Determining predictive metabolomic biomarkers of meniscal injury in dogs with cranial cruciate ligament rupture.

OBJECTIVES: This study used hydrogen nuclear magnetic resonance spectroscopy for the first time to examine differences in the metabolomic profile of stifle joint synovial fluid from dogs with cranial cruciate ligament rupture with and without meniscal injuries, in order to identify biomarkers of meniscal injury. Identifying a biomarker of meniscal injury could then ultimately be used to design a minimally invasive diagnostic test for meniscal injuries in dogs. MATERIALS AND METHODS: Stifle joint synovial fluid was collected from dogs undergoing stifle joint surgery or arthrocentesis for lameness investigations. We used multi-variate statistical analysis using principal component analysis and univariate statistical analysis using one-way analysis of variance and analysis of co-variance to identify differences in the metabolomic profile between dogs with cranial cruciate ligament rupture and meniscal injury, cranial cruciate ligament rupture without meniscal injury, and neither cranial cruciate ligament rupture nor meniscal injury, taking into consideration clinical variables. RESULTS: A total of 154 samples of canine synovial fluid were included in the study. Sixty-four metabolites were annotated to the hydrogen nuclear magnetic resonance spectroscopy spectra. Six spectral regions were found to be significantly altered (false discovery rate adjusted P-value <0.05) between groups with cranial cruciate ligament rupture with and without meniscal injury, including three attributed to nuclear magnetic resonance mobile lipids [mobile lipid -CH3 (P=0.016), mobile lipid -n(CH3 )3 (P=0.017), mobile unsaturated lipid (P=0.031)]. CLINICAL SIGNIFICANCE: We identified an increase in nuclear magnetic resonance mobile lipids in the synovial fluid of dogs with meniscal injury which are of interest as potential biomarkers of meniscal injury.

Emergency admissions' diagnoses and risk of in-hospital death according to the primary ICD-10 chapter assigned at discharge and the National Early Warning Score on admission.

BACKGROUND: The relationship between diagnosis, illness severity, and mortality risk for unselected emergency admissions is poorly defined. AIM: To define primary ICD-10 diagnostic chapters at discharge, admission illness severity by the National Early Warning Score, and in-hospital mortality for all unselected emergency admissions. METHOD: Retrospective, observational, cohort study of 122,259 unselected, adult emergency admissions to Salford Royal Hospital between 2014 and 2022. RESULTS: In-hospital mortality was 4.3% but most patients had an ICD-10 chapter associated with a lower risk of death. 60% of in-hospital deaths were in four chapters, infections, circulatory and respiratory diseases, or neoplasms. An admission NEWS ≥3 was associated with earlier mortality and an eight-fold increased risk of in-hospital mortality. 45% of all in-hospital deaths occurred in patients with an admission NEWS <3. CONCLUSION: Mortality in emergency hospital admissions is associated with illness severity and four diagnostic chapters. NEWS should not be the only arbiter of hospital admission, as for certain diagnostic chapters the risk of death is high even if vital signs on presentation are normal.

Universal use of surgical masks is tolerated and prevents respiratory viral infection in stem cell transplant recipients.

Prevention of respiratory viral infection in stem cell transplant patients is important due to its high risk of adverse outcome. This single-centre, mixed methods study, conducted before the severe acute respiratory syndrome coronavirus-2 pandemic, explored the barriers and facilitators to a policy of universal mask use by visitors and healthcare workers, and examined the impact of the first year of introduction of the policy on respiratory viral infection rates compared with preceding years, adjusted for overall incidence. Education around universal mask use was highlighted as being particularly important in policy implementation. A significant decrease in respiratory viral infection was observed following introduction.

Evaluation of procalcitonin as a contribution to antimicrobial stewardship in SARS-CoV-2 infection: a retrospective cohort study.

