Gestational weight gain in twin gestations and pregnancy outcomes: a systematic review and meta-analysis.

BACKGROUND: Data on the association of inappropriate gestational weight gain (GWG) and adverse outcomes in twin pregnancies are limited and inconsistent. OBJECTIVES: To perform a systematic review and meta-analysis on the association between GWG and adverse outcomes in twin pregnancies. SEARCH STRATEGY: Ovid, Medline, EMBASE and Cochrane Central databases from 1 January 1990 until 23 September 2020. SELECTION CRITERIA: Interventional and observational studies evaluating the association between GWG and adverse outcomes in twin pregnancies. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers. Summary odds ratios (OR) were calculated using a random-effects model in a subset of studies that analysed GWG as a categorical variable in relation to the Institute of Medicine (IOM) recommendations. The primary outcome was preterm birth. MAIN RESULTS: From 277 citations, 19 studies involving 36 023 women with twin pregnancies were included in the qualitative analysis, of which 14 were included in the meta-analysis. Overall, 56.8% of women experienced inappropriate GWG: 35.4% (95% CI 30.0-41.0%) gained weight below and 21.4% (95% CI 14.2-29.5%) gained weight above IOM recommendations. Compared with GWG within IOM guidelines, GWG below IOM guidelines was associated with preterm birth before 32 weeks of gestation (OR 3.38; 95% CI 2.05-5.58), and a reduction in the risk of pre-eclampsia (OR 0.68; 95% CI 0.48-0.97). GWG above IOM guidelines was associated with an increased risk of pre-eclampsia that was consistent across all body mass index categories. CONCLUSIONS: Inappropriate GWG affects over half of twin pregnancies, so is a common and potentially modifiable risk factor for preterm birth and pre-eclampsia.

The impact of cannabis use on vasomotor symptoms, mood, insomnia and sexuality in perimenopausal and postmenopausal women: a systematic review.

OBJECTIVE: This study aimed to evaluate the published data on the effect of cannabis use in perimenopausal and postmenopausal women to alleviate menopausal symptoms, insomnia and anxiety. METHODS: Databases searched included Ovid MEDLINE, PubMed, Ovid Embase, Web of Science, Scopus, CINAHL, PsycINFO, Cochrane, LILACS and AMED. Selected studies assessed perimenopausal or postmenopausal women, cannabis use impact and menopausal symptoms. RESULTS: A total of 564 studies were retrieved. Three studies met the inclusion criteria. One study controlled for participant cannabis use and reported on the effects of cannabis and placebo cigarette smoking on mood in 10 postmenopausal women. Another study assessed associations between drug use with hot flashes and insomnia in 120 HIV-infected women and found that menopausal status and cannabis use was crudely associated with the presence of hot flashes. The last study evaluated expectancies of 115 menopausal patients who endorsed lifetime cannabis use and reported that women expected cannabis to improve depression, anxiety, hot flashes and problems with sleep. None of these studies assessed quality of life as an outcome. CONCLUSION: There is a paucity of literature on the impact of cannabis use in menopause. Research into cannabis consumption in menopause is essential, as it is frequently used to alleviate symptoms without evidence of its benefits.

Control of Hypertension In Pregnancy Study randomised controlled trial-are the results dependent on the choice of labetalol or methyldopa?

OBJECTIVE: To determine whether the difference in outcomes between 'less tight' (target diastolic blood pressure [dBP] of 100 mmHg) versus 'tight' control (target dBP of 85 mmHg) in the CHIPS Trial (ISRCTN 71416914, http://pre-empt.cfri.ca/;CHIPS) depended on the choice of labetalol or methyldopa, the two most commonly used antihypertensive agents in CHIPS. DESIGN: Secondary analysis of CHIPS Trial data. SETTING: International multicentre randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: A total of 987 women with non-severe non-proteinuric pregnancy hypertension. METHODS: Logistic regression was used for comparisons of 'less tight' versus 'tight' control among women treated with labetalol (but not methydopa) versus methyldopa (but not labetalol). Analyses were adjusted for the influence of baseline factors, including use of any antihypertensive therapy at randomisation. MAIN OUTCOME MEASURES: Main CHIPS Trial outcomes: primary (perinatal loss or high-level neonatal care for > 48 hours), secondary (serious maternal complications), birthweight < 10th centile, severe maternal hypertension, pre-eclampsia, and delivery at < 34 or < 37 weeks. RESULTS: Of 987 women in CHIPS, antihypertensive therapy was taken by 566 women at randomisation (labetalol 111 ['less tight'] versus 127 ['tight'] or methyldopa 126 ['less tight'] versus 117 ['tight']) and 815 women after randomisation (labetalol 186 ['less tight'] versus 247 ['tight'] and methyldopa by 98 ['less tight'] versus 126 ['tight']). Following adjustment, odds ratios for outcomes in 'less tight' versus 'tight' control were similar between antihypertensive groups according to 'at randomisation' and 'after randomisation' therapy. CONCLUSION: Outcomes for 'less tight' versus 'tight' control were not dependent on use of methyldopa or labetalol. TWEETABLE ABSTRACT: In the CHIPS Trial, maternal and infant outcomes were not dependent on use of labetalol or methyldopa.

