Microbiota members from body sites of dairy cows are largely shared within individual hosts throughout lactation but sharing is limited in the herd.

BACKGROUND: Host-associated microbes are major determinants of the host phenotypes. In the present study, we used dairy cows with different scores of susceptibility to mastitis with the aim to explore the relationships between microbiota composition and different factors in various body sites throughout lactation as well as the intra- and inter-animal microbial sharing. RESULTS: Microbiotas from the mouth, nose, vagina and milk of 45 lactating dairy cows were characterized by metataxonomics at four time points during the first lactation, from 1-week pre-partum to 7 months post-partum. Each site harbored a specific community that changed with time, likely reflecting physiological changes in the transition period and changes in diet and housing. Importantly, we found a significant number of microbes shared among different anatomical sites within each animal. This was between nearby anatomic sites, with up to 32% of the total number of Amplicon Sequence Variants (ASVs) of the oral microbiota shared with the nasal microbiota but also between distant ones (e.g. milk with nasal and vaginal microbiotas). In contrast, the share of microbes between animals was limited (< 7% of ASVs shared by more than 50% of the herd for a given site and time point). The latter widely shared ASVs were mainly found in the oral and nasal microbiotas. These results thus indicate that despite a common environment and diet, each animal hosted a specific set of bacteria, supporting a tight interplay between each animal and its microbiota. The score of susceptibility to mastitis was slightly but significantly related to the microbiota associated to milk suggesting a link between host genetics and microbiota. CONCLUSIONS: This work highlights an important sharing of microbes between relevant microbiotas involved in health and production at the animal level, whereas the presence of common microbes was limited between animals of the herd. This suggests a host regulation of body-associated microbiotas that seems to be differently expressed depending on the body site, as suggested by changes in the milk microbiota that were associated to genotypes of susceptibility to mastitis.

Neuroma Treatment With the Acellular Nerve Allograft Reconstruction Technique.

Treatment of a painful neuroma is a challenging problem for both the patient and the providers. Current surgical treatment options typically include excision of the neuroma and stump relation. However, with both treatment options, patients have high rates of persistent pain and rates of neuroma recurrence. We describe two patients with neuromas treated with our acellular nerve allograft reconstruction technique. This technique involves the excision of the neuroma and bridging the proximal nerve end to the surrounding tissue with an acellular nerve allograft. Both patients had immediate resolution of their neuropathic pain that was maintained at their final follow-up. Acellular nerve allograft reconstruction is a promising treatment option for the treatment of painful neuromas.

Free Vascularized Fibula Graft for Staged Reconstruction of Infected Humerus Nonunions.

OBJECTIVE: To evaluate the union rate and rate of postoperative complications in patients with septic nonunions of the humerus after a two-stage reconstruction using a free vascularized fibula graft. DESIGN: Retrospective case series. SETTING: Academic, tertiary referral center. PATIENTS/PARTICIPANTS: Adult patients with staged reconstruction for infected nonunion of the humerus with at least 2 years follow-up after vascularized fibula graft transfer. INTERVENTION: First, infected nonunion debridement with antibiotic spacer and external fixator placement. After antimicrobial treatment, free vascularized fibula transfer with internal fixation. MAIN OUTCOME MEASUREMENTS: Time to union, pain, affected extremity range of motion, and function. RESULTS: 10 patients with septic humerus nonunion treated with staged reconstruction using a free vascularized fibula graft, with a mean follow-up of 32.3 months were included. After the two-stage reconstruction using a free fibula, radiographic union was achieved in 6/10 patients, with a mean time to union of 19.9 weeks. The remaining 4 patients required an additional procedure with graft augmentation and/or implant revision. After the revision procedure, union was noted in 3/4 patients, 21 weeks postoperatively. Mean patient visual analog scale pain scores improved from 5.8 preoperatively to 0.9 at final follow-up ( P = 0.02). Postoperatively, mean elbow flexion was 110 ± 20 degrees and extension 15 ± 7.5 degrees. CONCLUSION: A two-stage reconstruction using a free fibula graft can be used in patients with septic nonunions of the humerus in the setting of multiple failed prior surgeries and compromised local biology. Additional procedures may be needed in some to achieve final union. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Standardized Whole Blood Assay and Bead-Based Cytokine Profiling Reveal Commonalities and Diversity of the Response to Bacteria and TLR Ligands in Cattle.

