Flow capabilities of arterial and drainage cannulae during venoarterial extracorporeal membrane oxygenation: A simulation model.

BACKGROUND: Large cannulae can increase cannula-related complications during venoarterial extracorporeal membrane oxygenation (VA ECMO). Conversely, the ability for small cannulae to provide adequate support is poorly understood. Therefore, we aimed to evaluate a range of cannula sizes and VA ECMO flow rates in a simulated patient under various disease states. METHODS: Arterial cannulae sizes between 13 and 21 Fr and drainage cannula sizes between 21 and 25 Fr were tested in a VA ECMO circuit connected to a mock circulation loop simulating a patient with severe left ventricular failure. Systemic and pulmonary hypertension, physiologically normal, and hypotension were simulated by varying systemic and pulmonary vascular resistances (SVR and PVR, respectively). All cannula combinations were evaluated against all combinations of SVR, PVR, and VA ECMO flow rates. RESULTS: A 15 Fr arterial cannula combined with a 21 Fr drainage cannula could provide >4 L/min of total flow and a mean arterial pressure of 81.1 mmHg. Changes in SVR produced marked changes to all measured parameters, while changes to PVR had minimal effect. Larger drainage cannulae only increased maximum circuit flow rates when combined with larger arterial cannulae. CONCLUSION: Smaller cannulae and lower flow rates could sufficiently support the simulated patient under various disease states. We found arterial cannula size and SVR to be key factors in determining the flow-delivering capabilities for any given VA ECMO circuit. Overall, our results challenge the notion that larger cannulae and high flows must be used to achieve adequate ECMO support.

Electrostatic properties of human germlines and biodistribution of small biologics.

Off-target biodistribution of biologics bears important toxicological consequences. Antibody fragments intended for use as vectors of cytotoxic payloads (e.g. antibody-drug conjugates, radiotherapy) can accumulate at clearance organs like kidneys and liver, where they can cause dose-limiting toxicities. Renal and hepatic uptakes are known to be affected by protein electrostatics, which promote protein internalization through pinocytosis. Using minibodies as a model of an antibody fragment lacking FcRn recycling, we compared the biodistributions of leads with different degrees of accumulation at the kidney and liver. We identified a positive electrostatic patch highly conserved in a germline family very commonly used in the humanization of approved biologics. Neutralization of this patch led to a drastic reduction in the kidney uptake, leading to a biodistribution more favorable to the delivery of highly cytotoxic payloads. Next, we conducted a high throughput study of the electrostatic properties for all combinations of VH and VL germlines. This analysis shows how different VH/VL combinations exhibit varying tendencies to create electrostatic patches, resulting in Fv variants with different isoelectric points. Our work emphasizes the importance of carefully selecting germlines for humanization with optimal electrostatic properties in order to control the unspecific tissue uptake of low molecular weight biologics.

Too hot to handle? An urgent need to understand climate change impacts on the biogeochemistry of tropical coastal waters.

Tropical regions contain ecologically and socio-economically important habitats, and are home to about 3.8 billion people, many of which directly depend on tropical coastal waters for their well-being. At the basis of these ecosystems are biogeochemical processes. Climate change is expected to have a greater impact in the tropics compared to temperate regions because of the relatively stable environmental conditions found there. However, it was surprising to find only 660 research articles published focusing on the impact of climate change on the biogeochemistry of coastal tropical waters compared to 4823 for temperate waters. In this perspective, we highlight important topics in need of further research. Specifically, we suggest that in tropical regions compared to temperate counterparts climate change stressors will be experienced differently, that organisms have a lower acclimation capacity, and that long-term baseline biogeochemical datasets useful for quantifying future changes are lacking. The low number of research papers on the impacts of climate change in coastal tropical regions is likely due to a mix of reasons including limited resources for research and limited number of long time series in many developing tropical countries. Finally, we propose some action points that we hope will stimulate more studies in tropical coastal waters.

Smaller Return Cannula in Venoarterial Extracorporeal Membrane Oxygenation Does Not Increase Hemolysis: A Single-Center, Cohort Study.