Do labetalol and methyldopa have different effects on pregnancy outcome? Analysis of data from the Control of Hypertension In Pregnancy Study (CHIPS) trial.

OBJECTIVE: To compare pregnancy outcomes, accounting for allocated group, between methyldopa-treated and labetalol-treated women in the CHIPS Trial (ISRCTN 71416914) of 'less tight' versus 'tight' control of pregnancy hypertension. DESIGN: Secondary analysis of CHIPS Trial cohort. SETTING: International randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: Of 987 CHIPS recruits, 481/566 (85.0%) women treated with antihypertensive therapy at randomisation. Of 981 (99.4%) women followed to delivery, 656/745 (88.1%) treated postrandomisation. METHODS: Logistic regression to compare outcomes among women who took methyldopa or labetalol, adjusted for the influence of baseline factors. MAIN OUTCOME MEASURES: CHIPS primary (perinatal loss or high level neonatal care for >48 hours) and secondary (serious maternal complications) outcomes, birthweight <10th centile, severe maternal hypertension, pre-eclampsia and delivery at <34 or <37 weeks. RESULTS: Methyldopa and labetalol were used commonly at randomisation (243/987, 24.6% and 238/987, 24.6%, respectively) and post-randomisation (224/981, 22.8% and 433/981, 44.1%, respectively). Following adjusted analyses, methyldopa (versus labetalol) at randomisation was associated with fewer babies with birthweight <10th centile [adjusted odds ratio (aOR) 0.48; 95% CI 0.20-0.87]. Methyldopa (versus labetalol) postrandomisation was associated with fewer CHIPS primary outcomes (aOR 0.64; 95% CI 0.40-1.00), birthweight <10th centile (aOR 0.54; 95% CI 0.32-0.92), severe hypertension (aOR 0.51; 95% CI 0.31-0.83), pre-eclampsia (aOR 0.55; 95% CI 0.36-0.85), and delivery at <34 weeks (aOR 0.53; 95% CI 0.29-0.96) or <37 weeks (aOR 0.55; 95% CI 0.35-0.85). CONCLUSION: These nonrandomised comparisons are subject to residual confounding, but women treated with methyldopa (versus labetalol), particularly those with pre-existing hypertension, may have had better outcomes. TWEETABLE ABSTRACT: There was no evidence that women treated with methyldopa versus labetalol had worse outcomes.

Development and certification of green tea-containing standard reference materials.

A suite of three green tea-containing Standard Reference Materials (SRMs) has been issued by the National Institute of Standards and Technology (NIST): SRM 3254 Camellia sinensis (Green Tea) Leaves, SRM 3255 Camellia sinensis (Green Tea) Extract, and SRM 3256 Green Tea-Containing Solid Oral Dosage Form. The materials are characterized for catechins, xanthine alkaloids, theanine, and toxic elements. As many as five methods were used in assigning certified and reference values to the constituents, with measurements carried out at NIST and at collaborating laboratories. The materials are intended for use in the development and validation of new analytical methods, and for use as control materials as a component in the support of claims of metrological traceability.

Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) through non-specialist providers and telemedicine: a study protocol for a non-inferiority randomized controlled trial.