Recent developments in multiplex technologies enable the determination of a large nu\mber of soluble proteins such as cytokines in various biological samples. More than a one-by-one determination of the concentration of immune mediators, they permit the establishment of secretion profiles for a more accurate description of conditions related to infectious diseases or vaccination. Cytokine profiling has recently been made available for bovine species with the development of a Luminex® technology-based 15-plex assay. Independently from the manufacturer, we evaluated the bovine cytokine/chemokine multiplex assay for limits of detection, recovery rate, and reproducibility. Furthermore, we assessed cytokine secretion in blood samples from 107 cows upon stimulation with heat-killed bacteria and TLR2/4 ligands compared to a null condition. Secretion patterns were analyzed either using the absolute concentration of cytokines or using their relative concentration with respect to the overall secretion level induced by each stimulus. Using Partial Least Square-Discriminant Analysis, we show that the 15-cytokine profile is different under Escherichia coli, Staphylococcus aureus, and Streptococcus uberis conditions, and that IFN-γ, IL-1ß, and TNF-α contribute the most to differentiate these conditions. LPS and E. coli induced largely overlapping biological responses, but S. aureus and S. uberis were associated with distinct cytokine profiles than their respective TLR ligands. Finally, results based on adjusted or absolute cytokine levels yielded similar discriminative power, but led to different stimuli-related signatures.

Flexor Tenosynovitis Caused by Mycobacterium heraklionense.

Mycobacterium heraklionense is a rare etiology of serious hand infection with only 2 cases having been reported in literature to date to our knowledge. We describe the case of a 58-year-old woman with persistent swelling and stiffness in her right index finger. Advanced imaging studies in addition to serial surgical debridement with tissue cultures helped to confirm the diagnosis of flexor tenosynovitis caused by M. heraklionense. In this case report, we highlight the clinical evaluation, operative treatment, and antimicrobial therapy leading to the successful care of this disease presentation. Due to its rarity and potential to cause substantial hand infection, M. heraklionense should be included in the differential diagnosis as the cause for chronic flexor tenosynovitis to appropriately minimize morbidity.

Necrotizing Soft Tissue Infection of the Upper Extremity as a Manifestation of Hansen's Disease.

Hansen's disease is a well-described, largely historic infection that is caused by Mycobacterium leprae. Lucio's phenomenon is an aggressive, rare form of untreated lepromatous leprosy characterized by diffuse cutaneous lesions and systemic symptoms. To date, cases of necrotizing soft tissue infection in the setting of leprosy have rarely been reported in the literature. We present the case of a 51-year-old man with no known past medical history who presented for the evaluation of acute-on-chronic left upper extremity ulceration, soft tissue swelling, and pain. The patient was diagnosed with necrotizing soft tissue infection of the left upper extremity and underlying multibacillary lepromatous leprosy with Lucio's phenomenon. He underwent dermatofasciectomy of the affected extremity, followed by staged soft tissue coverage, including dermal allograft placement. Proper antibiotic management was also undertaken. In this article, we describe a case of previously undiagnosed leprosy with Lucio's phenomenon manifesting as necrotizing fasciitis of the upper extremity.

Forearm and Arm Tourniquet Tolerance.

