Reassessing the alternative ecosystem states proposition in the African savanna-forest domain.

Ecologists are being challenged to predict how ecosystems will respond to climate changes. According to the Multi-Colored World (MCW) hypothesis, climate impacts may not manifest because consumers such as fire and herbivory can override the influence of climate on ecosystem state. One MCW interpretation is that climate determinism fails because alternative ecosystem states (AES) are possible at some locations in climate space. We evaluated theoretical and empirical evidence for the proposition that forest and savanna are AES in Africa. We found that maps which infer where AES zones are located were contradictory. Moreover, data from longitudinal and experimental studies provide inconclusive evidence for AES. That is, although the forest-savanna AES proposition is theoretically sound, the existing evidence is not yet convincing. We conclude by making the case that the AES proposition has such fundamental consequences for designing management actions to mitigate and adapt to climate change in the savanna-forest domain that it needs a more robust evidence base before it is used to prescribe management actions.

Unveiling Fall Risk Factors: Nurse-Driven Corpus Development for Natural Language Processing.

Hospital-acquired falls are a continuing clinical concern. The emergence of advanced analytical methods, including NLP, has created opportunities to leverage nurse-generated data, such as clinical notes, to better address the problem of falls. In this nurse-driven study, we employed an iterative process for expert manual annotation of RNs clinical notes to enable the training and testing of an NLP pipeline to extract factors related to falls. The resulting annotated data corpus had moderately high interrater reliability (F-score=0.74) and captured a breadth of clinical concepts for extraction with potential utility beyond patient falls. Further research is needed to determine which annotation tasks most benefit from nursing expert annotators, to optimize efficiency when tapping into the invaluable resource represented by the nursing workforce.

A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models.

Inherited retinopathies are devastating diseases that in most cases lack treatment options. Disease-modifying therapies that mitigate pathophysiology regardless of the underlying genetic lesion are desirable due to the diversity of mutations found in such diseases. We tested a systems pharmacology-based strategy that suppresses intracellular cAMP and Ca2+ activity via G protein-coupled receptor (GPCR) modulation using tamsulosin, metoprolol, and bromocriptine coadministration. The treatment improves cone photoreceptor function and slows degeneration in Pde6ßrd10 and RhoP23H/WT retinitis pigmentosa mice. Cone degeneration is modestly mitigated after a 7-month-long drug infusion in PDE6A-/- dogs. The treatment also improves rod pathway function in an Rpe65-/- mouse model of Leber congenital amaurosis but does not protect from cone degeneration. RNA-sequencing analyses indicate improved metabolic function in drug-treated Rpe65-/- and rd10 mice. Our data show that catecholaminergic GPCR drug combinations that modify second messenger levels via multiple receptor actions provide a potential disease-modifying therapy against retinal degeneration.

Assessment of Early Glaucomatous Optic Neuropathy in the Dog by Spectral Domain Optical Coherence Tomography (SD-OCT).

BACKGROUND: Inherited primary open-angle glaucoma (POAG) in Beagle dogs is a well-established large animal model of glaucoma and is caused by a G661R missense mutation in the ADAMTS10 gene. Using this model, the study describes early clinical disease markers for canine glaucoma. METHODS: Spectral-domain optical coherence tomography (SD-OCT) was used to assess nine adult, ADAMTS10-mutant (median age 45.6 months, range 28.8-52.8 months; mean diurnal intraocular pressure (IOP): 29.9 +/- SEM 0.44 mmHg) and three related age-matched control Beagles (mean diurnal IOP: 18.0 +/- SEM 0.53 mmHg). RESULTS: Of all the optic nerve head (ONH) parameters evaluated, the loss of myelin peak height in the horizontal plane was most significant (from 154 +/- SEM 38.4 µm to 9.3 +/- SEM 22.1 µm; p < 0.01). There was a strong significant negative correlation between myelin peak height and IOP (Spearman correlation: -0.78; p < 0.003). There were no significant differences in the thickness of any retinal layers evaluated. CONCLUSIONS: SD-OCT is a useful tool to detect early glaucomatous damage to the ONH in dogs before vision loss. Loss in myelin peak height without inner retinal thinning was identified as an early clinical disease marker. This suggests that initial degenerative changes are mostly due to the loss of myelin.

Age-Friendly Health Systems and Meeting the Principles of High Reliability Organizations in the VHA.

