Infective endocarditis in dogs in the UK: 77 cases (2009-2019).

OBJECTIVES: To determine the causative organisms, clinical features and outcome of canine infective endocarditis in the UK. MATERIALS AND METHODS: Medical records of three veterinary referral hospitals were searched for dogs with infective endocarditis between December 2009 and December 2019. Signalment, clinical signs, causative organism, valve affected, treatment and survival data were recorded. RESULTS: Seventy-seven cases with possible or definite infective endocarditis (according to the modified Duke criteria) were included. The majority were large breed (40/77 - 51.9%). There were 47 of 77 (61%) male dogs and the mean age was 7.3 ±3 years. A causative organism was identified in 26 of 77 (33.8%) cases. The most common organisms were Escherichia coli (7/27 - 25.9%), Pasteurella spp. (5/27 - 18.5%), Staphylococcus spp. (4/27 - 14.8%) and Corynebacterium spp. (4/27 - 14.8%). Bartonella spp. were not detected in any patients. The mitral valve was most commonly affected (48/77 - 62.3%). Clinical features were non-specific, with lethargy being the most common clinical sign observed (53/77 - 68.8%). Fifty-three dogs (68.8%) survived to discharge. The median survival time post discharge was 425 days (2 to 3650 days). The development of congestive heart failure was associated with a poorer outcome. Cardiac troponin concentration, antithrombotic use and the development of thromboembolism or arrhythmias were not significantly associated with outcome. CLINICAL SIGNIFICANCE: Some dogs with infective endocarditis that survive to discharge can have a long lifespan. The inability to detect an underlying organism is common and Bartonella spp. may be a less prevalent cause of canine infective endocarditis in the UK than in the USA.

Preoperative detection and evaluation of the need for psychological intervention in cancer and non-cancer patients referred to thoracic surgery / Detección y evaluación de la necesidad de atención psicológica preoperatoria en pacientes oncológicos y no oncológicos derivados a cirugía torácica

Objectives (a) to evaluate and compare the psychological treatment needs of patients with cancer and non-cancer, who are going to undergo scheduled thoracic surgery, and (b) evaluate and compare the diagnostic accuracy of the screening tests of psychological treatment needs for cancer and non-cancer patients. Method The need for psychological treatment was evaluated in a total of 169 patients prior to thoracic surgery, through a clinical interview. The screening tests used were: the physician's judgment (yes/no), the Hospital Anxiety and Depression Scale (HADS) and, the single-item interview to assess depression “Do you feel depressed?” (DEPQ). Results The number of patients who needed psychological treatment in the total sample was 47 (27.81%), in non-cancer-patients: 22 (30.99%) and in cancer patients: 25 (25.51%). The participants with treatment needs were more often young women with primary education levels, with more fears and concerns regarding their disease. With respect to the screening tests, the HADS-T (cut-off point ≥13) obtained a sensitivity (SE) of 0.75 and Specificity (SP) of 0.81 in the total sample. In patients with cancer, the HADS total score (cut-off point ≥10) obtained an SE=0.84 and SP=0.80, and, in non-cancer patients, the HADS total score (cut-off point ≥13) showed an SE=0.59 and SP=0.84. The DEPQ and the physician's judgment did not achieve adequate levels of precision. Conclusions A high percentage of patients have psychological treatment needs before performing thoracic surgery, which are similar for cancer and non-cancer patients. Preoperative detection of patients who need psychological intervention is feasible with a simple screening test: HADS, which achieves greater precision in cancer patients (AU)