The aim of this study was to explore the association between arterial return cannula diameter and hemolysis during peripheral VA ECMO. We identified 158 adult patients who received peripheral VA ECMO at our institution from the national ECMO database (EXCEL) between January 2019 and July 2021. We classified patients into a small cannula group (15 Fr diameter, n = 45) and a large cannula group (≥17 Fr diameter, n = 113), comparing incidences of clinical hemolysis and plasma free hemoglobin ( pf Hb). Moderate hemolysis is defined as having pf Hb 0.05-0.10 g/L and severe hemolysis as having pf Hb >0.10 g/L sustained for at least two consecutive readings or leading to a circuit change. There were no significant differences in rates of moderate hemolysis between small and large cannula groups (1 vs . 6; p = 0.39) and severe hemolysis (0 vs . 3; p = 0.27), nor was the pf Hb level significantly different at 4 hours (0.086 ± 0.096 vs . 0.112 ± 0.145 g/L; p = 0.58) and at 24 hours (0.042 ± 0.033 vs . 0.051 ± 0.069 g/L; p = 0.99). There were no increased rates of hemolysis when comparing small versus large arterial return cannula diameter in peripheral VA ECMO.

Marine heatwaves of different magnitudes have contrasting effects on herbivore behaviour.

Global climate change is leading to shifts in abiotic conditions. Short-term temperature stresses induced by marine heatwaves (MHWs) can affect organisms both during and after the events. However, the recovery capacity of organisms is likely dependent on the magnitude of the initial stress event. Here, we experimentally assessed the effect of MHW magnitude on behavioural and physiological responses of a common marine gastropod, Lunella granulata, both during and after the MHW. Self-righting behaviours tended to become faster under moderate MHWs, whereas there was a trend toward these behaviours slowing under extreme MHWs. After a recovery period at ambient temperatures, individuals that experienced extreme MHWs showed persistent small, but not significant, negative effects. Survival and oxygen consumption rates were unaffected by MHW magnitude both during and after the event. While extreme MHWs may have negative behavioural consequences for tropical marine gastropods, their physiological responses may allow continued survival.

Microplastics, both non-biodegradable and biodegradable, do not affect the whole organism functioning of a marine mussel.

Microplastics are ubiquitous in the marine environment, and their uptake by many organisms has been well documented. Concern about increasing plastic waste in ecosystems and organisms has led to the production of biodegradable alternatives. However, long breakdown times of biodegradable plastics in natural environments mean they still have the potential to induce ecological impacts. The impacts of microplastics on organisms remain unclear, especially as many experimental microplastic exposures employ particle concentrations orders of magnitude greater than those found in natural ecosystems. Here, we exposed the ecosystem engineer, the Asian green mussel Perna viridis, to non-biodegradable and biodegradable microplastics at two environmentally relevant concentrations (~17-20 particles L-1 and ~ 135-140 particles L-1). After four weeks of exposure, there were no significant effects of microplastic type or concentration on the mortality, oxygen consumption rate, clearance rate, or condition index of P. viridis. With the increasing body of microplastic literature, future exposure studies considering biotic effects should make efforts to employ environmentally relevant concentrations. Further, we suggest that, while a high-profile threat to ecosystems, investigating the effects of microplastics on ecosystems should be conducted alongside, and not draw focus away from, other major threats such as climate change.

Oncolytic herpesvirus therapy for mesothelioma - A phase I/IIa trial of intrapleural administration of HSV1716.