BACKGROUND: In distal upper extremity surgeries, there can be a choice to use an upper arm or forearm tourniquet. This study examines discomfort and tolerance in healthy volunteers to determine whether one is more comfortable. METHODS: Forty healthy, study participants were randomized to an upper extremity laterality and site. Tourniquets were inflated to 100 mm Hg over systolic blood pressure. Participants experienced an upper arm and a forearm tourniquet sequentially. Visual analog scores (VAS) were recorded at 2-minute intervals. Time until request and VAS at tourniquet deflation were recorded. Time until the complete resolution of paresthesias was also recorded. Participants subjectively stated which tourniquet felt more comfortable. RESULTS: Tourniquets were inflated longer on the forearm than the upper arm (mean 16.1 minutes versus 12.2 minutes; P < 0.0001). VAS at tourniquet removal was not different between the sites (means 7.3 and 7.3) (P = 0.839). Time until paresthesia resolution after the tourniquet was deflated was not different (means 8.1 and 7.7 minutes) (P = 0.675). Time until paresthesia resolution was proportional to tourniquet inflation time for both sites (regression coefficient 0.41; P < 0.00001). Participants found the forearm more comfortable (95% confidence interval, 0.63 to 0.92). CONCLUSION: Forearm placement allows the tourniquet to be inflated for an average of 4 minutes longer. Forearm tourniquet is subjectively more comfortable.

Differentiating Upper Extremity Necrotizing Soft Tissue Infection From Serious Cellulitis and Abscess.

Introduction Necrotizing soft tissue infection (NSTI) of the upper extremity (UE) is a rapidly progressing infection that requires early diagnosis and emergent treatment to decrease risks of loss of limb or life. Clinical presentation, particularly of early NSTI, can appear similar to serious cellulitis or abscess. The purpose of this study was to identify factors that are associated with NSTI rather than serious cellulitis and abscess to differentiate patients with similar clinical presentations. Methods This study uses a retrospective cohort design that compares patients ultimately diagnosed with UE NSTI versus those diagnosed with UE serious cellulitis or abscess. Cohorts were matched using the Laboratory Risk Indicators for Necrotizing Fasciitis (LRINEC) score in the setting of UE soft tissue infection. Laboratory values, vital signs, subjective symptoms, and social factors including substance abuse and domiciled status were recorded. Continuous variables were compared using the Mann-Whitney U test, whereas categorical variables were compared using the chi-squared test or the Fisher exact test (for expected values less than 5). A binary logistic regression for continuous and categorical variables was also performed. Significance was set at p<0.05. Univariate and multivariate analyses were performed. Results Multivariate statistical analysis and clinical interpretation of data identified four factors more associated with a diagnosis of NSTI than serious cellulitis or abscess: elevated lactate on hospital presentation, a patient-reported history of fever, male gender, and homelessness.  Conclusions In patients with upper extremity infections, the clinical presentation of NSTI and serious cellulitis or abscess may appear similar. In this retrospective cohort of patients matched with LRINEC scores, elevated lactate, subjective fever, male gender, and homelessness were significantly associated with NSTI rather than serious cellulitis or abscess.

Google trends as a tool for evaluating public interest in total knee arthroplasty and total hip arthroplasty.