Objetivos Evaluar y comparar: a) las necesidades de tratamiento psicológico de pacientes con cáncer y sin cáncer, que van a someterse a una cirugía torácica programada, y b) la precisión diagnóstica de las pruebas de detección de necesidades psicológicas para pacientes con y sin cáncer. Métodos Se evaluó la necesidad de tratamiento psicológico en un total de 169 pacientes antes de la cirugía torácica, a través de una entrevista clínica. Las pruebas de cribado fueron: el criterio médico (sí/no), la Escala de Ansiedad y Depresión Hospitalaria (HADS) y la entrevista de un solo ítem de depresión «¿Se siente deprimido?» (DEPQ). Resultados El número de pacientes que necesitaron tratamiento psicológico fue en el total 47 (27,81%), en pacientes sin cáncer: 22 (30,99%) y con cáncer: 25 (25,51%). Las participantes con necesidades de tratamiento eran con mayor frecuencia mujeres jóvenes con niveles de educación primaria y más temores con respecto a su enfermedad. Con respecto a las pruebas de detección, el HADS total (corte ≥ 13) obtuvo una sensibilidad (S)=0,75/especificidad (E)=0,81 en la muestra total. En pacientes con cáncer el HADS total (corte ≥ 10): S=0,84/E=0,80 y en pacientes sin cáncer, la HADS total (corte ≥ 13): S=0,59/E=0,84. DEPQ y juicio médico obtuvieron bajos niveles de precisión. Conclusiones Un alto porcentaje de pacientes antes de realizar una cirugía torácica tiene necesidades de tratamiento psicológico, similares para pacientes con y sin cáncer. La HADS total es un buen método de cribado de necesidades psicológicas, especialmente en pacientes con cáncer (AU)

Elevación hemidiafragmática / Elevated hemidiaphragm

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Data on genotypic distribution and linkage disequilibrium of several ANRIL polymorphisms in hemodialysis patients.

A long non-coding RNA called ANRIL located on chromosome 9p21.3 has been identified as a novel genetic factor associated with cardiovascular disease. Investigation of several single nucleotide polymorphisms (SNPs) of Noncoding Antisense RNA in the INK4 Locus (ANRIL) gene are of particular interest. This article reports data related to the research article entitled: "Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients" (Arbiol-Roca et al. [1]). Data presented show the genotypic distribution of four selected ANRIL SNPs: rs10757278, rs4977574, rs10757274 and rs6475606 in a cohort constituted by 284 hemodialysis patients. This article analyzes the Hardy-Weinberg disequilibrium of each studied SNP, and the linkage disequilibrium between them.

Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Single nucleotide polymorphisms (SNPs) in ANRIL gene have been associated with higher cardiovascular morbidity and mortality in general population. The main objective was to ascertain whether ANRIL polymorphisms could identify risk of major adverse cardiovascular event (MACE) in patients starting on hemodialysis (HD). METHODS: This was a prospective observational cohort study. 284 CKD patients starting on HD were included in the study and followed until achievement of the primary end-point (MACE) or end of the study. All patients were genotyped for four ANRIL SNPs (rs10757278, rs4977574, rs10757274 and rs6475606). Kaplan-Meier curves and multivariate Cox survival analyses, together with multiple logistic regression were used to analyze the association between ANRIL SNPs and MACE. RESULTS: We found that ANRIL SNP rs10757278 was a representative SNP of a strong linkage disequilibrium block and showed significant genotypic associations with MACE in hemodialysis patients. Homozygous patients for the risk allele (GG) showed 2.17 (1.05-4.49) fold increased risk of MACE during hemodialysis than carriers of the protective allele (AA or AG). Diabetes mellitus was a strong enhancer of this effect. CONCLUSIONS: Our results indicate that ANRIL polymorphisms may confer risk to development of MACE in incident patients on hemodialysis.

Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial.

In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10-14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus -1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10-14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Contribution of Population Pharmacokinetics to Dose Optimization of Ganciclovir-Valganciclovir in Solid-Organ Transplant Patients.

