%; P < 0.001) and ≤5 (69.7% vs. 50.8%; P < 0.001). In patients with more severe psoriasis (baseline mPASI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved mPASI ≤1 (20.2% vs. 5.9%; P < 0.05), ≤3 (49.2% vs. 8.8%; P < 0.001) and ≤5 (63.7% vs. 26.5%; P < 0.001) at week 4. In patients with severely impaired HRQoL (baseline DLQI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved target DLQI ≤1 or 0 (week 4: DLQI ≤1, 25.0% vs. 4%; P = 0.001; DLQI 0, 17.4% vs. 2.0%; P = 0.006). CONCLUSION: We report rapid onset of action and greater efficacy with Cal/BD foam vs. foam vehicle, even in patients with more severe psoriasis, manageable with topical treatments. This may support physician management of patient expectations and improve patient adherence, translating into overall topical treatment effectiveness.

The role of autoimmunity in women with type 1 diabetes and adverse pregnancy outcome: A missing link.

The incidence of pregnancy complications in women with type 1 Diabetes Mellitus (T1D) is greater than in healthy pregnant women. This has mostly been attributed to hyperglycemia. However, despite the implementation of stricter guidelines regarding glycemic control, pregnancy complications remain more common in women with T1D. This may suggest that other etiological factors are involved. We suggest that the immune response may play a role, since the immune response has to adapt during pregnancy in order to facilitate implantation, placental and fetal development, and aberrant immunological adaptations to pregnancy are involved in various pregnancy complications. Since T1D is an autoimmune disorder, the question rises whether the immune response of women with T1D is able to adapt properly during pregnancy. Here we review the current proof and views on the role of aberrant immunological adaptations in pregnancy complications and whether such aberrant adaptations could be involved in the pregnancy complications of T1D patients.

Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta-analysis.

OBJECTIVE: Hypertensive disorders affect 3-10% of pregnancies. Delayed delivery carries maternal risks, while early delivery increases fetal risk, so appropriate timing is important. The aim of this study was to compare immediate delivery with expectant management for prevention of adverse maternal and neonatal outcomes in women with hypertensive disease in pregnancy. METHODS: CENTRAL, PubMed, MEDLINE and ClinicalTrials.gov were searched for randomized controlled trials comparing immediate delivery to expectant management in women presenting with gestational hypertension or pre-eclampsia without severe features from 34 weeks of gestation. The primary neonatal outcome was respiratory distress syndrome (RDS) and the primary maternal outcome was a composite of HELLP syndrome and eclampsia. The PRISMA-IPD guideline was followed and a two-stage meta-analysis approach was used. Relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% CI were calculated to evaluate the effect of the intervention. RESULTS: Main outcomes were available for 1724 eligible women. Compared with expectant management, immediate delivery reduced the composite risk of HELLP syndrome and eclampsia in all women (0.8% vs 2.8%; RR, 0.33 (95% CI, 0.15-0.73); I2  = 0%; NNT, 51 (95% CI, 31.1-139.3)) as well as in the pre-eclampsia subgroup (1.1% vs 3.5%; RR, 0.39 (95% CI, 0.15-0.98); I2  = 0%). Immediate delivery increased RDS risk (3.4% vs 1.6%; RR, 1.94 (95% CI 1.05-3.6); I2  = 24%; NNH, 58 (95% CI, 31.1-363.1)), but depended upon gestational age. Immediate delivery in the 35th week of gestation increased RDS risk (5.1% vs 0.6%; RR, 5.5 (95% CI, 1.0-29.6); I2  = 0%), but immediate delivery in the 36th week did not (1.5% vs 0.4%; RR, 3.4 (95% CI, 0.4-30.3); I2 not applicable). CONCLUSION: In women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, whilst the effect on the neonate depends on gestational age. Specifically, women with a-priori higher risk of progression to HELLP, such as those already presenting with pre-eclampsia instead of gestational hypertension, were shown to benefit from earlier delivery. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Itch relief in patients with psoriasis: effectiveness of calcipotriol plus betamethasone dipropionate foam.

BACKGROUND: Itch is common in psoriasis, adversely affecting health-related quality of life (HRQoL) and sleep. OBJECTIVE: We evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) on itch, itch-related sleep loss and HRQoL vs. foam vehicle. METHODS: We pooled data from three Phase II/III trials (NCT01536886/NCT01866163/NCT02132936) of Cal/BD foam vs. foam vehicle in adults with mild-severe psoriasis. For itch-related analyses, patients with baseline itch visual analogue scale (VAS) >40 (range 0-100) were analysed. Outcomes included the following: itch VAS reduction >40, ≥70% improvement in itch (Itch70) or itch-related sleep loss, 75% improvement in modified Psoriasis Area and Severity Index (excluding head; mPASI75) and Dermatology Life Quality Index (DLQI) scores 0/1 through 4 weeks. RESULTS: Of 837 patients, 800 had baseline itch VAS >0 (Cal/BD foam, n = 610; foam vehicle, n = 190); 484 had baseline itch VAS >40. There was no correlation between itch VAS score and mPASI at baseline (R2  = 0.021). In patients with baseline itch VAS >40, more patients achieved itch VAS reduction >40 in the active vs. vehicle group from Day 5 onwards (Day 5: 57.5% vs. 40.2% [P < 0.05]; Week 4: 83.0% vs. 45.8% [P < 0.001]). More Cal/BD-foam-treated patients achieved Itch70 at Day 3 (34.2% vs. 22.5%; P < 0.05) through to Week 4 (79.3% vs. 38.1%; P < 0.001). In patients with baseline itch VAS >40 and sleep loss >20, improvements in itch-related sleep loss occurred at Week 1 and continued through 4 weeks. Itch-related improvements occurred before improvements in mPASI75. There were significant differences in the proportion of Cal/BD-foam- vs. foam-vehicle-treated patients with baseline DLQI >10 (n = 172 vs. n = 50) achieving DLQI ≤1 (25.0% vs. 4.0%; P = 0.001) and DLQI 0 (17.4% vs. 2.0%; P = 0.006) at Week 4. CONCLUSION: Compared with foam vehicle, Cal/BD foam offers more rapid and effective itch relief, with associated significant improvements in sleep and DLQI.

