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PurposeIn children with cerebral palsy, flexion deformities of the knee can be treated with a distal femoral extension osteotomy combined with either patellar tendon advancement or patellar tendon shortening. The purpose of this study was to establish a consensus through expert orthopedic opinion, using a modified Delphi process to describe the surgical indications for distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening. A literature review was also conducted to summarize the recent literature on distal femoral extension osteotomy and patellar tendon shortening/patellar tendon advancement.MethodA group of 16 pediatric orthopedic surgeons, with more than 10 years of experience in the surgical management of children with cerebral palsy, was established. The group used a 5-level Likert-type scale to record agreement or disagreement with statements regarding distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening. Consensus for the surgical indications for distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening was achieved through a modified Delphi process. The literature review, summarized studies of clinical outcomes of distal femoral extension osteotomy/patellar tendon shortening/patellar tendon advancement, published between 2008 and 2022.ResultsThere was a high level of agreement with consensus for 31 out of 44 (70%) statements on distal femoral extension osteotomy. Agreement was lower for patellar tendon advancement/patellar tendon shortening with consensus reached for 8 of 21 (38%) of statements. The literature review included 25 studies which revealed variation in operative technique for distal femoral extension osteotomy, patellar tendon advancement, and patellar tendon shortening. Distal femoral extension osteotomy and patellar tendon advancement/patellar tendon shortening were generally effective in correcting knee flexion deformities and extensor lag, but there was marked variation in outcomes and complication rates.ConclusionThe results from this study will provide guidelines for surgeons who care for children with cerebral palsy and point to unresolved questions for further research.Level of evidencelevel V.

Berberine, an isoquinoline alkaloid derived from plants, is a traditional medicine for treating bacterial diarrhea and intestinal parasite infections. Although berberine has recently been shown to suppress growth of several tumor cell lines, information regarding the effect of berberine on colon tumor growth is limited. Here, we investigated the mechanisms underlying the effects of berberine on regulating the fate of colon tumor cells, specifically the mouse immorto-Min colonic epithelial (IMCE) cells carrying the Apc(min) mutation, and of normal colon epithelial cells, namely young adult mouse colonic epithelium (YAMC) cells. Berberine decreased colon tumor colony formation in agar, and induced cell death and LDH release in a time- and concentration-dependent manner in IMCE cells. In contrast, YAMC cells were not sensitive to berberine-induced cell death. Berberine did not stimulate caspase activation, and PARP cleavage and berberine-induced cell death were not affected by a caspase inhibitor in IMCE cells. Rather, berberine stimulated a caspase-independent cell death mediator, apoptosis-inducing factor (AIF) release from mitochondria and nuclear translocation in a ROS production-dependent manner. Amelioration of berberine-stimulated ROS production or suppression of AIF expression blocked berberine-induced cell death and LDH release in IMCE cells. Furthermore, two targets of ROS production in cells, cathepsin B release from lysosomes and PARP activation were induced by berberine. Blockage of either of these pathways decreased berberine-induced AIF activation and cell death in IMCE cells. Thus, berberine-stimulated ROS production leads to cathepsin B release and PARP activation-dependent AIF activation, resulting in caspase-independent cell death in colon tumor cells. Notably, normal colon epithelial cells are less susceptible to berberine-induced cell death, which suggests the specific inhibitory effects of berberine on colon tumor cell growth.

Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

PurposeThere is marked variation in indications and techniques for hamstring surgery in children with cerebral palsy. There is particular uncertainty regarding the indications for hamstring transfer compared to traditional hamstring lengthening. The purpose of this study was for an international panel of experts to use the Delphi method to establish consensus indications for hamstring surgery in ambulatory children with cerebral palsy.MethodsThe panel used a five-level Likert-type scale to record agreement or disagreement with statements regarding hamstring surgery, including surgical indications and techniques, post-operative care, and outcome measures. Consensus was defined as at least 80% of responses being in the highest or lowest two of the five Likert-type ratings. General agreement was defined as 60%-79% falling into the highest or lowest two ratings. There was no agreement if neither of these thresholds was reached.ResultsThe panel reached consensus or general agreement for 38 (84%) of 45 statements regarding hamstring surgery. The panel noted the importance of assessing pelvic tilt during gait when considering hamstring surgery, and also that lateral hamstring lengthening is rarely needed, particularly at the index surgery. They noted that repeat hamstring lengthening often has poor outcomes. The panel was divided regarding hamstring transfer surgery, with only half performing such surgery.ConclusionThe results of this study can help pediatric orthopedic surgeons optimize decision-making in their choice and practice of hamstring surgery for ambulatory children with cerebral palsy. This has the potential to reduce practice variation and significantly improve outcomes for ambulatory children with cerebral palsy.Level of evidencelevel V.

PurposeThe purpose of this study was to develop consensus for the surgical indications of anterior distal femur hemiepiphysiodesis in children with cerebral palsy using expert surgeon opinion through a modified Delphi technique.MethodsThe panel used a 5-level Likert-type scale to record agreement or disagreement with 27 statements regarding anterior distal femur hemiepiphysiodesis. Consensus was defined as at least 80% of responses being in the highest or lowest 2 of the Likert-type ratings. General agreement was defined as 60%-79% falling into the highest or lowest 2 ratings.ResultsFor anterior distal femur hemiepiphysiodesis, 27 statements were surveyed: consensus or general agreement among the panelists was achieved for 22 of 27 statements (22/27, 82%) and 5 statements had no agreement (5/27, 18%). There was general consensus that anterior distal femur hemiepiphysiodesis is indicated for ambulatory children with cerebral palsy, with at least 2 years growth remaining, and smaller (

PurposeThe purpose of this study was for an international panel of experts to establish consensus indications for distal rectus femoris surgery in children with cerebral palsy (CP) using a modified Delphi method.MethodsThe panel used a five-level Likert scale to record agreement or disagreement with 33 statements regarding distal rectus femoris surgery. The panel responded to statements regarding general characteristics, clinical indications, computerized gait data, intraoperative techniques and outcome measures. Consensus was defined as at least 80% of responses being in the highest or lowest two of the five Likert ratings, and general agreement as 60% to 79% falling into the highest or lowest two ratings. There was no agreement if neither threshold was reached.ResultsConsensus or general agreement was reached for 17 of 33 statements (52%). There was general consensus that distal rectus femoris surgery is better for stiff knee gait than is proximal rectus femoris release. There was no consensus about whether the results of distal rectus femoris release were comparable to those following distal rectus femoris transfer. Gross Motor Function Classification System (GMFCS) level was an important factor for the panel, with the best outcomes expected in children functioning at GMFCS levels I and II. The panel also reached consensus that they do distal rectus femoris surgery less frequently than earlier in their careers, in large part reflecting the narrowing of indications for this surgery over the last decade.ConclusionThis study can help paediatric orthopaedic surgeons optimize decision-making for, and outcomes of, distal rectus femoris surgery in children with CP.Level of evidenceV.