BACKGROUND AND AIMS: There are approximately 1 million total knee arthroplasty (TKA) and total hip arthroplasty (THA) procedures performed annually in the United States. With this number projected to increase, it is vital for orthopedic surgeons and health-care systems to properly anticipate healthcare utilization related to TKA and THA. Google Trends (GT) is a free, open source tool that provides customizable analysis of search terms entered into the Google search engine. We aim to explore the relationship between public interest in TKA and THA as determined by GT data and volume of TKA and THA procedures. METHODS: GT data were compiled for ten search terms related to TKA and ten search terms related to THA from January 2009 to December 2017. Annual case volumes for TKA/THA procedures were obtained from the Healthcare Cost and Utilization Project National Inpatient Sample from 2009 to 2017. Trend analysis was performed using univariate linear regression of GT data and TKA/THA case volumes. RESULTS: There was a statistically significant positive correlation between GT data and procedure volume for 14 of the 20 search terms studied. Seven TKA-related search terms with a positive correlation to procedure volumes include "total knee replacement," "knee replacement," "knee osteoarthritis," "knee ache," "knee swelling," "knee stiffness," and "chronic knee pain." Seven THA-related search terms with a positive correlation to procedure volumes include "hip arthroplasty," "total hip replacement," "hip replacement," "hip osteoarthritis," "hip ache," "hip swelling," and "chronic hip pain." CONCLUSION: GT may provide a high utility as a convenient and informative data set for orthopedic surgeons to analyze public interest in TKA and THA procedures. The data provided by GT have the potential to provide real-time, actionable information that may help surgeons and health systems to characterize public interest in TKA and THA and to best identify and address patient needs. RELEVANCE FOR PATIENTS: The GT tool can be used to measure public interest in TKA/THA, which can inform physician expectations for the patient encounter and lead to the creation of decision aids that better inform the public about the risks and benefits of TKA/THA.

Risk Factors Associated With Progression to Surgical Release After Injection of Trigger Digits.

INTRODUCTION: The mainstay of trigger finger treatment is a corticosteroid injection of the affected digits and is associated with a very high success rate. However, some patients do not respond to nonsurgical management and undergo subsequent surgical release. The purpose of this study is to investigate the comorbidities that predispose patients to progressing from injection to surgical release. METHODS: Patient data were obtained from a national insurance database. All patients aged 20 years or older who underwent trigger digit injection were included. Any injection that did not specify the digit was excluded. Subsequent procedures, including repeat injection and surgical release, were identified using relevant Current Procedural Terminology codes. A multivariate model was constructed to evaluate potential risk factors for requiring release after prior injection of the same digit. Stepwise backward selection was used to retain significant variables. RESULTS: A total of 42,537 trigger digits were identified in 31,830 patients, most of whom were female. The right hand was affected more commonly than the left. The middle and ring fingers were the most commonly affected digits. Over 80% of all trigger digits underwent only a single injection, and approximately 90% of injected digits did not require subsequent release. In the multivariate model, factors associated with higher risk of release were male sex, involvement of additional digits, multiple injections of the same digit, chronic pulmonary disease, HIV/AIDS, obesity, alcohol abuse, and depression. The model also found small fingers to be less likely to progress to release. DISCUSSION: Patients with the risk factors identified in this study are more likely to progress to surgical release after trigger finger injection. Although prospective studies are required, the information may be beneficial in counseling patients and their treatment options.

Treatment of Iatrogenic Saphenous Neuroma after Knee Arthroscopy with Excision and Allograft Reconstruction.

The treatment of postoperative, painful sensory neuromas is an ongoing challenge for surgeons. Here, we describe a technique for treatment with excision and allograft reconstruction and report on early results of its use in treating painful saphenous neuromas after knee arthroscopy. METHODS: A retrospective review of a single surgeon's peripheral nerve clinic from January 1, 2013, to December 31, 2019, was conducted to identify post-knee arthroscopy saphenous neuroma cases in which reconstruction with processed human nerve allograft distally implanted into healthy muscle belly was performed. We examined the outcomes for each patient, including subjective pain self-assessment and need for further surgical treatment. RESULTS: In total, 9 cases were identified, with patient ages ranging from 21 to 74 years. The average time to referral to peripheral nerve clinic was 31 months (range: 4-143 months). Upon exploration, all nerves were found to have a neuroma in continuity. Six of the 9 patients reported subjective improvement through final follow-up. Three of the 9 patients reported initial improvement, with recurrence of pain at/near the site of the neuroma. The average follow-up time was 9 months (range: 1-21 months). CONCLUSIONS: Here, we report on a novel technique of using a processed human nerve allograft after neuroma resection to provide an organized environment for bridging regenerated axons into muscle tissue. We also describe our early results using this technique to treat iatrogenic saphenous neuromas after knee arthroscopy. Results are encouraging, with 6 of the 9 patients experiencing subjective reduction in pain at final follow-up.