BACKGROUND: Depression and anxiety impact up to 1 in 5 pregnant and postpartum women worldwide. Yet, as few as 20% of these women are treated with frontline interventions such as evidence-based psychological treatments. Major barriers to uptake are the limited number of specialized mental health treatment providers in most settings, and problems with accessing in-person care, such as childcare or transportation. Task sharing of treatment to non-specialist providers with delivery on telemedicine platforms could address such barriers. However, the equivalence of these strategies to specialist and in-person models remains unproven. METHODS: This study protocol outlines the Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) randomized trial. SUMMIT is a pragmatic, non-inferiority test of the comparable effectiveness of two types of providers (specialist vs. non-specialist) and delivery modes (telemedicine vs. in-person) of a brief, behavioral activation (BA) treatment for perinatal depressive and anxiety symptoms. Specialists (psychologists, psychiatrists, and social workers with ≥ 5 years of therapy experience) and non-specialists (nurses and midwives with no formal training in mental health care) were trained in the BA protocol, with the latter supervised by a BA expert during treatment delivery. Consenting pregnant and postpartum women with Edinburgh Postnatal Depression Scale (EPDS) score of ≥ 10 (N = 1368) will be randomized to one of four arms (telemedicine specialist, telemedicine non-specialist, in-person specialist, in-person non-specialist), stratified by pregnancy status (antenatal/postnatal) and study site. The primary outcome is participant-reported depressive symptoms (EPDS) at 3 months post-randomization. Secondary outcomes are maternal symptoms of anxiety and trauma symptoms, perceived social support, activation levels and quality of life at 3-, 6-, and 12-month post-randomization, and depressive symptoms at 6- and 12-month post-randomization. Primary analyses are per-protocol and intent-to-treat. The study has successfully continued despite the COVID-19 pandemic, with needed adaptations, including temporary suspension of the in-person arms and ongoing randomization to telemedicine arms. DISCUSSION: The SUMMIT trial is expected to generate evidence on the non-inferiority of BA delivered by a non-specialist provider compared to specialist and telemedicine compared to in-person. If confirmed, results could pave the way to a dramatic increase in access to treatment for perinatal depression and anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153864 . Registered on November 6, 2019.

Prevalence of deafness in dogs heterozygous or homozygous for the merle allele.

BACKGROUND: Deafness in dogs is frequently associated with the pigment genes piebald and merle. Little is known about the prevalence of deafness in dogs carrying the merle allele. OBJECTIVE: To determine the prevalence of deafness in dogs heterozygous and homozygous for the merle allele of the mouse Silver pigment locus homolog (SILV) gene. ANIMALS: One hundred and fifty-three privately owned merle dogs of different breeds and both sexes. METHODS: Hearing was tested by brainstem auditory-evoked response and classified as bilaterally hearing, unilaterally deaf, or bilaterally deaf. DNA from buccal cells was genotyped as either heterozygous or homozygous for the merle allele. Deafness association tests among merle genotype, eye color, and sex were performed by the chi(2) test. RESULTS: Deafness prevalence in merles overall was 4.6% unilaterally deaf and 4.6% bilaterally deaf. There was a significant association between hearing status and heterozygous versus homozygous merle genotype. For single merles (Mm), 2.7% were unilaterally deaf and 0.9% were bilaterally deaf. For double merles (MM), 10% were unilaterally deaf and 15% were bilaterally deaf. There was no significant association with eye color or sex. CONCLUSIONS: Deafness prevalence in merle dogs was greater than that in some dog breeds homozygous for the piebald gene, such as the English Cocker Spaniel, but comparable to, or lower than, that in the Dalmatian and white Bull Terrier. Dogs homozygous for the merle allele were significantly more likely to be deaf than heterozygotes.

X chromosome inactivation patterns in normal and X-linked hereditary nephropathy carrier dogs.

Alport syndrome (AS) and hereditary nephropathy (HN) are glomerular nephropathies caused by mutations in the genes encoding the type IV collagens. In a mixed breed of dog, termed Navasota (NAV) dogs, X-linked hereditary nephropathy (XLHN) is caused by a 10-bp deletion in exon 9 of COL4A5. Males harboring this mutation succumb to end-stage renal disease before 18 months of age. In contrast, female carriers of this disease survive much longer, most have a normal life-span, and vary in disease progression as compared with XLHN-affected males. X chromosome inactivation (XCI) patterns have been studied in human X-linked AS carriers and some have been shown to have a high degree of skewed XCI. However, similar studies have never been reported in an animal model of this disease. Therefore, patterns of XCI were examined in XLHN-carrier NAV dogs. The variation in XCI among the 26 XLHN-carrier and seven normal female NAV dogs studied was low and only three were found to preferentially inactivate one X chromosome, all of which were XLHN-carriers. The average skewedness among all dogs was 59% and 57% among the XLHN-carriers. No significant difference in XCI was found between the two groups (P = 0.477). It is clear from these data that genotype does not seem to have an effect on inactivation; the majority of these dogs have random patterns of XCI. Highly skewed X chromosome inactivation also appears to be random, given that no difference was observed between the XLHN-carriers and normal females. Because of the apparent rarity of skewed XCI, these dogs may not be a suitable model for studying a potential correlation between this phenomenon and disease progression.