Abstract Background Publicly available phenotype data and genotyping array data from two citizen science projects: “Doberman Health Surveys” and “The Doberman Diversity Project” were analyzed to explore relative homozygosity, diversity, and disorder risk according to geographical locale and breeding purpose in the Doberman. Results From the phenotypic data cohort, life expectancy of a Doberman at birth is 9.1 years. The leading causes of death were heart disease (accounting for 28% of deaths) and cancers (collectively accounting for 14% of deaths). By genotyping, the world Doberman population exists as four major cohorts (European exhibition-bred, Americas exhibition-bred, European work, Americas pet/informal). Considering the entire Doberman population, four genomic regions longer than 500 Kb are fixed in 90% or more of 3,226 dogs included in this study. The four fixed regions reside on two autosomal chromosomes: CFA3:0.8–2.3 Mb (1.55 Mb); CFA3: 57.9–59.8 Mb (1.8 Mb); CFA31:0–1.2 Mb (1.2 Mb); and CFA31:4.80–6.47 Mb (1.67 Mb). Using public variant call files including variants for eight Doberman pinschers, we observed 30 potentially functional alternate variants that were evolutionarily diverged relative to the wider sequenced dog population within the four strongly homozygous chromosomal regions. Effective population size (Ne) is a statistical measure of breed diversity at the time of sampling that approximates the number of unique individuals. The major identified sub-populations of Dobermans demonstrated Ne in the range 70–236. The mean level of inbreeding in the Doberman breed is 40% as calculated by the number of array variants in runs of homozygosity divided by the assayed genome size (excluding the X chromosome). The lowest observed level of inbreeding in the Dobermans assayed was 15% in animals that were first generation mixes of European and USA bred Dobermans. Array variant analysis shows that inter-crossing between European and USA-bred Dobermans has capacity to re-introduce variation at many loci that are strongly homozygous. Conclusions We conclude that efforts to improve breed diversity first should focus on regions with the highest fixation levels, but managers must ensure that mutation loads are not worsened by increasing the frequencies of rarer haplotypes in the identified regions. The analysis of global data identified regions of strong fixation that might impact known disorder risks in the breed. Plausible gene candidates for future analysis of the genetic basis of cardiac disease and cancer were identified in the analysis.

PurposeEquinus is the most common deformity in cerebral palsy (CP) and gastrocsoleus lengthening (GSL) is the most commonly performed surgery to improve gait and function in ambulatory children with CP. Substantial variation exists in the indications for GSL and surgical technique. The purpose of this study was to review surgical anatomy and biomechanics of the gastrocsoleus and to utilize expert orthopaedic opinion through a Delphi technique to establish consensus for surgical indications for GSL in ambulatory children with CP.MethodsA 17-member panel, of Fellowship-trained paediatric orthopaedic surgeons, each with at least 9 years of clinical post-training experience in the surgical management of children with CP, was established. Consensus for the surgical indications for GSL was achieved through a standardized, iterative Delphi process.ResultsConsensus was reached to support conservative Zone 1 surgery in diplegia and Zone 3 surgery (lengthening of the Achilles tendon) was contraindicated. Zone 2 or Zone 3 surgery reached general agreement as a choice in hemiplegia and under-correction was preferred to any degree of overcorrection. Agreement was reached that the optimum age for GSL surgery was 6 years to 10 years and should be avoided in children aged under 4 years. Physical examination measures with the child awake and under anaesthesia were important in decision making. Gait analysis was supported both for decision making and for assessing outcomes, in combination with patient reported outcomes (PROMS).ConclusionsThe results from this study may encourage informed practice evaluation, reduce practice variability, improve clinical outcomes and point to questions for further research.Level of evidenceV.

IntroductionPlasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease.MethodsWe measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort.Results and discussionWe observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P

Abstract Congenital sensorineural deafness (CSD) has been reported to affect up to 30% of Dalmatian dogs world-wide and while unilaterally deaf dogs can live a close to normal life, dogs suffering bilateral deafness are frequently euthanized. Extreme-white coat patterning as encoded by the gene Melanocyte Inducing Transcription Factor (MITF) has long been postulated as the major risk factor for CSD in the Dalmatian breed. While attempts to identify causative risk variants associated with CSD have been numerous, no genome-wide association study has positively identified MITF as a risk locus for either bilateral or unilateral deafness in the Dalmatian breed to date. In this study, we identified an association with CSD on CFA20 in the vicinity of MITF within Australian Dalmatian dogs. Although not genome-wide significant, the association signal was validated by reanalysing publicly available data and merging the wider data resource with the local data to improve statistical power. The merged data, representing three major global populations of Dalmatian dogs, enabled us to identify a single, well-defined genome-wide significant risk haplotype for CSD. The haplotype was formed by three genome-wide significant associated markers (BICF2G630233852T>C, BICF2G630233861T>C, BICF2G630233888G>A) on CFA20 with 62% of bilaterally deaf dogs homozygous for the risk haplotype (CCA), while 30% of bilaterally deaf and 45% of hearing dogs carried one copy of the risk haplotype. Animals homozygous or heterozygous for the low-risk haplotype were less likely to be unilaterally deaf. While the association between the risk haplotype and deafness is incomplete, animals homozygous for the risk haplotype were 10-times more likely to be bilaterally deaf. Although the underlying causative variants are yet to be discovered, results from this study can now assist with reducing deafness in Dalmatian dogs.