OBJECTIVES: Malignant Pleural Mesothelioma (MPM) remains a major oncological challenge with limited therapeutic options. HSV1716 is a replication restricted oncolytic herpes simplex virus with anti-tumor effects in multiple cell lines including MPM. Intrapleural treatment appeals because MPM is typically multifocal but confined to the pleura, and distant metastases are uncommon. We assessed the safety and possible efficacy of intrapleural HSV1716 for inoperable MPM. MATERIALS AND METHODS: Patients with MPM received 1 × 107iu HSV1716 injected via an indwelling intrapleural catheter (IPC) on one, two or four occasions a week apart. The primary endpoint was the safety and tolerability of HSV1716. Secondary endpoints were assessment of HSV1716 replication, detection of immune response and evaluation of tumor response. RESULTS: Of thirteen patients enrolled, five had received previous pemetrexed-cisplatin chemotherapy, and eight were chemotherapy naïve. Three patients were enrolled to receive one dose, three patients to two doses and seven patients to four doses. The treatment was well-tolerated with few virus-related adverse events and no dose limiting toxicities. Twelve patients were evaluable for response, as one patient withdrew early after a catheter fracture. There was evidence of viral replication/persistence in pleural fluid in seven of the twelve patients. Induction of Th1 cytokine responses to HSV1716 treatment occurred in eight patients and four patients developed novel anti-tumor IgG. No objective responses were observed but disease stabilization was reported in 50 % of patients at 8 weeks. CONCLUSIONS: Intrapleural HSV1716 was well-tolerated and demonstrated an anti-tumor immune response in MPM patients. These results provide a rationale for further studies with this agent in MPM and in combination with other therapies.

A retrospective observational study of sarcopenia and outcomes in critically ill patients.

Frailty assessment in patients admitted to intensive care is often limited using traditional clinical frailty assessment tools. Opportunistic use of contemporary computed tomography (CT) can provide an objective estimate of low skeletal muscle mass (sarcopenia) as a proxy for frailty. The aim of this study was to establish the prevalence of sarcopenia in an Australian intensive care unit (ICU) population and to examine the relationship between sarcopenia and clinical outcomes. We undertook a single centre retrospective study of 1085 adult patients admitted to a single ICU over 12 months. Patients with a contemporary CT scan including the L3 vertebral body were included. Patients were categorised as sarcopenic or non-sarcopenic using previously published data. A total of 279 patients with a mean age of 67 years had an eligible CT scan; 163 (58%) were male. Higher 30-day mortality was associated with the use of CRRT (continuous renal replacement therapy) during the ICU admission (OR 6.84, P < 0.001) and also associated with lower cross-sectional muscle area (odds ratio (OR) 0.98, P = 0.004). Sarcopenia was found to be highly prevalent in this particular Australian ICU population (68%) and associated with older age (68 versus 55 years, P < 0.001), lower body mass index (27 versus 32 kg m-2, P < 0.001), more comorbidities (3 versus 2, P = 0.009), and longer stays in hospital (279 versus 223 h, P = 0.043). As a continuous predictor, lumbar muscle mass was associated with 30-day mortality with and without adjusting for other covariates.

Is out-patient based treatment of bronchiectasis exacerbations in children comparable to inpatient based treatment?

BACKGROUND AND OBJECTIVE: Children with bronchiectasis have recurrent exacerbations and may require hospitalization. "Hospital in the home (HITH)" is used as an alternative to hospitalization for children with cystic fibrosis (CF) but to date, there is no published data on children without CF. We describe our experience of HITH (intravenous [IV] antibiotics and at least once-daily physiotherapy-treated airway clearance therapy) in a cohort of children with bronchiectasis, comparing outcomes between hospital and HITH-based pathways. METHODS: Medical records were retrospectively reviewed in children with bronchiectasis who were hospitalized in our center from July 2016 to July 2018. We compared treatment duration, symptom resolution, adverse events, oral antibiotic prescription on discharge and "time-to-next hospitalization" between children managed with the two treatment pathways. RESULTS: Exacerbations in 63 children (median age = 6 years [range: 1-17]; females = 33, indigenous = 8) with bronchiectasis treated with IV antibiotic therapy were analyzed (HITH n = 45, 71.5%). Duration of treatment and symptom resolution was similar between groups (hospital: median = 14 days [interquartile range {IQR}: 14-14] and 12/18 [66.6%], respectively vs HITH: 14 [14-15.5] and 31/45 [69%]; P = .53 and .85, respectively). There was no significant difference in adverse events (16.6% vs 9%), prescription of oral antibiotics on discharge (44% vs 24%), or "time-to-next hospitalization" (median 42 [IQR: 24-100] vs 67 [IQR: 32-95] weeks) between hospital and HITH groups, respectively. CONCLUSIONS: In children with bronchiectasis treated for a severe exacerbation, receiving treatment in the home setting with HITH does not compromise short-term clinical outcomes compared to hospital only treatment. Prospective studies are required to provide more robust evidence in this under-researched area.

