Association between a genetic index for digital dermatitis resistance and the presence of digital dermatitis, heel horn erosion, and interdigital hyperplasia in Holstein cows.

Digital dermatitis (DD) is a polybacterial disease endemic to most UK dairy farms. It poses a major financial and welfare threat and is characterized by high incidence and recurrence rates. We aimed to investigate the association between the UK EBV for resistance to digital dermatitis, the digital dermatitis index (DDI), and the frequency of DD, heel horn erosion (HHE), and interdigital hyperplasia (IH) in a population of Holstein dairy cows. We enrolled and genotyped 2,352 cows from 4 farms in a prospective cohort study. Foot lesion records were recorded by veterinary surgeons for each animal at 4 time points during a production cycle, starting at approximately 2 mo before calving and ending in late lactation. Importantly, these records were not used in the calculation of the DDI. Lesion records were matched to the animal's own DDI (n = 2,101) and their sire's DDI (n = 1,812). Digital dermatitis index values in our study population ranged from -1.41 to +1.2 and were transformed to represent distance from the mean expressed in SD. The relationship between the DDI and the presence of DD was investigated using a logistic regression model, with farm, parity, and a farm-parity interaction fitted as covariates. A multivariable logistic regression model was fitted to evaluate the relationship between HHE and DDI with farm fitted as a covariate. Finally, a univariable logistic regression model with DDI as explanatory variable was used to investigate the relationship between IH and DDI. The odds ratio of an animal being affected by DD was 0.69 for 1 SD increase in the animal's DDI (95% CI = 0.63-0.76). The odds of HHE and IH were 0.69 (95% CI = 0.62-0.76) and 0.58 (95% CI = 0.49-0.68) respectively for 1 SD increase in DDI. The adjusted probability of DD was 32% (95% CI = 27-36%) for cows with mean DDI value of 0, while it was 24% (95% CI = 20-29%) in cows with a DDI value of +1. Sire DDI breeding values were standardized in the same way and then binned into terciles creating an ordinal variable representing bulls of high, medium, and low genetic merit for DD resistance. The daughters of low genetic merit bulls were at 2.05 (95% CI = 1.60-2.64), 1.96 (95% CI = 1.53-2.50), and 2.85 (95% CI = 1.64-5.16) times greater odds of being affected by DD, HHE, and IH, respectively, compared with the daughters of high genetic merit bulls. The results of this study highlight the potential of digital dermatitis genetic indexes to aid herd management of DD, and suggest that breeding for resistance to DD, alongside environmental and management control practices, could reduce the prevalence of the disease.

Molecular and Clinical Characteristics of Different Toxicity Rates in Anti-CD19 Chimeric Antigen Receptor T Cells: Real-World Experience.

Commercially available anti-CD19 chimeric antigen receptor T cells (CARΤ cells) have offered long-term survival to a constantly expanding patient population. Given that novel toxicities including cytokine release syndrome (CRS) and neurotoxicity (ICANS) have been observed, we aimed to document the safety and toxicity of this treatment in a real-world study. We enrolled 31 adult patients referred to our center for CAR T therapy. Tisagenlecleucel was infused in 12 patients, axicabtagene ciloleucel in 14, and brexucabtagene autoleucel in 5. Cytokine release syndrome was noted in 26 patients while neurotoxicity was observed in 7. Tocilizumab was administered for CRS in 18 patients, along with short-term, low-dose steroid administration in one patient who developed grade III CRS and, subsequently, grade I ICANS. High-dose steroids, along with anakinra and siltuximab, were administered in only two MCL patients. With a median follow-up time of 13.4 months, nine patients were then in CR. The progression-free (PFS) and overall survival (OS) rates were 41.2% and 88.1% at one year, respectively. MCL diagnosis, which coincides with the administration of brexucabtagene autoleucel, was the only factor to be independently associated with poor OS (p < 0.001); meanwhile, increased LDH independently predicted PFS (p = 0.027).In addition, CRP at day 14 was associated with a poor OS (p = 0.001). Therefore, our real-world experience confirmed that commercial CAR T therapy can be administered with minimal toxicity.