Certification of standard reference materials containing bitter orange.

A suite of three dietary supplement standard reference materials (SRMs) containing bitter orange has been developed, and the levels of five alkaloids and caffeine have been measured by multiple analytical methods. Synephrine, octopamine, tyramine, N-methyltyramine, hordenine, total alkaloids, and caffeine were determined by as many as six analytical methods, with measurements performed at the National Institute of Standards and Technology and at two collaborating laboratories. The methods offer substantial independence, with two types of extractions, two separation methods, and four detection methods. Excellent agreement was obtained among the measurements, with data reproducibility for most methods and analytes better than 5% relative standard deviation. The bitter-orange-containing dietary supplement SRMs are intended primarily for use as measurement controls and for use in the development and validation of analytical methods.

Hypertensive disorders of pregnancy and outcomes of preterm infants of 24 to 28 weeks' gestation.

OBJECTIVE: To examine the relationship between hypertensive disorders of pregnancy (HDPs) and mortality and major morbidities in preterm neonates born at 24 to 28 weeks of gestation. STUDY DESIGN: Using an international cohort, we retrospectively studied 27 846 preterm neonates born at 240 to 286 weeks of gestation during 2007 to 2010 from 6 national neonatal databases. The incidence of HDP was compared across countries, and multivariable logistic regression analyses were conducted to examine the association of HDP and neonatal outcomes including mortality to discharge, bronchopulmonary dysplasia, severe brain injury, necrotizing enterocolitis and treated retinopathy of prematurity. RESULTS: The incidence of HDP in the entire cohort was 13% (range 11 to 16% across countries). HDP was associated with reduced odds of mortality (adjusted odds ratio (aOR) 0.77; 95% confidence interval (CI) 0.67 to 0.88), severe brain injury (aOR 0.74; 95% CI 0.62 to 0.89) and treated retinopathy (aOR 0.82; 95% CI 0.70 to 0.96), but increased odds of bronchopulmonary dysplasia (aOR 1.16; 95% CI 1.05 to 1.27). CONCLUSIONS: In comparison with neonates born to mothers without HDP, neonates of HDP mothers had lower odds of mortality, severe brain injury and treated retinopathy, but higher odds of bronchopulmonary dysplasia. The impact of maternal HDP on newborn outcomes was inconsistent across outcomes and among countries; therefore, further international collaboration to standardize terminology, case definition and data capture is warranted.

Large scale accelerator production of 225Ac: Effective cross sections for 78-192MeV protons incident on 232Th targets.

Actinium-225 and 213Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225Ac. The high-energy proton spallation reaction on natural thorium metal targets has been utilized to produce millicurie quantities of 225Ac. The results of sixteen irradiation experiments of thorium metal at beam energies between 78 and 192MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridge National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes, as well as for some of the fission products, are presented. The cross sections for production of 225Ac range from 3.6 to 16.7mb in the incident proton energy range of 78-192MeV. Based on these data, production of curie quantities of 225Ac is possible by irradiating a 5.0gcm-2 232Th target for 10 days in either BNL or LANL proton irradiation facilities.

Heritability and segregation analysis of deafness in U.S. Dalmatians.

Hereditary loss of hearing affects many breeds of the domestic dog, but the Dalmatian has the highest prevalence. Approximately 30% are affected in the United States (U.S.) population. It is widely accepted that a relationship exists between deafness and pigmentation in the dog and also in other animals. While the Dalmatian exemplifies this relationship, the genetic origin and mode of inheritance of deafness in this breed are unknown. The goals of this study were to: (1) estimate the heritability of deafness in an extended kindred of U.S. Dalmatians and (2) determine, through complex segregation analysis, whether there is a major segregating locus that has a large effect on the expression of deafness. A kindred of 266 Dalmatians was assembled, of which 199 had been diagnosed using the brainstem auditory evoked response to determine auditory status. Of these, 74.4% (N = 148) had normal hearing, 18.1% (N = 36) were unilaterally deaf, and 7.5% (N = 15) were bilaterally deaf. A heritability of 0.73 was estimated considering deafness a dichotomous trait and 0.75 considering it as a trichotomous trait. Although deafness in the Dalmatian is clearly heritable, the evidence for the presence of a single major gene affecting the disorder is not persuasive.