It can be a diagnostic challenge to identify patients with coronavirus disease 2019 in whom antibiotics can be safely withheld. This study evaluated the effectiveness of a guideline implemented at Sheffield Teaching Hospitals NHS Foundation Trust that recommends withholding antibiotics in patients with low serum procalcitonin (PCT), defined as ≤0.25 ng/mL. Results showed reduced antibiotic consumption in patients with PCT ≤0.25 ng/mL with no increase in mortality, alongside a reduction in subsequent carbapenem prescriptions during admission. The results support the effectiveness of this guideline, and further research is recommended to identify the optimal cut-off value for PCT in this setting.

Detection of multiple hypervirulent Klebsiella pneumoniae strains in a New York City hospital through screening of virulence genes.

OBJECTIVES: The 'hypervirulent' variant of Klebsiella pneumoniae (hvKp) is a predominant cause of community-acquired pyogenic liver abscess in Asia, and is an emerging pathogen in Western countries. hvKp infections have demonstrated 'metastatic' dissemination in immunocompetent hosts, an unusual mode of infection associated with severe complications. Two cases alerted us to the possible presence of hvKp at our hospital, both involving elderly Hispanic males who presented with recurrent fever, bacteraemia, epigastric pain and liver abscesses/phlegmon, thus prompting an assessment of hvKp prevalence. METHODS: A surveillance of K. pneumoniae blood, body fluid and wound isolates was conducted using real-time PCR to detect virulence-associated genes (uni-rmpA, iucA and peg344). Positive isolates were further characterized by wzi gene sequencing to determine capsular types (K-type) and by multilocus sequence typing and pulsed-field gel electrophoresis to determine strain relatedness. RESULTS: Four-hundred and sixty-three K. pneumoniae isolates, derived from 412 blood, 21 body fluids and 30 abdominal wound specimens, were screened over a 3-year period. Isolates included 98 multidrug-resistant strains. Eighteen isolates from 17 patients, including two from the index patient, screened positive for all three virulence genes. Sixteen of 18 positive isolates had K-types associated with hvKp, and isolates from different patients were unrelated strains, indicating likely community acquisition. Of 13 patients with significant morbidity, five died; eight patients had co-existing hepatobiliary disease, and six had diabetes mellitus. CONCLUSIONS: Multiple strains of hvKp are emerging in New York City and are associated with high mortality relative to multidrug-resistant and classical Klebsiella infections. Co-existing hepatobiliary disease appears to be a potential risk factor for these infections.

Palliative care advanced practice nursing in Israel: bridging creation and implementation.

AIM: To describe Israel's development of the palliative care advanced practice registered nurse as a foundation for the development of the advanced practice registered nurse role in other specialties. BACKGROUND: Palliative care centres on alleviating physical, emotional, social and spiritual distress associated with life-limiting illness. In 2009, Israel introduced the palliative care advanced practice nurse role, that is, registered nurses with specialized training in palliative care, to address increasing palliative care needs. INTRODUCTION: While there has been investment in its development, full implementation of the advanced practice nurse has not yet been achieved. METHODS: In this qualitative descriptive study, we conducted a document analysis (n = 11) and key informant interviews (n = 11), extracted themes using qualitative content analysis and triangulated data sets. RESULTS: Documents reflected growing palliative care needs and uniform requirements for advanced practice nurse training. Interviews uncovered a perceived lack of awareness of palliative care, the need for increased role definition and practice authority for advanced practice nurses, and barriers to entry and training for this role. DISCUSSION: Findings highlight ongoing needs in palliative care and advanced practice nursing and a trajectory of growth. CONCLUSIONS: The challenges Israel faces in implementation of the palliative care advanced practice nurse role inform development of other advanced practice nursing roles in Israel and other countries. IMPLICATIONS FOR NURSING PRACTICE: Streamlining training pathways and resolving scope of practice issues will assist in implementation of advanced practice nursing roles. IMPLICATIONS FOR HEALTH POLICY: Our data offer targets for policymakers advocating the advanced practice nurse role, including training requirements and scope of practice.

The prevalence of pulmonary hypertension in Cavalier King Charles spaniels compared with other breeds with myxomatous mitral valve disease.