Sensitivity and specificity of microRNA-122 for liver disease in dogs.

BACKGROUND: Current tests for diagnosing liver disease in dogs are sub-optimal. MicroRNA-122 (miR-122) is a sensitive and specific biomarker of liver injury in humans and rodents. Circulating miR-122 could have utility in identifying dogs with liver disease. OBJECTIVE: Establish the reference interval for miR-122 in healthy dogs and determine performance in a range of dog breeds with liver disease and control animals with non-liver disease. ANIMALS: Stored serum from 120 healthy dogs, 100 dogs with non-liver diseases, and 30 dogs with histologically confirmed liver disease was analyzed. METHODS: Retrospective study. Medical records of dogs with liver disease, non-liver disease and healthy dogs were reviewed. Serum miR-122 concentrations were measured by PCR and compared with the characteristics of the dogs and their conventional clinical measurements. RESULTS: In healthy dogs the 2.5th, 50th, and 97.5th quartiles of miR-122 were 110 (90% CI 80-114), 594 (505-682), and 3312 (2925-5144) copies/µL, respectively. There was no difference between healthy dogs and dogs with non-liver disease (median ± IQR: healthy dogs 609 [327-1014] copies/µL; non-liver disease 607 [300-1351] copies/µL). miR-122 was higher in dogs with liver disease (11 332 [4418-20 520] copies/µL, P < .001 compared to healthy dogs). miR-122 identified dogs with liver disease with high accuracy (receiver operating characteristic area under curve for comparison with healthy dogs: 0.93 [95% CI 0.86-0.99]). The upper limit of normal for healthy dogs (3312 copies/µL) had a sensitivity of 77% and specificity of 97% for identifying liver disease. CONCLUSION AND CLINICAL IMPORTANCE: Liver disease can be sensitively and specifically diagnosed in dogs by measurement of miR-122.

Attending a social event and consuming alcohol is associated with changes in serum microRNA: a before and after study in healthy adults.

PURPOSE: Circulating microRNAs represent a reservoir for biomarker discovery. Our objective was to profile the change in human circulating microRNA associated with recreational use of alcohol at a social event. MATERIAL AND METHODS: Blood was collected from healthy volunteers (N = 16) before and after recreational consumption of alcohol (ethanol). Biochemistry, hematology and ethanol measurements were performed. The change in the serum small RNA fraction was quantified by RNA sequencing. RESULTS: Blood ethanol was undetectable at study entry in all subjects [<10 mg/dL]. After consuming alcohol the median concentration was 89 mg/dL [IQR: 71-138. Min-max 20-175]. There were no changes in biochemistry and hematology parameters. Serum RNA sequencing identified 1371 small RNA species (1305 microRNAs). There were significant increases [adjusted p-value <0.05, fold increase 2 or more] in 265 microRNAs, around a fifth of the total [median fold increase 2.3 [IQR: 2.1-2.5; Max: 3.7]]. miR-185-5p decreased following alcohol exposure [adjusted p-value <0.05, fold decrease 2 or more]. CONCLUSIONS: The microRNA composition of human serum is dynamic and environmental factors may have a significant impact. Within its context of use the fold change 'signal' of a microRNA must be large enough to negate the risk of false results due to background 'noise'.

Hydrochlorothiazide and acute urinary acidification: The "voltage hypothesis" of ENaC-dependent H+ secretion refuted.

AIM: The "voltage hypothesis" of H+ secretion states that urinary acidification following increased Na+ delivery to the collecting duct (CD) is ENaC dependent leading to transepithelial voltage-dependent increase in H+ secretion. We recently showed that furosemide acidifies the urine independently of ENaC activity. If the voltage hypothesis holds, hydrochlorothiazide (HCT) must acidify the urine. We here tested the acute effect of HCT on urine pH under normal and high ENaC expression. METHODS: Mice subjected to a control or a low-Na+ diet were anesthetized and infused (0.5 mL h-1 ) with saline. Catheterization of the urinary bladder allowed real-time measurement of diuresis and urine pH. Mice received either HCT (1 mg mL-1 ) or vehicle. Urinary Na+ and K+ excretions were determined by flame photometry. ENaC expression levels were measured by semi-quantitative Western blotting. RESULTS: (1) HCT increased diuresis and natriuresis in both diet groups. (2) K+ excretion rates increased after HCT administration from 18.6 ± 1.3 to 31.7 ± 2.5 µmol h-1 in the control diet group and from 23.0 ± 1.3 to 48.7 ± 3.0 µmol h-1 in the low-Na+ diet group. (3) Mice fed a low-Na+ diet showed a marked upregulation of ENaC. (4) Importantly, no acute changes in urine pH were observed after the administration of HCT in either group. CONCLUSION: Acute administration of HCT has no effect on urine pH. Similarly, substantial functional and molecular upregulation of ENaC did not cause HCT to acutely change urine pH. Thus, an increased Na+ load to the CD does not alter urine pH. This supports our previous finding and likely falsifies the voltage hypothesis of H+ secretion.