Identification of isoforms and RH mapping of canine KIT.

The proto-oncogene, C-KIT (KIT), encodes a tyrosine kinase receptor, and mutations in this gene are causative for several mammalian diseases, including cancer and a form of pigmentation-associated hereditary deafness. Our laboratories are interested in a form of hereditary deafness that is associated with abnormalities in pigmentation and is common in the Dalmatian. Thus, KIT is being analyzed as a candidate gene for deafness in this breed. In addition to our interest in deafness, we are involved in mapping gene loci in the canine genome. Reported here is the identification of two isoforms of canine C-kit and radiation hybrid mapping of KIT to CFA13.

Digging up the canine genome--a tale to wag about.

There is incredible morphological and behavioral diversity among the hundreds of breeds of the domestic dog, CANIS FAMILIARIS. Many of these breeds have come into existence within the last few hundred years. While there are obvious phenotypic differences among breeds, there is marked interbreed genetic homogeneity. Thus, study of canine genetics and genomics is of importance to comparative genomics, evolutionary biology and study of human hereditary diseases. The most recent version of the map of the canine genome is comprised of 3,270 markers mapped to 3,021 unique positions with an average intermarker distance of approximately 1 Mb. The markers include approximately 1,600 microsatellite markers, about 1,000 gene-based markers, and almost 700 bacterial artificial chromosome-end markers. Importantly, integration of radiation hybrid and linkage maps has greatly enhanced the utility of the map. Additionally, mapping the genome has led directly to characterization of microsatellite markers ideal for whole genome linkage scans. Thus, workers are now able to exploit the canine genome for a wide variety of genetic studies. Finally, the decision to sequence the canine genome highlights the dog's evolutionary and physiologic position between the mouse and human and its importance as a model for study of mammalian genetics and human hereditary diseases.

Transvaginal color Doppler sonography of the ureteral jets: a method to detect ureteral patency.

OBJECTIVE: To evaluate the feasibility of the detection of ureteral jets into the bladder in obstetric-gynecologic patients using transvaginal color Doppler ultrasound. METHODS: Fifty-two women were recruited and categorized into four groups: 1) 20 normal nonsurgical, 2) 17 post-cesarean delivery, 3) 12 post-total abdominal hysterectomy, and 4) three with only one functional kidney or ureter. In the first three groups, transvaginal color Doppler sonography was used to evaluate the time to detection of the first jet and the number of jets in 5 minutes bilaterally. In the last group, the presence or absence of the jet was documented only on the functional side. Statistical analysis was performed using Student t test and analysis of variance followed by Tukey honestly significant difference. RESULTS: Urine jets could be detected bilaterally in all women except for those with only one functional kidney (accuracy 100%). Time to detection of the first jet did not differ significantly in the nonsurgical, cesarean, or hysterectomy patients on either the right side (P = .07) or the left side (P = .43). The total number of jets was similar in the nonsurgical and cesarean patients, but was significantly lower in the hysterectomy group (right side P = .006; left side P = .004). In the women with one functional kidney, the normal side was identified in all cases. CONCLUSION: Transvaginal color Doppler sonography is a simple, accurate technique that can be used to evaluate ureteral jets into the bladder in women. The length of time to detection of the first jet is not affected by the postoperative status. Fewer jets should be expected in women who have undergone hysterectomies. This method should be used when ureteral integrity is in question, especially after surgery.

Assignment of canine MSS1 microsatellite markers to chromosomes by linkage data.

Recent advances in mapping the canine genome have led to an increase in the number of linkage studies aimed at dissecting the genetic causes of many hereditary diseases that affect the domestic dog. The first step in developing molecular tools for a whole genome scan was the characterization of a set of microsatellite markers, termed minimal screening set 1 (MSS1), that provided an estimated coverage of 10 cM. A limiting factor in use of the MSS1 is not all of the 172 MSS1 markers have been localized to specific chromosomes. Seventy-five of the markers were positioned on a total of 15 chromosomes with the original publication of the MSS1. The localization based on linkage data of 14 additional MSS1 markers to chromosomes using CRIMAP v. 2.4 to build a linkage map of 113 MSS1 markers that were polymorphic in a kindred of Dalmatians is reported here.