Mutations in FLNA, which encodes the cytoskeletal protein FLNA, cause a spectrum of sclerosing skeletal dysplasias. Although many of these genetic variants are recurrent and cluster within the gene, the pathogenic mechanism that underpins the development of these skeletal phenotypes is unknown. To determine if the skeletal dysplasia in FLNA-related conditions is due to a cell-autonomous loss-of-function localising to osteoblasts and/or osteocytes, we utilised mouse models to conditionally remove Flna from this cellular lineage. Flna was conditionally knocked out from mature osteocytes using the Dmp1-promoter driven Cre-recombinase expressing mouse, as well as the committed osteoblast lineage using the Osx-Cre or Col1a1-Cre expressing lines. We measured skeletal parameters with μCT and histological methods, as well as gene expression in the mineralised skeleton. We found no measureable differences between the conditional Flna knockout mice, and their control littermate counterparts. Moreover, all of the conditional Flna knockout mice, developed and aged normally. From this we concluded that the skeletal dysplasia phenotype associated with pathogenic variants in FLNA is not caused by a cell-autonomous loss-of-function in the osteoblast-osteocyte lineage, adding more evidence to the hypothesis that these phenotypes are due to gain-of-function in FLNA.

ABSTRACT: Studies of dairy cow longevity usually focus on the animal life after first calving, with few studies considering early life conditions and their effects on longevity. The objective was to evaluate the effect of birth conditions routinely collected by Dairy Herd Improvement agencies on offspring longevity measured as length of life and length of productive life. Lactanet provided 712,890 records on offspring born in 5,425 Quebec dairy herds between January 1999 and November 2015 for length of life, and 506,066 records on offspring born in 5,089 Quebec dairy herds between January 1999 and December 2013 for length of productive life. Offspring birth conditions used in this study were calving ease (unassisted, pull, surgery, or malpresentation), calf size (small, medium, or large), and twinning (yes or no). Observations were considered censored if the culling reason was “exported,” “sold for dairy production,” or “rented out” as well as if the animals were not yet culled at the time of data extraction. If offspring were not yet culled when the data were extracted, the last test-day date was considered the censoring date. Conditional inference survival trees were used in this study to analyze the effect of offspring birth conditions on offspring longevity. The hazard ratio of culling between the groups of offspring identified by the survival trees was estimated using a Cox proportional hazard model with herd-year-season as a frailty term. Five offspring groups were identified with different length of life based on their birth condition. Offspring with the highest length of life [median = 3.61 year; median absolute deviation (MAD) = 1.86] were those classified as large or medium birth size and were also the result of an unassisted calving. Small offspring as a result of a twin birth had the lowest length of life (median = 2.20 year; MAD = 1.69) and were 1.52 times more likely to be culled early in life. Six groups were identified with different length of productive life. Offspring that resulted from an unassisted or surgery calving and classified as large or medium when they were born were in the group with the highest length of productive life (median = 2.03 year; MAD = 1.63). Offspring resulting from a malpresentation or pull in a twin birth were in the group with the lowest length of productive life (median = 1.15 year; MAD = 1.11) and were 1.70 times more likely to be culled early in life. In conclusion, birth conditions of calving ease, calf size, and twinning greatly affected offspring longevity, and such information could be used for early selection of replacement candidates.