Treatment of solid-organ transplant (SOT) patients with ganciclovir (GCV)-valganciclovir (VGCV) according to the manufacturer's recommendations may result in over- or underexposure. Bayesian prediction based on a population pharmacokinetics model may optimize GCV-VGCV dosing, achieving the area under the curve (AUC) therapeutic target. We conducted a two-arm, randomized, open-label, 40% superiority trial in adult SOT patients receiving GCV-VGCV as prophylaxis or treatment of cytomegalovirus infection. Group A was treated according to the manufacturer's recommendations. For group B, the dosing was adjusted based on target exposures using a Bayesian prediction model (NONMEM). Fifty-three patients were recruited (27 in group A and 26 in group B). About 88.6% of patients in group B and 22.2% in group A reached target AUC, achieving the 40% superiority margin (P< 0.001; 95% confidence interval [CI] difference, 47 to 86%). The time to reach target AUC was significantly longer in group A than in group B (55.9 ± 8.2 versus 15.8 ± 2.3 days,P< 0.001). A shorter time to viral clearance was observed in group B than in group A (12.5 versus 17.6 days;P= 0.125). The incidences of relapse (group A, 66.67%, and group B, 9.01%) and late-onset infection (group A, 36.7%, and group B, 7.7%) were higher in group A. Neutropenia and anemia were related to GCV overexposure. GCV-VCGV dose adjustment based on a population pharmacokinetics Bayesian prediction model optimizes GCV-VGCV exposure. (This study has been registered at ClinicalTrials.gov under registration no. NCT01446445.).

Sterile leukocyturia is associated with interstitial fibrosis and tubular atrophy in kidney allograft protocol biopsies.

Kidney allograft interstitial fibrosis and tubular atrophy (IF/TA) is associated with a poorer renal function and outcome. In the current clinical practice, an early diagnosis can only be provided by invasive tests. We aimed to investigate the association of sterile leukocyturia with Banff criteria histological findings in kidney allograft protocol biopsies. We studied 348 allograft biopsies from two different European countries performed at 8.5 + 3.5 months after transplantation. In these cases, the presence of sterile leukocyturia (Leuc+, n = 70) or no leukocyturia (Leuc-, n = 278) was analyzed and related to Banff elementary lesions. Only IF/TA was significantly different between Leuc+ and Leuc- groups. IF/TA was present in 85.7% of Leuc+ and 27.7% of Leuc- patients (p < 0.001). IF/TA patients had higher serum creatinine and presence of proteinuria (p < 0.05). Independent predictors of IF/TA were donor age, donor male sex, serum creatinine and Leuc+ (hazard ratio 18.2; 95% confidence interval, 8.1-40.7). The positive predictive value of leukocyturia for predicting IF/TA was 85.7% whereas the negative predictive value was 72.3%. These studies suggest that leukocyturia is a noninvasive and low-cost test to identify IF/TA. An early diagnosis may allow timely interventional measures directed to minimize its impact and improve graft outcome.

Cross-validation of IFN-γ Elispot assay for measuring alloreactive memory/effector T cell responses in renal transplant recipients.

Assessment of donor-specific alloreactive memory/effector T cell responses using an IFN-γ Elispot assay has been suggested to be a novel immune-monitoring tool for evaluating the cellular immune risk in renal transplantation. Here, we report the cross-validation data of the IFN-γ Elispot assay performed within different European laboratories taking part of the EU RISET consortium. For this purpose, development of a standard operating procedure (SOP), comparisons of lectures of IFN-γ plates assessing intra- and interlaboratory assay variability of allogeneic or peptide stimuli in both healthy and kidney transplant individuals have been the main objectives. We show that the use of a same SOP and count-settings of the Elispot bioreader allow low coefficient variation between laboratories. Frozen and shipped samples display slightly lower detectable IFN-γ frequencies than fresh samples. Importantly, a close correlation between different laboratories is obtained when measuring high frequencies of antigen-specific primed/memory T cell alloresponses. Interestingly, significant high donor-specific alloreactive T cell responses can be similarly detected among different laboratories in kidney transplant patients displaying histological patterns of acute T cell mediated rejection. In conclusion, assessment of circulating alloreactive memory/effector T cells using an INF-γ Elispot assay can be accurately achieved using the same SOP, Elispot bioreader and experienced technicians in kidney transplantation.

Coping and distress in caregivers of patients with disorders of consciousness.