INTRODUCTION: Pulmonary hypertension (PH) is a common consequence of myxomatous mitral valve disease (MMVD). Cavalier King Charles spaniels (CKCS) are frequently affected with MMVD and appear to have different disease progression compared to other dogs. This study aimed to determine if CKCS are more likely to develop PH as a result of MMVD than dogs of other breeds. A secondary aim was to explore whether breed or PH impacted survival. ANIMALS: A total of 187 dogs diagnosed with MMVD, 94 CKCS and 93 non-CKCS, were included in this study. METHODS: This is a retrospective review of dogs with MMVD. Data were analyzed for presence of PH, congestive heart failure (CHF) and echocardiographic variables including the ratio between mitral E wave velocity (E vel) and isovolumic relaxation time (E/IVRT) and were compared between CKCS/non-CKCS and dogs with/without PH. Survival analysis was also performed. RESULTS: American College of Veterinary Internal Medicine (ACVIM) stage (p < 0.001), CKCS (p = 0.005), left atrium-to-aortic ratio (LA/Ao) (p < 0.001), E vel (p < 0.001) and log10(E/IVRT) (p < 0.001) were significant at the univariate level for PH development. At the multivariate level, only ACVIM stage remained significant (p = 0.044), suggesting that worsening MMVD was the predominant determinant of PH development in this study. Pulmonary hypertension was associated with greater likelihood of CHF (p < 0.001) and death (both cardiac [p < 0.001] and all-cause mortality [p = 0.011]). Cavalier King Charles spaniels were more likely to experience cardiac death than non-CKCS (p = 0.004). CONCLUSIONS: In this study, development of PH was associated with worse MMVD, according to ACVIM stage.

Cerebral oximetry and its role in adult cardiac, non-cardiac surgery and resuscitation from cardiac arrest.

Monitors using near-infra red spectroscopy to assess cerebral oxygenation levels non-invasively in discrete areas of the brain have been used clinically for over 20 years. Interest has intensified recently, especially during cardiac surgery, and there are now five commercially available devices. Despite the attraction of being able to measure oxygen supply/demand in such a critical area, there has been only limited uptake of this technology in overall clinical anaesthetic practice. This narrative review aims to explore not only the rationale for using this technology but also the factors which have restricted its more widespread use.

Critical role of caspase-8-mediated IL-1 signaling in promoting Th2 responses during asthma pathogenesis.

Allergic asthma is a chronic inflammatory disorder of the airways that affects >300 million people worldwide. The pro-inflammatory cytokines interleukin (IL)-1α and IL-1ß have essential roles in the pathogenesis of asthma. However, the mechanisms underlying the production of IL-1 cytokines in allergic asthma remain unclear. In this study, we used a mouse model of ovalbumin-induced asthma to identify a crucial role for caspase-8 in the development of allergic airway inflammation. We further demonstrated that hematopoietic cells have dominant roles in caspase-8-mediated allergic airway inflammation. Caspase-8 was required for the production of IL-1 cytokines to promote Th2 immune response, which promotes the development of pulmonary eosinophilia and inflammation. Thus, our study identifies caspase-8 as a master regulator of IL-1 cytokines that contribute to the pathogenesis of asthma and implicates caspase-8 inhibition as a potential therapeutic strategy for asthmatic patients.

Caspase-2-mediated cell death is required for deleting aneuploid cells.

Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2-/-) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2-/- mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.

Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma.

Chemotherapeutic agents without cross-resistance to prior therapies may enhance PBSC collection and improve patient outcomes by exacting a more potent direct antitumor effect before autologous stem cell transplant. Bendamustine has broad clinical activity in transplantable lymphoid malignancies, but concern remains over the potential adverse impact of this combined alkylator-nucleoside analog on stem cell mobilization. We performed a prospective, nonrandomized phase II study including 34 patients with multiple myeloma (MM) (n=34; International Staging System (ISS) stages I (35%), II (29%) and III (24%); not scored (13%)) to evaluate bendamustine's efficacy and safety as a stem cell mobilizing agent. Patients received bendamustine (120 mg/m2 IV days 1, 2), etoposide (200 mg/m2 IV days 1-3) and dexamethasone (40 mg PO days 1- 4) (bendamustine, etoposide and dexamethasone (BED)) followed by filgrastim (10 µg/kg/day SC; through collection). All patients (100%) successfully yielded stem cells (median of 21.60 × 106/kg of body weight; range 9.24-55.5 × 106/kg), and 88% required a single apheresis. Six nonhematologic serious adverse events were observed in 6 patients including: neutropenic fever (1, grade 3), bone pain (1, grade 3) and renal insufficiency (1, grade 1). In conclusion, BED safely and effectively mobilizes hematopoietic stem cells.