Stay clean: direct steam exposure to manage biofouling risks.

Biofouling by marine organisms can result in a variety of negative environmental and economic consequences, with decontamination procedures remaining problematic, costly and labour-intensive. Here, we examined the efficacy of direct steam exposure to induce mortality of selected biofouling species: Mytilus edulis; Magallana gigas; Semibalanus balanoides; Fucus vesiculosus; and an Ulva sp. Total mortality occurred at 60-sec of steam exposure for M. edulis and juvenile M. gigas, at 30-sec for S. balanoides, while 300-sec was required for adult M. gigas. Application of steam reduced the biomass of F. vesiculosus and significantly reduced Ulva sp. biomass, with complete degradation being observed for Ulva sp. following 120-sec of exposure. Accordingly, it appears that steam exposure can cause mortality of biofouling organisms through thermal shock. Although preliminary, our novel and promising results suggest that steam applications could potentially be used to decontaminate niche areas and equipment.

Using functional responses and prey switching to quantify invasion success of the Pacific oyster, Crassostrea gigas.

Invasive alien species continue to proliferate and cause severe ecological impacts. Functional responses (FRs) have shown excellent utility in predicting invasive predator success, however, their use in predicting invasive prey success is limited. Here, we assessed invader success by quantifying FRs and prey switching patterns of two native predators, the common sea star, Asterias rubens, and the green crab, Carcinus maenas, towards native blue mussels, Mytilus edulis, and invasive Pacific oysters, Crassostrea gigas. Asterias displayed destabilising type II FRs, whereas Carcinus displayed stabilising type III FRs towards both prey species. Both predators exhibited greater search efficiencies and maximum feeding rates towards native compared to invasive prey. Both predators disproportionately consumed native mussels over invasive oysters when presented simultaneously, even when native mussels were rare in the environment, therefore indicating negligible prey switching. We demonstrate that invasion success may be mediated through differential levels of biotic resistance exerted by native predators.

Health-related quality of life in 22q11.2 deletion syndrome: The child's perspective.

AIM: The 22q11.2 deletion syndrome (22qDS) is a genetic syndrome that results in a complex physical, behavioural and psychological phenotype. Health-related quality of life (HRQOL) is an established clinical outcome that has been minimally studied in children with 22qDS. The purpose of this study was to explore HRQOL among children and adolescents with 22qDS from the perspective of the child and to determine how their HRQOL measures compare to those of a healthy peer group and a chronic disease peer group. METHODS: We recruited individuals between the ages of 8 and 18 with a positive genetic diagnosis of 22qDS (n = 28) and a parent of the child. Participants completed the paired Paediatric Quality of Life Inventory 4.0 questionnaires. Comparisons were made with a previous study of healthy and diseased children. RESULTS: Children with 22qDS had a significantly poorer HRQOL when compared to age-matched cohorts of healthy children and children with chronic disease. Within the study, there was variable proxy-self agreement, and children with 22qDS reported lower HRQOL than adolescents with 22qDS. CONCLUSION: This study is the first to explore HRQOL from the perspective of the child with 22qDS, and our findings support the existing literature that this condition is associated with a poor HRQOL.

Persistence of Trichomonas vaginalis serostatus in men over time.