Maternal pre-gravid body mass index and obstetric outcomes in twin gestations.

OBJECTIVE: The aim of this study is to evaluate the impact of maternal pre-gravid and/or first trimester overweight and obesity, and the adverse obstetrics outcome in twin pregnancies. STUDY DESIGN: This is a retrospective study of women who delivered viable twins after 23 weeks of gestation with available prepregnancy body mass index (BMI) and/or were at their earliest visit during the first trimester of pregnancy in the period 2007-2011. The patients were divided into four subgroups according to their BMI (underweight, normal weight, overweight and obese) according to the WHO classification and their outcomes were compared. Obstetrical outcomes of interest including gestational diabetes, gestational hypertension, preterm birth, antepartum hemorrhage, intrahepatic cholestasis of pregnancy, method of delivery and neonatal intensive care unit (NICU) admission were all studied and compared. RESULT: Electronic records of 1228 pregnant subjects who delivered twins were abstracted. Five hundred and four patients with twin gestations with available BMI were identified (underweight BMI<18.5% (n=22), normal weight BMI 18.5-24.9% (n=260), overweight 25-29.9% (n=114) and obese ⩾30% (n=108)). Obstetric complications occurred more often in the overweight and obese groups as compared with the normal weight group. There was an increased risk of gestational diabetes in overweight and obese women (odds ratio (OR), 3.3; 95% confidence interval (CI) 1.52-7.3; P=0.001) and (OR, 3.2; 95% CI, 1.41-7.1; P=0.002), respectively. There was an increased risk of gestational hypertension in the obese group compared with the normal weight group (OR, 2.29; 95% CI, 1.1-4.7; P=0.02) but not in the overweight group (OR, 1.71; 95% CI, 0.8-3.6; P=0.1). In addition, an increased risk of very preterm delivery (<32 weeks) in the overweight group and obese groups was seen when compared with the normal weight group (OR, 2.2; 95% CI, 1.18-4.20; P=0.014 and OR, 2; 95% CI, 1.024-3.91; P=0.04, respectively). Increased rate of cesarean section in the obese group was seen when compared with the normal weight group (OR, 2; 95% CI, 1.2-3.4; P=0.006). Risks of antepartum hemorrhage, intrahepatic cholestasis and NICU admission were similar between the groups. CONCLUSION: In addition to the known obstetrics complications associated with twin gestations, the pregnancy outcomes in twins are further adversely influenced by increased maternal prepregnancy BMI.

Characterization of the genetic basis for autosomal recessive hereditary nephropathy in the English Springer Spaniel.

BACKGROUND: Autosomal recessive hereditary nephropathy (ARHN) was diagnosed in 2 English Springer Spaniels (ESS), a breed not previously reported to be affected by hereditary nephropathy (HN). OBJECTIVE: To identify and characterize the genetic cause of ARHN in ESS. ANIMALS: Sixty-three ESS (2 with ARHN, 2 obligate carriers, and 59 others), 2 mixed-breed dogs with X-linked HN, and 2 English Cocker Spaniels (ECS) with ARHN were included. METHODS: ARHN was diagnosed based on transmission electron microscopy and immunostaining of kidney. DNA from affected dogs was screened for the mutation known to cause ARHN in ECS. Quantities of COL4A3, COL4A4, and COL4A5 mRNA transcripts in renal cortex were determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for ARHN-affected dogs and 7 other dogs. The coding regions of COL4A3 and COL4A4 were sequenced for the 2 ARHN-affected ESS and an unaffected dog. Exon 30 of COL4A4 was sequenced for all 63 ESS. RESULTS: qRT-PCR indicated a significant reduction in transcript levels of both COL4A3 and COL4A4 mRNA in the kidney of ARHN-affected ESS. Sequencing identified a single nucleotide substitution in COL4A4 at base 2806 resulting in a premature stop codon. Thirteen of 25 related dogs were identified as carriers. CONCLUSIONS AND CLINICAL IMPORTANCE: A mutation highly likely to cause ARHN in ESS has been identified.