OBJECTIVES: To study depression, anxiety, maladjustment and coping in caregivers of patients in vegetative state (VS) or minimally conscious state (MCS). MATERIALS AND METHODS: Fifty-three caregivers of 43 patients with VS or MCS were assessed using Beck Anxiety Inventory, Beck Depression Inventory, maladjustment scale and Brief Coping Orientation of Problems Experienced (COPE-28). RESULTS: There were 15 clinical cases (cut-off ≥ 21) of anxiety (28.30%); 16 cases (cut-off ≥ 21) of depression (30.20%); and 45 cases (cut-off ≥ 12) of maladjustment (84.8%). Active and problem-focused (Active coping, Instrumental support, Planning and Acceptance) were the most frequently used coping strategies. Acceptance predicted the absence of depression (p = 0.000, Cohen's d = 1.08) and anxiety (p = 0.000, Cohen's d = 1.08). Denial was associated with depression (p = 0.000, Cohen's d = 1.65) and anxiety (p = 0.000, Cohen's d = 1.23). Self-blame was associated with greater anxiety (p = 0.001, Cohen's d = 1.06) and depression (p = 0.001, Cohen's d = 1.07). Emotion-focused coping was associated with anxiety (p = 0.000, Cohen's d = 1.29) and depression (p = 0.001, Cohen's d = 1.11). CONCLUSIONS: Caregivers of patients with VS or MCS presented high levels of distress. Psychological support for caregivers of patients with VS or MCS is necessary. The most frequently used coping strategies were Active and Problem-focused. Acceptance was highly protective, but Denial, Self-blame and Emotion-focused strategies were very negative.

Pretransplant immediately early-1-specific T cell responses provide protection for CMV infection after kidney transplantation.

Cytomegalovirus (CMV) infection is still a major complication after kidney transplantation. Although cytotoxic CMV-specific T cells play a crucial role controlling CMV survival and replication, current pretransplant risk assessment for CMV infection is only based on donor/recipient (IgG)-serostatus. Here, we evaluated the usefulness of monitoring pre- and 6-month CMV-specific T cell responses against two dominant CMV antigens (IE-1 and pp65) and a CMV lysate, using an IFN-γ Elispot, for predicting the advent of CMV infection in two cohorts of 137 kidney transplant recipients either receiving routine prophylaxis (n = 39) or preemptive treatment (n = 98). Incidence of CMV antigenemia/disease within the prophylaxis and preemptive group was 28%/20% and 22%/12%, respectively. Patients developing CMV infection showed significantly lower anti-IE-1-specific T cell responses than those that did not in both groups (p < 0.05). In a ROC curve analysis, low pretransplant anti-IE-1-specific T cell responses predicted the risk of both primary and late-onset CMV infection with high sensitivity and specificity (AUC > 0.70). Furthermore, when using most sensitive and specific Elispot cut-off values, a higher than 80% and 90% sensitivity and negative predictive value was obtained, respectively. Monitoring IE-1-specific T cell responses before transplantation may be useful for predicting posttransplant risk of CMV infection, thus potentially guiding decision-making regarding CMV preventive treatment.

Dendritic cells phenotype fitting under hypoxia or lipopolysaccharide; adenosine 5'-triphosphate-binding cassette transporters far beyond an efflux pump.