PURPOSE: Previous epidemiologic studies have observed positive associations between Trichomonas vaginalis (Tv) serostatus and both prostate cancer (PCa) risk and mortality. However, only a few small older studies have examined Tv antibody persistence over time, all of which were composed mainly of female patients. Therefore, we examined Tv antibody persistence over time, as well as intra-individual variability, among middle- to older-aged men in the Southern Community Cohort Study (SCCS). METHODS: We tested baseline and repeat plasma specimens (collected 1-3 years later) from 248 male participants for Tv antibodies. We used the same enzyme-linked immunosorbent assay as in previous studies of Tv serostatus and PCa. RESULTS: At baseline, 46 (18.5 %) participants were seropositive for Tv infection. Seventy-six percent of these men were still seropositive 1-3 years later. A similar proportion of men "seroconverted" (4.0 %) as "seroreverted" (4.4 %), all of whom had absorbance values near the cutoff point for seropositivity. Overall, substantial agreement was observed between baseline and repeat serostatus (κ = 0.72, 95 % confidence interval 0.60-0.83). CONCLUSION: Tv seropositivity was largely persistent between plasma specimens collected 1-3 years apart from middle- to older-aged men. These high levels of persistence are similar to those observed for other sexually transmitted infections frequently investigated in relation to PCa.

Risk assessment for healthcare workers after a sentinel case of rabies and review of the literature.

BACKGROUND: After a case of rabies, healthcare workers (HCWs) had fear of contagion from the infected patient. Although transmission of rabies to HCWs has never been documented, high-risk exposures theoretically include direct contact of broken skin and/or mucosa with saliva, tears, oropharyngeal secretions, cerebrospinal fluid, and neural tissue. Urine/kidney exposure posed a concern, as our patient's renal transplant was identified as the infection source. METHODS: Our risk assessment included (1) identification of exposed HCWs; (2) notification of HCWs; (3) risk assessment using a tool from the local health department; (4) supplemental screening for urine/kidney exposure; and (5) postexposure prophylaxis (PEP) when indicated. RESULTS: A total of 222 HCWs including diverse hospital staff and medical trainees from university affiliates were evaluated. Risk screening was initiated within 2 hours of rabies confirmation, and 95% of HCWs were assessed within the first 8 days. There were 8 high-risk exposures related to broken skin contact or mucosal splash with the patient's secretions, and 1 person without high-risk contact sought and received PEP outside our hospital. Nine HCWs (4%) received PEP with good tolerance. Due to fear of rabies transmission, additional HCWs without direct patient contact required counseling. There have been no secondary cases after our sentinel rabies patient. CONCLUSIONS: Rabies exposure represents a major concern for HCWs and requires rapid, comprehensive risk screening and counseling of staff and timely PEP. Given the lack of human-to-human rabies transmission from our own experience and the literature, a conservative approach seems appropriate for providing PEP to HCWs.

A DNA hypermethylation module for the stem/progenitor cell signature of cancer.

Many DNA-hypermethylated cancer genes are occupied by the Polycomb (PcG) repressor complex in embryonic stem cells (ESCs). Their prevalence in the full spectrum of cancers, the exact context of chromatin involved, and their status in adult cell renewal systems are unknown. Using a genome-wide analysis, we demonstrate that ~75% of hypermethylated genes are marked by PcG in the context of bivalent chromatin in both ESCs and adult stem/progenitor cells. A large number of these genes are key developmental regulators, and a subset, which we call the "DNA hypermethylation module," comprises a portion of the PcG target genes that are down-regulated in cancer. Genes with bivalent chromatin have a low, poised gene transcription state that has been shown to maintain stemness and self-renewal in normal stem cells. However, when DNA-hypermethylated in tumors, we find that these genes are further repressed. We also show that the methylation status of these genes can cluster important subtypes of colon and breast cancers. By evaluating the subsets of genes that are methylated in different cancers with consideration of their chromatin status in ESCs, we provide evidence that DNA hypermethylation preferentially targets the subset of PcG genes that are developmental regulators, and this may contribute to the stem-like state of cancer. Additionally, the capacity for global methylation profiling to cluster tumors by phenotype may have important implications for further refining tumor behavior patterns that may ultimately aid therapeutic interventions.

Evaluating a decade of exposures to blood and body fluids in an inner-city teaching hospital.