Laparoscopic surgery in a child with a failing Fontan circulation.

A child with early failure of a Fontan circulation was listed for cardiac transplantation and then developed a subhepatic abscess. Surgical drainage was deemed necessary after the failure of an attempted percutaneous procedure. Following a multidisciplinary discussion, a laparoscopic technique was chosen to optimise postoperative recovery. To our knowledge, the literature does not describe any case of laparoscopic surgery in a patient with a failing Fontan circulation. This case report highlights the physiological variations involved with this management strategy, discusses the implications and risks, and offers some recommendations.

A study on the use of thermal imaging as a diagnostic tool for the detection of digital dermatitis in dairy cattle.

Our aims were to (1) determine how interdigital skin temperature (IST), measured using infrared thermography, was associated with different stages of digital dermatitis (DD) lesions and (2) develop and validate models that can use IST measurements to identify cows with an active DD lesion. Between March 2019 and March 2020, infrared thermographic images of hind feet were taken from 2,334 Holstein cows across 4 farms. We recorded the maximum temperature reading from infrared thermographic images of the interdigital skin between the heel bulbs on the hind feet. Pregnant animals were enrolled approximately 1 to 2 mo precalving, reassessed 1 wk after calving, and again at approximately 50 to 100 d postpartum. At these time points, IST and the clinical stage of DD (M-stage scoring system: M1-M4.1) were recorded in addition to other data such as the ambient environmental temperature, height, body condition score, parity, and the presence of other foot lesions. A mixed effect linear regression model with IST as the dependent variable was fitted. Interdigital skin temperature was associated with DD lesions; compared to healthy feet, IST was highest in feet with M2 lesions, followed by M1 and M4.1 lesions. Subsequently, the capacity of IST measurements to detect the presence or absence of an active DD lesion (M1, M2, or M4.1) was explored by fitting logistic regression models, which were tested using 10-fold validation. A mixed effect logistic regression model with the presence of active DD as the dependent variable was fitted first. The average area under the curve for this model was 0.80 when its ability to detect presence of active DD was tested on 10% of the data that were not used for the model's training; an average sensitivity of 0.77 and an average specificity of 0.67 was achieved. This model was then restricted so that only explanatory variables that could be practically recorded in a nonresearch, external setting were included. Validation of this model demonstrated an average area under the curve of 0.78, a sensitivity of 0.88, and a specificity of 0.66 for 1 of the time points (precalving). Lower sensitivity and specificity were achieved for the other 2 time points. Our study adds further evidence to the relationship between DD and foot skin temperature using a large data set with multiple measurements per animal. Additionally, we highlight the potential for infrared thermography to be used for routine on-farm diagnosis of active DD lesions.

Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

[Painful lymphadenopathy after an insect bite-a case report]. / Schmerzhafte Lymphadenopathie nach Insektenstich ­ ein Fallbericht.

Tularemia is a bacterial zoonosis which is commonly transmitted through tick or insect bites or contact with meat of infected animals. We report the case of a 36-year-old man who developed fever, chills, headaches, and a painful, unilateral, inguinal lymphadenopathy with a red-livid skin discoloration after an insect bite on his abdomen. Ulceroglandular tularemia was diagnosed through polymerase chain reaction (PCR) and serology. Treatment with doxycycline for 21 days resulted in an excellent outcome.

Pediatric brain tumors: Update of proteome-based studies.

Pediatric brain tumors (PBTs) are the most common solid malignancies in childhood and continue to pose a serious burden to modern societies. Existing treatments impose debilitating effects on the developing child, highlighting the need for molecularly targeted treatments with reduced toxicity, as well as the necessity of markers that reliably assess efficacy of, and tumor response to targeted-therapies of PBTs. On this regard advances in technologies of protein identification and quantification, the large-scale, high-throughput investigation of the proteome, as well the newly-emerging field of "proteogenomics" aim to further our knowledge towards understanding the molecular pathophysiology of PBTs. This mini review article presents all updates on knowledge produced and published during the last years on PBT research derived from "omics" technologies, mainly involving protein research and proteomics.