Confirmed effects of candidate variants for milk production, udder health, and udder morphology in dairy cattle.

BACKGROUND: Over the last years, genome-wide association studies (GWAS) based on imputed whole-genome sequences (WGS) have been used to detect quantitative trait loci (QTL) and highlight candidate genes for important traits. However, in general this approach does not allow to validate the effects of candidate mutations or determine if they are truly causative for the trait(s) in question. To address these questions, we applied a two-step, within-breed GWAS approach on 15 traits (5 linked with milk production, 2 with udder health, and 8 with udder morphology) in Montbéliarde (MON), Normande (NOR), and Holstein (HOL) cattle. We detected the most-promising candidate variants (CV) using imputed WGS of 2515 MON, 2203 NOR, and 6321 HOL bulls, and validated their effects in three younger populations of 23,926 MON, 9400 NOR, and 51,977 HOL cows. RESULTS: Bull sequence-based GWAS detected 84 QTL: 13, 10, and 30 for milk production traits; 3, 0, and 2 for somatic cell score (SCS); and 8, 2 and 16 for udder morphology traits, in MON, NOR, and HOL respectively. Five genomic regions with effects on milk production traits were shared among the three breeds whereas six (2 for production and 4 for udder morphology and health traits) had effects in two breeds. In 80 of these QTL, 855 CV were highlighted based on the significance of their effects and functional annotation. The subsequent GWAS on MON, NOR, and HOL cows validated 8, 9, and 23 QTL for production traits; 0, 0, and 1 for SCS; and 4, 1, and 8 for udder morphology traits, respectively. In 47 of the 54 confirmed QTL, the CV identified in bulls had more significant effects than single nucleotide polymorphisms (SNPs) from the standard 50K chip. The best CV for each validated QTL was located in a gene that was functionally related to production (36 QTL) or udder (9 QTL) traits. CONCLUSIONS: Using this two-step GWAS approach, we identified and validated 54 QTL that included CV mostly located within functional candidate genes and explained up to 6.3% (udder traits) and 37% (production traits) of the genetic variance of economically important dairy traits. These CV are now included in the chip used to evaluate French dairy cattle and can be integrated into routine genomic evaluation.

Characteristics of Iatrogenic Nerve Injury from Orthopedic Surgery Correlate with Time to Subspecialty Presentation.

There is no current literature examining iatrogenic nerve injury resulting from orthopedic procedures across subspecialties and anatomic areas. This study uses a single peripheral nerve surgeon's experience to investigate the variable time to presentation of adult patients with iatrogenic nerve injury after orthopedic surgery. METHODS: A retrospective review of patients examined in Peripheral Nerve Clinic (PNC) from January 1, 2012, to April 1, 2018, at a single, private, university hospital was performed. Fifty-eight adult patients met inclusion criteria. Charts were reviewed to determine the index orthopedic procedure, peripheral nerve affected, clinical deficits, patient demographics, and time from injury to PNC presentation. RESULTS: The average patient age was 51.2 years, and the average time to PNC referral was 10.9 months after the procedure that resulted in nerve injury. The orthopedic procedures included fracture fixation (13), joint arthroplasty (10) knee arthroscopy and ligament reconstruction (9), mass excision (9), shoulder arthroscopy (7), irrigation and debridement (2), removal of deep hardware (2), tendon procedures (2), trigger digit release (2), nerve decompression (1), and release of exertional compartment syndrome (1). Time from injury to PNC presentation was substantially shorter for patients with upper extremity versus lower extremity deficits (5.9 months vs 19.8 months; P = 0.0173) and for patients with motor nerve involvement versus those with isolated sensory nerve injury (4.5 months vs 24.3 months; P = 0.0164). CONCLUSIONS: Iatrogenic nerve injury is a risk across orthopedic subspecialties. Nerve injuries in the lower extremity and those with isolated sensory deficits have significantly delayed time to subspecialty presentation.