This study examines adenosine 5'-triphosphate-binding cassette (ABC) transporters as a potential therapeutic target in dendritic cell (DC) modulation under hypoxia and lipopolysaccharide (LPS). Functional capacity of dendritic cells (DCs) (mixed lymphocyte reaction: MLR) and maturation of iDCs were evaluated in the presence or absence of specific ABC-transporter inhibitors. Monocyte-derived DCs were cultured in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF). Their maturation under hypoxia or LPS conditions was evaluated by assessing the expression of maturation phenotypes using flow cytometry. The effect of ABC transporters on DC maturation was determined using specific inhibitors for multi-drug resistance (MDR1) and multi-drug resistance proteins (MRPs). Depending on their maturation status to elicit T cell alloresponses, the functional capacity of DCs was studied by MLR. Mature DCs showed higher P-glycoprotein (Pgp) expression with confocal microscopy. Up-regulation of maturation markers was observed in hypoxia and LPS-DC, defining two different DC subpopulation profiles, plasmacytoid versus conventional-like, respectively, and different cytokine release T helper type 2 (Th2) versus Th1, depending on the stimuli. Furthermore, hypoxia-DCs induced more B lymphocyte proliferation than control-iDC (56% versus 9%), while LPS-DCs induced more CD8-lymphocyte proliferation (67% versus 16%). ABC transporter-inhibitors strongly abrogated DC maturation [half maximal inhibitory concentration (IC50 ): P-glycoprotein inhibition using valspodar (PSC833) 5 µM, CAS 115104-28-4 (MK571) 50 µM and probenecid 2·5 µM], induced significantly less lymphocyte proliferation and reduced cytokine release compared with stimulated-DCs without inhibitors. We conclude that diverse stimuli, hypoxia or LPS induce different profiles in the maturation and functionality of DC. Pgp appears to play a role in these DC events. Thus, ABC-transporters emerge as potential targets in immunosuppressive therapies interfering with DCs maturation, thereby abrogating innate immune response when it is activated after ischaemia.

Caregivers of patients with disorders of consciousness: coping and prolonged grief.

OBJECTIVES: To study the relationship between coping strategies and prolonged grief disorder (PGD) in caregivers of patients with disorders of consciousness: vegetative state (VS) or minimally conscious state (MCS). MATERIALS AND METHODS: Fifty-three caregivers of 43 patients with VS or MCS were assessed using PG-12 and Brief COPE-28. Mean differences for each coping strategy between caregivers of patients with/without PGD were compared using Bonferroni-adjusted t-tests, and the size effect was calculated (Cohen's d). RESULTS: The frequency of PGD was very high (n = 32; 60.40%). The most common coping strategies were problem-focused: active coping (mean = 6.41; SD = 1.02), Instrumental support (mean = 6.41; SD = 1.06), Planning (mean = 6.32; SD = 1.01) and Acceptance (mean = 6.20; SD = 1.29). Acceptance predicted a lower presence of PGD (P = 0.001; Cohen's d = 1.02), while Denial (P = 0.003; Cohen's d = 0.98) and Self-blame (P = 0.004, Cohen's d = 0.91) increased the presence of PGD. CONCLUSIONS: The caregivers of patients with VS or MCS show a high risk of PGD. Problem-focused coping strategies are the most used. Acceptance is highly protective of PGD, and Denial and Self-blame are associated with an increased presence of PGD. PGD in caregivers of patients in VS or MCS should be evaluated, Acceptance and problem-focused strategies should be promoted, and Denial and Self-blame should be diminished.

Clinical features and outcomes of tuberculosis in solid organ transplant recipients.

BACKGROUND: Tuberculosis (TB) remains a significant opportunistic infection in solid organ transplant (SOT) recipients. Moreover, its optimal treatment in SOT recipients is challenging due to the toxicity and potential drug-drug interactions of antituberculus drugs. We sought to assess the frequency, clinical characteristics, treatments, and outcomes of TB among SOT recipients. METHODS: We reviewed retrospectively the medical charts of all TB cases occurring among SOT recipients from January 2000 to December 2011, retrieving data regarding baseline and clinical features, as well as treatment and outcomes. RESULTS: Eighteen of 2005 SOT recipients developed TB (0.9%). The frequency according to the type of allograft was 0.9% (10 of 1120) for kidney, 1% (7 of 701) for liver, and 0.5% (1 of 184) for heart recipients. Six patients (33%) had prior exposure to TB: a positive tuberculin test (n = 3), a positive quantiferon-TB (n = 1) for a prior history of TB (n = 3). None of them received antituberculus prophylaxis. The mean time after transplantation to TB diagnosis was 64 months (range 2-169). Five patients (28%) developed TB within the first year posttransplantation. The mean duration of symptoms before diagnosis was 30 days (range 1-180). Nine patients (50%) displayed pulmonary TB; 7 (39%) had disseminated infections, and 2 (11%) had lymph node involvement. None of the Mycobacterium tuberculosis isolates were resistant to first-line antituberculus drugs. All patients were given isoniazide. Most of them received a 3-drug regimen. Rifampin was prescribed in 11 cases. Seven patients (5 liver and 2 kidney recipients) developed hepatotoxicity. One patient developed rejection without allograft loss. Mortality during antituberculus treatment was 17% (3/18). CONCLUSIONS: In this study, 0.9% of SOT recipients developed TB, which frequently presented with extrapulmonary involvement, causing considerable mortality. Hepatotoxicity mainly among liver transplant recipients was a significant therapeutic drawback.