[Long-term results of the compatibility of a coralline hydroxyapatite implant as eye replacement]. / Langzeitergebnisse zur Verträglichkeit eines korallinen Hydroxylapatitimplantats als Bulbusersatz.

BACKGROUND: Coralline hydroxyapatite has been used since 1983 as volume replacement. Through 2001, a total of 200 hydroxyapatite implants were used in our department. OBJECTIVE: This prospective study was undertaken to measure the subjective and objective long-term tolerance of this implant. MATERIALS AND METHODS: In 2012, a total of 20 patients were examined, who were enucleated or eviscerated between 1993 and 2001 (average follow-up 16.2 years) and had an hydroxyapatite implant placed with a scleral sheath. We evaluated the subjective tolerance and measured the motility, the prominence of the globe, lid positions, changes of the conjunctiva and postoperative complications. RESULTS: The subjective long-term tolerance was reported to be good. All patients had a ptosis; an ectropion was found in 50% of patients. In 40% of the patients additional surgery was performed. The motility was better in primary than in secondary placed implants. Volume replacement was successful in 10 patients, 9 patients had a retraction and 1 patient a prominent prosthesis. DISCUSSION: Hydroxyapatite implants with sclera sheathing were well tolerated and showed good motility on long-term follow-up over more than 16 years. Lid malpositions such as ptosis or ectropion are common but might be due to mechanical stress through the prosthesis and atrophy of the orbital fat.

Transplant-associated thrombotic microangiopathy: opening Pandora's box.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an early complication of hematopoietic cell transplantation (HCT). A high mortality rate is documented in patients who are refractory to calcineurin inhibitor cessation. Estimates of TA-TMA prevalence vary significantly and are higher in allogeneic compared with autologous HCT. Furthermore, our understanding of the pathophysiology that is strongly related to diagnosis and treatment options is limited. Recent evidence has linked TA-TMA with atypical hemolytic uremic syndrome, a disease of excessive activation of the alternative pathway of complement, opening the Pandora's box in treatment options. As conventional treatment management is highly inefficient, detection of complement activation may allow for early recognition of patients who will benefit from complement inhibition. Preliminary clinical results showing successful eculizumab administration in children and adults with TA-TMA need to be carefully evaluated. Therefore, realizing the unmet needs of better understanding TA-TMA in this complex setting, we aimed to summarize current knowledge focusing on (1) critical evaluation of diagnostic criteria, (2) epidemiology and prognosis, (3) recent evidence of complement activation and endothelial damage and (4) treatment options.

Safety and Cost Considerations during the Introduction Period of Laparoscopic Radical Hysterectomy.

Objective. To compare the safety, efficacy, and direct cost during the introduction of laparoscopic radical hysterectomy within an enhanced recovery pathway. Methods. A 1 : 1 single centre retrospective case control study of 36 propensity matched pairs of patients receiving open or laparoscopic surgery for early cervical cancer. Results. There were no significant differences in the baseline characteristics of the two cohorts. Open surgery cohort had significantly higher intraoperative blood loss (189 versus 934 mL) and longer postoperative hospital stay (2.3 versus 4.1 days). Although no significant difference in the intraoperative or postoperative complications was found more urinary tract injuries were recorded in the laparoscopic cohort. Laparoscopic surgery had significantly longer duration (206 versus 159 minutes), lower lymph node harvest (12.6 versus 16.9), and slower bladder function recovery. The median direct hospital cost was £4850 for laparoscopic radical hysterectomy and £4400 for open surgery. Conclusions. Laparoscopic radical hysterectomy can be safely introduced in an enhanced recovery environment without significant increase in perioperative morbidity. The 10% higher direct hospital cost is not statistically significant and is expected to even out when indirect costs are included.

Restrictions in the T-cell repertoire of chronic lymphocytic leukemia: high-throughput immunoprofiling supports selection by shared antigenic elements.