Background: The Veterans Health Administration (VHA) is the largest integrated health care system in the US, providing care to more than 9 million enrolled veterans. In February 2019, the VHA identified key actionable steps to become a high reliability organization (HRO), transforming how employees think about patient safety and care quality. The VHA is also working toward becoming the largest age-friendly health system in the US to be recognized by the Institute for Healthcare Improvement for its commitment to providing care guided by the 4Ms (what matters, medication, mentation, and mobility), causing no harm, and aligning care with what matters to older veterans. Observations: In this article, we describe how the Age-Friendly Health Systems (AFHS) movement supports the culture shift observed in HROs. AFHS use the 4Ms as a framework to be implemented in every care setting. The 4Ms are used in conjunction with the 3 pillars (leadership commitment, culture of safety, and continuous process improvement) and 5 principles (sensitivity to operations, reluctance to simplify, preoccupation with failure, deference to clinical expertise, and commitment to resilience) that guide an HRO. We also share an HRO case study that is representative of many Community Living Centers involved in AFHS. Conclusions: AFHS empower VHA teams to honor veterans' care preferences and values, supporting their independence, dignity, and quality of life across care settings. The adoption of AFHS brings evidence-based practices to the point of care by addressing common pitfalls in the care of older adults, drawing attention to, and calling for action on inappropriate medication use, physical inactivity, and assessment of the vulnerable brain. The 4Ms also serve as a framework to continuously improve care and cause zero harm, reinforcing HRO pillars and principles across the VHA and ensuring that older adults reliably receive the evidence-based, high-quality care they deserve.

In-hospital outcomes and postdischarge mortality in patients with acute coronary syndrome and atrial fibrillation.

BACKGROUND: It is unclear whether advances in management of acute coronary syndrome (ACS) and introduction of novel oral anticoagulants have changed outcomes in patients with ACS with concomitant atrial fibrillation (AF). OBJECTIVE: This study aimed to examine the incidence of AF in patients admitted for ACS and to evaluate its association with adverse outcomes, given the recent advances in management of both diseases. METHODS: Natural language processing search algorithms identified AF in patients admitted with ACS across 13 Northwell Health Hospitals from 2015 to 2021. Hierarchical generalized linear mixed modeling was used to assess the association between AF and in-hospital mortality, bleeding, and stroke outcomes; marginal Cox regression modeling was used to assess the association between AF and postdischarge mortality. RESULTS: Of 12,315 patients admitted for ACS, 3018 (24.5%) had AF with 1609 (53.3%) newly diagnosed. AF patients more commonly received anticoagulation with an oral anticoagulant (80.4% vs 12.3%) or heparin (61.9% vs 56.9%), had lengthier intensive care unit stay (72 vs 49 hours), and underwent fewer percutaneous coronary interventions (31.9% vs 53.1%). In-hospital bleeding, stroke, and mortality were higher in the AF group (15.3% vs 5.0%, 7.4% vs 2.4%, and 6.9% vs 2.1%, respectively). AF was an independent risk factor for all in-hospital outcomes (odds ratios of 2.5, 2.7, and 2.0 for bleeding, stroke, and mortality, respectively) as well as for postdischarge mortality (hazard ratio, 1.3; 95% CI, 1.2-1.5). CONCLUSION: AF is present in 25% of ACS patients and increases risk of in-hospital and postdischarge adverse outcomes. Additional data are required to direct optimal management.

Direct oral anticoagulants and venous malformations: literature review and retrospective study of 29 patients.

Background: Venous malformations (VMs) are commonly associated with localized intravascular coagulopathy leading to elevated D-dimer and risks of hemorrhagic and thromboembolic events, particularly in extensive lesions. While low-molecular-weight heparin (LMWH) has been effective in managing coagulopathy and pain, direct oral anticoagulants (DOACs) emerge as a promising alternative. Objectives: This study aims to evaluate the efficacy and safety of DOACs in treating VMs associated with localized intravascular coagulopathy, offering a comparative perspective to LMWH. Methods: A retrospective study was conducted on 29 patients with VMs and secondary localized intravascular coagulopathy treated with DOACs between 2013 and 2023 in a single tertiary center specialized in vascular anomalies. Data were collected from February 24, 2023, to September 1, 2023. Results: Patients' median age was 40 years (range, 22-76 years), with a female predominance of 66%. Descriptive statistical analysis showed that 85% of patients experienced pain improvement, and 86% showed a reduction in D-dimer by at least 25%, with a mean reduction of 57% (SD, ±32%; IQR, [38-81%]). Additionally, 37% of patients reported a bleeding event, mostly minor. Conclusion: The study findings suggests that DOACs may serve as an alternative to LMWH for patients with VMs associated with pain management and reduced D-dimer, alongside a low observed risk of major bleeding. Tailored dosing considering the location of the malformation, bleeding and thrombotic tendencies, and laboratory abnormalities is recommended. Future studies with larger cohorts and extended follow-up are necessary for more conclusive evidence on DOACs' role in this patient population.