Marrow adipogenesis and bone loss that parallels estrogen deficiency is slowed by low-intensity mechanical signals.

UNLABELLED: Ovariectomized mice were used to assess the ability of low-intensity vibrations to protect bone microarchitecture and marrow composition. Results indicate that low-intensity vibrations (LIV), introduced 2 weeks postsurgery, slows marrow adipogenesis in OVX mice but does not restore the bone within the period studied. However, immediate application of LIV partially protects quality. INTRODUCTION: The aim of this study was to evaluate consequences of estrogen depletion on bone marrow (BM) phenotype and bone microarchitecture, and effects of mechanical signals delivered as LIV on modulating these changes. METHODS: LIV (0.3 g, 90 Hz) was applied to C57BL/6 mice immediately following ovariectomy or 2 weeks postestrogen withdrawal for 2 (ST-LIV) or 6 weeks (LT-LIV), respectively. Sham-operated age-matched controls (ST-AC, LT-AC) and ovariectomized controls (ST-OVX, LT-OVX) received sham LIV treatment. Bone microstructure was evaluated through µCT and BM adipogenesis through histomorphometry, serum markers, and genes expression analysis. RESULTS: LT-OVX increased BM adipogenesis relative to LT-AC (+136 %, p ≤ 0.05), while LT-LIV introduced for 6w suppressed this adipose encroachment (-55 %, p ≤ 0.05). In parallel with the fatty marrow, LT-OVX showed a marked loss of trabecular bone, -40 % (p ≤ 0.05) in the first 2 weeks following ovariectomy compared to LT-AC. Application of LT-LIV for 6w following this initial 2w bone loss failed to restore the lost trabeculae but did initiate an anabolic response as indicated by increased serum alkaline phosphatase (+26 %, p ≤ 0.05). In contrast, application of LIV immediately following ovariectomy was more efficacious in the protection of trabecular bone, with a +29 % (p > 0.05) greater BV/TV compared to ST-OVX at the 2w time period. CONCLUSIONS: LIV can mitigate adipocyte accumulation in OVX marrow and protect it by favoring osteoblastogenesis over adipogenesis. These data also emphasize the rapidity of bone loss with OVX and provide perspective in the timing of treatments for postmenopausal osteoporosis where sooner is better than later.

A randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for patients with multiple myeloma undergoing auto-SCT.

We aimed to examine whether doses of melphalan higher than 200 mg/m(2) improve response rates when used as conditioning before autologous transplant (ASCT) in multiple myeloma (MM) patients. Patients with MM, n=131, were randomized to 200 mg/m(2) (mel200) vs 280 mg/m(2) (mel280) using amifostine pretreatment. The primary end point was the proportion of patients achieving near complete response (⩾nCR). No treatment-related deaths occurred in this study. Responses following ASCT were for mel200 vs mel280, respectively, ⩾nCR 22 vs 39%, P=0.03, ⩾PR 57 vs 74%, P=0.04. The hazard of mortality was not statistically significantly different between groups (mel200 vs mel280; hazard ratio (HR)=1.15 (95% confidence interval (CI), 0.62-2.13, P=0.66)) nor was the rate of progression/mortality (HR=0.81 (0.52-1.27, P=0.36)). The estimated PFS at 1 and 3 years were 83 and 46%, respectively, for mel200 and 78 and 54%, respectively, for mel280. Amifostine and mel280 were well tolerated, with no grade 4 regimen-related toxicities and only one grade 3 mucositis (none with mel200) and three grade 3 gastrointestinal (GI) toxicities (two in mel200). Hospitalization rates were more frequent in the mel280 group (59 vs 43%, P=0.08). Mel280 resulted in a higher major response rate (CR+nCR) and should be evaluated in larger studies.