Horseshoe abscess of the hand with rice bodies secondary to mycobacterium avium intracellulare infection.

A horseshoe abscess is caused by infection that spreads between the flexor tendon sheath of the thumb or little finger through the radial and ulnar bursae through communication between the two and/or the space of Parona. We present a case of an 80-year-old woman with rheumatoid arthritis who presented with 6 months of right hand and wrist soft tissue swelling, initially treated as a rheumatoid arthritis flare. MRI demonstrates the horseshoe abscess and after surgical irrigation and debridement with synovectomy, cultures demonstrated infection with mycobacterium avium intracellulare (MAI). This case demonstrates the importance of MRI in diagnosing and evaluating the extent of hand infections and for considering mycobacterial organisms for appropriate treatment and antibiotic regimen.

Management of Critical Bone Defects.

Bone defects may occur after trauma, infection, or oncologic resection. A critical sized defect is any defect that is unable to spontaneously heal and will require secondary procedure(s) to obtain union. Autologous grafting is widely used, but may be insufficient to obtain union in these situations. Other options include the induced membrane technique, bone transport through distraction osteogenesis, or free vascularized bone transfer. This chapter will review options for obtaining graft, and the aforementioned special techniques for managing these challenging problems.

Public Interest in Elective Orthopedic Surgery Following Recommendations During COVID-19: A Google Trends Analysis.

Introduction Precautions issued by organizations such as the American Academy of Orthopaedic Surgeons (AAOS) recommending against any elective, or non-essential, surgical procedures have significantly affected healthcare resource utilization by the public during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In this study, we demonstrate the value of the Google Trends (GT) interface to characterize and monitor in real-time the response in public interest toward various elective orthopedic procedures. Methods Search volume databases were generated from January 2015 to May 2020 for keywords related to anterior cruciate ligament (ACL) reconstruction, elbow arthroplasty, hip arthroplasty, knee arthroplasty, and rotator cuff repair. To measure the immediate effects on public interest, the percent change was calculated from the AAOS, and Centers for Medicare and Medicaid Services (CMS) defined a 30-day pre-recommendations period to a 30-day post-recommendations period. To measure long-term effects, mean search volumes from January 1, 2015, to February 29, 2020, were compared to mean search volumes from March 1, 2020, to May 21, 2020. Results In the 30-day period following statements by the AAOS and CMS, interest in all search terms except "partial knee arthroplasty" decreased as follows: "ACL reconstruction" (-32.7%); "ACL repair" (-22.6%); "anterior cruciate ligament reconstruction" (-39.8%); "elbow arthroplasty" (-17.2%); "elbow joint replacement" (-15.1%); "total elbow arthroplasty" (-40.0%); "hip arthroplasty" (-23.0%); "hip replacement" (-41.2%); "total hip arthroplasty" (-23.0%); "knee arthroplasty" (-43.0%); "total knee arthroplasty" (-33.3%); "rotator cuff repair" (-34.2%); "rotator cuff surgery" (-50.6%); "shoulder arthroplasty" (-26.7%). Discussion GT data have previously demonstrated utility in characterizing and anticipating shifts in real-world healthcare utilization, making it an invaluable tool for physicians to anticipate and address the emerging needs of our patient population. Our study further illustrates the value of GT in localizing rapidly recovering interest in several of the most common elective orthopedic surgeries, enabling surgeons with up-to-date actionable data to guide the management of practices and healthcare facilities as the US slowly emerges from precautions endorsed during the COVID-19 pandemic.

Bridge Plate Failure with Extensor Tendon Injury: A Case Report and Literature Review.