Has Propranolol Eradicated the Need for Surgery in the Management of Infantile Hemangioma?

BACKGROUND: To assess the impact of propranolol as the first-line treatment of infantile hemangioma (IH) on the need for surgery in the management of IH. METHODS: Retrospective study of 420 patients, with IH, referred to our multidisciplinary center between January 2005 and August 2014. Clinical data including sex, age at first consultation and at treatment initiation, location, size, number, aspect, and complication of IH, as well as the type of treatment were collected. Statistical analyses were conducted considering each patient and each tumor independently. RESULTS: A total of 625 IH(420 patients (P))were reviewed, 113 patients had more than one IH (26.91%). Median age at first consultation was 7 months old. Overall, 243 patients were treated (57.86%) using either surgery (n=128 P/141 IH), propranolol (n=79 P/89 IH), corticosteroids (n=51 P/56 IH), and/or laser (n=34 P /36 IH). Propranolol was effective in all but 2 infants with IH. Seven patients (n=7/79 P; 8.86%) initially treated with propranolol, still required surgery, in contrast to 18 patients (n=18/51 P; 35.29%) initially treated with corticosteroids, and 103 patients (n=103/290 P; 35.51%) with no medical treatment. Since the availability of propranolol, patients were less likely to undergo surgery (48 P versus 80 P; P-Value < 0.001). This demonstrated that the use of propranolol reduced the need for surgery (P-Value < 0.001 with an OR of 0.177: CI 95% 0.079-0.396). CONCLUSION: Propranolol has dramatically reduced the need for surgery, regarding indications and number of patients. Surgical correction remains important for sequelae management, non-responders or strawberry-like IH.

Managing Implanted Cardiac Electronic Devices in Patients With Severe Tricuspid Regurgitation: JACC State-of-the-Art Review.

Orthotopic transcatheter tricuspid valve replacement (TTVR) devices have been shown to be highly effective in reducing tricuspid regurgitation (TR), and interest in this therapy is growing with the recent commercial approval of the first orthotopic TTVR. Recent TTVR studies report preexisting cardiac implantable electronic device (CIED) transvalvular leads in ∼35% of patients, with entrapment during valve implantation. Concerns have been raised regarding the safety of entrapping leads and counterbalanced against the risks of transvenous lead extraction (TLE) when indicated. This Heart Valve Collaboratory consensus document attempts to define the patient population with CIED lead-associated or lead-induced TR, describe the risks of lead entrapment during TTVR, delineate the risks and benefits of TLE in this setting, and develop a management algorithm for patients considered for TTVR. An electrophysiologist experienced in CIED management should be part of the multidisciplinary heart team and involved in shared decision making.

Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema.

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2/TIE1 pathway in lymphatic function.