Immunoglobulin (IG) gene repertoire restrictions strongly support antigen selection in the pathogenesis of chronic lymphocytic leukemia (CLL). Given the emerging multifarious interactions between CLL and bystander T cells, we sought to determine whether antigen(s) are also selecting T cells in CLL. We performed a large-scale, next-generation sequencing (NGS) study of the T-cell repertoire, focusing on major stereotyped subsets representing CLL subgroups with undisputed antigenic drive, but also included patients carrying non-subset IG rearrangements to seek for T-cell immunogenetic signatures ubiquitous in CLL. Considering the inherent limitations of NGS, we deployed bioinformatics algorithms for qualitative curation of T-cell receptor rearrangements, and included multiple types of controls. Overall, we document the clonal architecture of the T-cell repertoire in CLL. These T-cell clones persist and further expand overtime, and can be shared by different patients, most especially patients belonging to the same stereotyped subset. Notably, these shared clonotypes appear to be disease-specific, as they are found in neither public databases nor healthy controls. Altogether, these findings indicate that antigen drive likely underlies T-cell expansions in CLL and may be acting in a CLL subset-specific context. Whether these are the same antigens interacting with the malignant clone or tumor-derived antigens remains to be elucidated.

Recurrent mutations refine prognosis in chronic lymphocytic leukemia.

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

Specific abnormalities versus number of abnormalities and cytogenetic scoring systems for outcome prediction after allogeneic hematopoietic SCT for myelodysplastic syndromes.

Newer cytogenetic scoring systems for myelodysplastic syndromes (MDSs), like cytogenetic stratification of the revised international prognostic scoring system (IPSS-R) or monosomal karyotype, may also improve outcome prediction after hematopoietic SCT (HCT). We compared the prognostic value of specific cytogenetic abnormalities, IPSS-R karyotype and monosomal karyotype for HCT outcome in 98 patients with MDS and AML post MDS. Higher-risk IPSS-R karyotype, 3q21q26 and transformation to AML before HCT were associated with increased cumulative incidence of relapse (CIR), whereas OS was adversely influenced by del 5q/-5, abnormalities of chromosomes 11 and 17 and cytogenetic IPSS-R very poor category. Karyotype with ⩽2 abnormalities and no abnormalities of chromosomes 3, 5, 7, 11 and 17 was an independent prognostic factor of lower CIR (hazard ratio (HR)=0.2, P=0.01) and longer OS (HR=0.5, P=0.03). In conclusion, some specific cytogenetic abnormalities and high cytogenetic complexity, as reflected by IPSS-R very poor karyotype, rather than monosomal karyotype, were associated with higher CIR and shorter OS after HCT. Conversely, results were encouraging in patients lacking those abnormalities, who may be very good candidates for HCT.

GVHD-associated chronic kidney disease after allogeneic haematopoietic cell transplantation.

Chronic kidney disease (CKD) has been related to allogeneic haematopoietic cell transplantation (HCT) as a late effect caused by a variety of factors. We retrospectively evaluated the development of CKD in 230 patients, aged 34 (5-65) years, who had undergone allogeneic HCT for haematological disease, using sibling or unrelated donors and myeloablative or reduced conditioning regimens. Pre-HCT glomerular filtration rate (GFR) was within normal limits (108±28 mL/min/1.73 m(2)) in patients who did not develop CKD and 95±24 mL/min/1.73 m(2) in those with CKD postHCT, while the GFR 12 months post transplant declined to 104±26 and 69±19 mL/min/1.73 m(2), respectively. CKD incidence was 20.4%, with a median time of development of 6 (3-18) months post transplant. On multivariate analysis, risk factors for CKD were the presence of chronic GVHD (cGVHD; P=0.001), unrelated donor transplantation (P=0.008), post-transplant event of acute kidney injury (AKI) (P=0.002) and older age (P=0.002). In long-term survivors stable significant predictors for CKD were older age at transplantation, cGVHD and AKI. CKD did not influence non-relapse mortality. In our study, cGVHD emerges as an important cause of kidney injury in HCT survivors, regardless of administration of nephrotoxic agents.

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications.

We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.