Long-term results of biopsy-guided selection and allocation of kidneys from older donors in older recipients.

In our old-for-old program, we discard or allocate older extended criteria donor kidneys to single (SKT) or dual kidney transplantation (DKT) depending on histological Remuzzi's score in recipients older than 60 years. Here, we analyze the long-term results of this program and try to identify independent predictors of patient and graft survival. Between December 1996 and January 2008, we performed 115 SKT and 88 DKT. Discard rate was 15%. Acute rejection incidence was higher in SKT than in DKT (22.6% vs. 11.4%, p = 0.04). Renal function was better in DKT than in SKT up to 5 years after transplantation. Surgical complications were frequent in DKT. Ten-year cumulative graft survival was significantly lower in the SKT group (31% vs. 53%, p = 0.03). In SKT, histological score 4 provided similar graft survival than 3 or less, whereas in DKT score 4, 5 or 6 displayed similar outcome. Finally, independent predictors of graft survival were history of major adverse cardiac event and 1-year serum creatinine, rather than SKT or DKT. In conclusion, this biopsy-guided old-for-old strategy resulted in acceptable long-term graft survival. Our results suggest that DKT should be considered for scores of 5 or 6 only.

Successful outcome of ganciclovir-resistant cytomegalovirus infection in organ transplant recipients after conversion to mTOR inhibitors.

Ganciclovir-resistant (GanR) cytomegalovirus (CMV) infection after organ transplantation is emerging as a significant therapeutic challenge. We report two cases of GanR CMV infection successfully managed by switching immunosuppression from calcineurin inhibitors to an mTOR inhibitor-based regimen. This salvage therapy should be considered when other options are not available.

Hepatocyte growth factor gene therapy enhances infiltration of macrophages and may induce kidney repair in db/db mice as a model of diabetes.

AIMS/HYPOTHESIS: We previously demonstrated hepatocyte growth factor (HGF) gene therapy was able to induce regression of glomerulosclerosis in diabetic nephropathy through local reparative mechanisms. The aim of this study was to test whether bone-marrow-derived cells are also involved in this HGF-induced reparative process. METHODS: We have created chimeric db/db mice as a model of diabetes that produce enhanced green fluorescent protein (EGFP) in bone marrow cells. We performed treatment with HGF gene therapy either alone or in combination with granulocyte-colony stimulating factor, in order to induce mobilisation of haematopoietic stem cells in these diabetic and chimeric animals. RESULTS: We find HGF gene therapy enhances renal expression of stromal-cell-derived factor-1 and is subsequently associated with an increased number of bone-marrow-derived cells getting into the injured kidneys. These cells are mainly monocyte-derived macrophages, which may contribute to the renal tissue repair and regeneration consistently observed in our model. Finally, HGF gene therapy is associated with the presence of a small number of Bowman's capsule parietal epithelial cells producing EGFP, suggesting they are fused with bone-marrow-derived cells and are contributing to podocyte repopulation. CONCLUSIONS/INTERPRETATION: Altogether, our findings provide new evidence about the therapeutic role of HGF and open new opportunities for inducing renal regeneration in diabetic nephropathy.