OBJECTIVE: To analyze a decade of hospital staff and student exposures to blood and body fluids (BBF) and to identify risk factors relevant to prevention strategies. DESIGN: Retrospective review of a 1999-2008 data set of BBF exposures. The data, maintained by occupational health staff, detailed the type of exposure, the setting in which the exposure occurred, and the occupational group of the BBF-exposed personnel. SETTING: Washington DC Veterans Affairs Medical Center (VA-DC), an inner-city tertiary care hospital. PARTICIPANTS: All healthcare workers and staff at the VA-DC. METHODS: Review of database. RESULTS: A review of 10 years of data revealed 564 occupational exposures to BBF, of which 66% were caused by needlesticks and 20% were caused by sharp objects. Exposures occurred most often in the acute care setting (which accounted for 39% of exposures) and the operating room (which accounted for 22%). There was a mean of 4.9 exposures per 10,000 acute care patient-days, 0.5 exposures per 10,000 long-term care patient-days, and 0.35 exposures per 10,000 outpatient visits. Housestaff accounted for the highest number of all exposures (196 [35%]). There were, on average, 15.2 exposures per 100 housestaff full-time equivalents. An average of only 1 exposure per year occurred in the hemodialysis center. CONCLUSIONS: Occupational exposures to BBF remain common, but rates vary widely by setting and occupational group. Overall rates are steady across a decade, despite the use of various antiexposure devices and provider education programs. Targeting occupational groups and hospital settings that have been shown to have the highest risk rates should become foundational to future preventative strategies.

Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia.

CD19 is a pan B-cell surface receptor expressed from pro-B-cell development until its down-regulation during terminal differentiation into plasma cells. CD19 represents an attractive immunotherapy target for cancers of lymphoid origin due to its high expression levels on the vast majority of non-Hodgkin's lymphomas and some leukemias. A humanized anti-CD19 antibody with an engineered Fc domain (XmAb5574) was generated to increase binding to Fcgamma receptors on immune cells and thus increase Fc-mediated effector functions. In vitro, XmAb5574 enhanced antibody-dependent cell-mediated cytotoxicity 100-fold to 1,000-fold relative to an anti-CD19 IgG1 analogue against a broad range of B-lymphoma and leukemia cell lines. Furthermore, XmAb5574 conferred antibody-dependent cell-mediated cytotoxicity against patient-derived acute lymphoblastic leukemia and mantle cell lymphoma cells, whereas the IgG1 analogue was inactive. XmAb5574 also increased antibody-dependent cellular phagocytosis and apoptosis. In vivo, XmAb5574 significantly inhibited lymphoma growth in prophylactic and established mouse xenograft models, and showed more potent antitumor activity than its IgG1 analogue. Comparisons with a variant incapable of Fcgamma receptor binding showed that engagement of these receptors is critical for optimal antitumor efficacy. These results suggest that XmAb5574 exhibits potent tumor cytotoxicity via direct and indirect effector functions and thus warrants clinical evaluation as an immunotherapeutic for CD19(+) hematologic malignancies.

Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies.

The humoral immune response requires antigen-specific B cell activation and subsequent terminal differentiation into plasma cells. Engagement of B cell antigen receptor (BCR) on mature B cells activates an intracellular signaling cascade, including calcium mobilization, which leads to cell proliferation and differentiation. Coengagement by immune complex of BCR with the inhibitory Fc receptor FcgammaRIIb, the only IgG receptor expressed on B cells, inhibits B cell activation signals through a negative feedback loop. We now describe antibodies that mimic the inhibitory effects of immune complex by high-affinity coengagement of FcgammaRIIb and the BCR coreceptor complex on human B cells. We engineered the Fc domain of an anti-CD19 antibody to generate variants with up to approximately 430-fold greater affinity to FcgammaRIIb. Relative to native IgG1, the FcgammaRIIb binding-enhanced (IIbE) variants strongly inhibited BCR-induced calcium mobilization and viability in primary human B cells. Inhibitory effects involved phosphorylation of SH2-containing inositol polyphosphate 5-phosphatase (SHIP), which is known to be involved in FcgammaRIIb-induced negative feedback of B cell activation by immune complex. Coengagement of BCR and FcgammaRIIb by IIbE variants also overcame the anti-apoptotic effects of BCR activation. The use of a single antibody to suppress B cell functions by coengagement of BCR and FcgammaRIIb may represent a novel approach in the treatment of B cell-mediated autoimmune diseases.