MR Angiographic-Guided Percutaneous Sclerotherapy for Venous Vascular Malformations: A Radiation Dose-Reduction Strategy.

We present a new technique using MRA instead of the usual DSA to provide guidance in the treatment of venous vascular malformations. When one performs this embolization procedure, appropriate needle positioning within the malformation must be confirmed before injection of the sclerosing agent to prevent untoward complications. Time-resolved imaging of contrast kinetics-MRA can accurately depict the angioarchitecture of the lesion, which substantially reduces the total radiation dose in these patients who are commonly in the pediatric age group and usually require numerous treatment episodes.

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

Cribriform adenocarcinoma of the minor salivary glands arising in the epiglottis--a previously undocumented occurrence.

A 39-year-old female was referred to her local Ear, Nose, and Throat department with tonsillar hypertrophy. During intubation for a tonsillectomy, a mass was also noted on the epiglottis. Histopathologic examination showed this mass to be a cribriform adenocarcinoma of the minor salivary glands (CAMSG). As far as the authors are aware, a CAMSG has never been documented in the larynx.

Utilization of stored autologous PBSCs to support second autologous transplantation in multiple myeloma patients in the era of novel agent therapy.

Outcomes in multiple myeloma (MM) have improved significantly with novel agent therapy and autologous stem cell transplantation (ASCT). ASCTs are typically planned as either tandem or a single transplant with additional stored PBSCs available for a second salvage transplant. To accommodate these strategies, many centers routinely collect and store adequate PBSCs for two ASCTs. We analyzed the cost associated with this practice by determining the expenses of PBSC collection, cryopreservation and storage, and the ultimate use of additional cryopreserved PBSCs in patients who had undergone at least one ASCT. There were 889 MM patients transplanted between 1993 and 2011 at our center. Most (N=726) had residual PBSCs in storage after their first ASCT (ASCT1). Only 135 patients underwent a second ASCT within a median of 14 months after ASCT1. The percentage of patients receiving a second ASCT declined over time. The resources required to collect and store unused PBSCs added up to 336 extra patient days of apheresis and 41 587 extra patient months of cryopreservation, translating into an average extra cost per patient of US$4981.12. A reconsideration of conventional PBSC collection and storage practices would save significant cost for the majority of MM patients who never undergo a second ASCT.

RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis.

Necroptosis is a form of programmed cell death that depends on the activation of receptor interacting protein kinase-1 (RIPK1) and RIPK3 by receptors such as tumor necrosis factor (TNF) receptor-1. Structural studies indicate that activation of RIPK3 by RIPK1 involves the formation of oligomers via interactions of the RIP homotypic interaction motif (RHIM) domains shared by both proteins; however, the molecular mechanisms by which this occurs are not fully understood. To gain insight into this process, we constructed versions of RIPK3 that could be induced to dimerize or oligomerize in response to a synthetic drug. Using this system, we find that although the formation of RIPK3 dimers is itself insufficient to trigger cell death, this dimerization seeds a RHIM-dependent complex, the propagation and stability of which is controlled by caspase-8 and RIPK1. Consistent with this idea, we find that chemically enforced oligomerization of RIPK3 is sufficient to induce necroptosis, independent of the presence of the RHIM domain, TNF stimulation or RIPK1 activity. Further, although RIPK1 contributes to TNF-mediated RIPK3 activation, we find that RIPK1 intrinsically suppresses spontaneous RIPK3 activation in the cytosol by controlling RIPK3 oligomerization. Cells lacking RIPK1 undergo increased spontaneous RIPK3-dependent death on accumulation of the RIPK3 protein, while cells containing a chemically inhibited or catalytically inactive form of RIPK1 are protected from this form of death. Together, these data indicate that RIPK1 can activate RIPK3 in response to receptor signaling, but also acts as a negative regulator of spontaneous RIPK3 activation in the cytosol.