BACKGROUND: Dorsal spanning plate fixation is an increasingly popular method of fixation for certain distal radius fractures. Published outcomes are encouraging, but complications are still reported. METHODS: We present a case report of a 26-year-old woman with spanning plate breakage and extensor pollicis longus (EPL) metallosis, fraying, and near-complete rupture. The patient's unsuccessful follow-up led to this complication. Metallosis and damage to the extensor indices (EI) and distal extensor carpi radialis longus (ECRL) were intraoperative obstacles for tendon transfer to restore EPL function. RESULTS: Tendon transfer in the setting of bridge plate failure has not yet been described in the literature. There are reports of spanning plate failure indicating that breakage often happens through the plate's holes and after fracture healing. CONCLUSIONS: The compounded complication of plate failure with extensor tendon injury emphasizes the important relationship between the local anatomy, barriers to patient care, and potential problems after spanning plate fixation.

Peripheral nerve injury with Nexplanon removal: case report and review of the literature.

BACKGROUND: Implantable devices offer convenient, long-acting, and reversible contraception. Injury to the peripheral nerves and blood vessels have been reported as rare complications of implantation and extraction. CASE PRESENTATION: We present a case of ulnar nerve injury in a 21-year-old woman from attempted in-office removal of a deeply implanted Nexplanon® device. The injury resulted in an ulnar nerve palsy requiring surgical exploration, neuroma excision, and sural nerve cable grafting. CONCLUSIONS: In-office attempts to remove contraceptive implants that are deep or have migrated can cause iatrogenic nerve injury. Devices that are non-palpable, deep, or migrated should be imaged before formal surgical exploration and removal. Any patient with neurologic symptoms after placement or after attempted removal requires prompt diagnosis and referral to a peripheral nerve surgeon.

Genome-wide association study for milking speed in French Holstein cows.

Using a combination of data from the BovineSNP50 BeadChip SNP array (Illumina, San Diego, CA) and a EuroGenomics (Amsterdam, the Netherlands) custom single nucleotide polymorphism (SNP) chip with SNP pre-selected from whole genome sequence data, we carried out an association study of milking speed in 32,491 French Holstein dairy cows. Milking speed was measured by a score given by the farmer. Phenotypes were yield deviations as obtained from the French evaluation system. They were analyzed with a linear mixed model for association studies. We identified SNP on 22 chromosomes significantly associated with milking speed. As clinical mastitis and somatic cell score have an unfavorable genetic correlation with milking speed, we tested whether the most significant SNP on these 22 chromosomes associated with milking speed were also associated with clinical mastitis or somatic cell score. Nine hundred seventy-one genome-wide significant SNP were associated with milking speed. Of these, 86 were associated with clinical mastitis and 198 with somatic cell score. The most significant association signals for milking speed were observed on chromosomes 7, 8, 10, 14, and 18. The most significant signal was located on chromosome 14 (ZFAT gene). Eleven novel milking speed quantitative trait loci (QTL) were observed on chromosomes 7, 10, 11, 14, 18, 25, and 26. Twelve candidate SNP for milking speed mapped directly within genes. Of these, 10 were QTL lead SNP, which mapped within the genes HMHA1, POLR2E, GNB5, KLHL29, ZFAT, KCNB2, CEACAM18, CCL24, and LHPP. Limited pleiotropy was observed between milking speed QTL and clinical mastitis.

Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response.

A central challenge for improving autoimmune therapy is preventing inflammatory pathology without inducing generalized immunosuppression. T helper 17 (TH17) cells, characterized by their production of interleukin-17, have emerged as important and broad mediators of autoimmunity. Here we show that the small molecule halofuginone (HF) selectively inhibits mouse and human TH17 differentiation by activating a cytoprotective signaling pathway, the amino acid starvation response (AAR). Inhibition of TH17 differentiation by HF is rescued by the addition of excess amino acids and is mimicked by AAR activation after selective amino acid depletion. HF also induces the AAR in vivo and protects mice from TH17-associated experimental autoimmune encephalomyelitis. These results indicate that the AAR pathway is a potent and selective regulator of inflammatory T cell differentiation in vivo.