A Modular Communicative Leadless Pacing-Defibrillator System.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) is associated with fewer lead-related complications than a transvenous ICD; however, the subcutaneous ICD cannot provide bradycardia and antitachycardia pacing. Whether a modular pacing-defibrillator system comprising a leadless pacemaker in wireless communication with a subcutaneous ICD to provide antitachycardia and bradycardia pacing is safe remains unknown. METHODS: We conducted a multinational, single-group study that enrolled patients at risk for sudden death from ventricular arrhythmias and followed them for 6 months after implantation of a modular pacemaker-defibrillator system. The safety end point was freedom from leadless pacemaker-related major complications, evaluated against a performance goal of 86%. The two primary performance end points were successful communication between the pacemaker and the ICD (performance goal, 88%) and a pacing threshold of up to 2.0 V at a 0.4-msec pulse width (performance goal, 80%). RESULTS: We enrolled 293 patients, 162 of whom were in the 6-month end-point cohort and 151 of whom completed the 6-month follow-up period. The mean age of the patients was 60 years, 16.7% were women, and the mean (±SD) left ventricular ejection fraction was 33.1±12.6%. The percentage of patients who were free from leadless pacemaker-related major complications was 97.5%, which exceeded the prespecified performance goal. Wireless-device communication was successful in 98.8% of communication tests, which exceeded the prespecified goal. Of 151 patients, 147 (97.4%) had pacing thresholds of 2.0 V or less, which exceeded the prespecified goal. The percentage of episodes of arrhythmia that were successfully terminated by antitachycardia pacing was 61.3%, and there were no episodes for which antitachycardia pacing was not delivered owing to communication failure. Of 162 patients, 8 died (4.9%); none of the deaths were deemed to be related to arrhythmias or the implantation procedure. CONCLUSIONS: The leadless pacemaker in wireless communication with a subcutaneous ICD exceeded performance goals for freedom from major complications related to the leadless pacemaker, for communication between the leadless pacemaker and subcutaneous ICD, and for the percentage of patients with a pacing threshold up to 2.0 V at a 0.4-msec pulse width at 6 months. (Funded by Boston Scientific; MODULAR ATP ClinicalTrials.gov NCT04798768.).

Targeted treatment in complex lymphatic anomaly: a case of synergistic efficacy of trametinib and sirolimus.

Repurposing anticancer drugs to vascular malformations has significantly improved patient outcomes. Complex Lymphatic Anomalies (CLA) are part of the spectrum of lymphatic malformations (LMs) that share similar oncogenic mutations to cancer. We report the case of a young patient with highly symptomatic CLA who was initially treated with sirolimus, due to the frequent involvement of the PI3K-AKT-mTOR pathway in CLA pathogenesis. Despite an initial reduction in symptoms, sirolimus progressively lost its effectiveness. After an unsuccessful attempt with trametinib alone, sirolimus was added to trametinib and resulted in a significant, rapid and sustained improvement in symptoms. This suggests that, contrary to current dogmas, combination therapy using sub-therapeutic doses targeting both the PI3K and RAS pathways retains efficacy without generating the toxicity known for combination therapies, and is beneficial in the management of CLAs and potentially other vascular anomalies.

Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function.

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.

Perceived stress from social isolation or loneliness among clinical and non-clinical healthcare workers during COVID-19.

BACKGROUND: Workplace social isolation and loneliness have been found to result in a decline in job satisfaction and an increase in burnout among working individuals. The COVID-19 pandemic exacerbated feelings of loneliness and social isolation among healthcare workers. The majority of research on healthcare worker experiences is conducted in siloes which does not reflect the shared experiences of interprofessional teams. The purpose of this study is to understand stress from social isolation or loneliness across the entire clinical and non-clinical healthcare team over the course of the pandemic. METHODS: Data was acquired using a cross-sectional survey distributed to healthcare workers once a year at a large academic medical center in the Southeastern United States during the COVID-19 pandemic (2020-2022). Information pertaining to job role, work location, and demographic factors was collected. Participants were also asked to assess individual well-being and resilience, in addition to reporting stress derived from various sources including job demands and social isolation or loneliness. Descriptive statistics and bivariate analyses were conducted to assess the association between stress from social isolation or loneliness and individual characteristics. RESULTS: Stress from social isolation or loneliness was found to decrease over the survey period across all measured variables. Trainees and physician-scientists were found to report the highest rates of this stressor compared to other job roles, while Hospital-Based ICU and Non-ICU work locations reported the highest rates of loneliness and social isolation stress. Younger workers and individuals from marginalized gender and racial groups were at greater risk for stress from social isolation or loneliness. CONCLUSIONS: Given the importance of social connections for well-being and job performance, organizations have a responsibility to create conditions and mechanisms to foster social connections. This includes establishing and reinforcing norms of behavior, and developing connection mechanisms, particularly for groups at high risk of loneliness and social isolation.

Acute pulmonary injury in hematology patients supported with pathogen-reduced and conventional platelet components.

ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Leadless pacemakers: Where are we?

Pacemakers have been the cornerstone of brady-arrhythmia management since the mid-20th century. Despite the widespread use and success of traditional transvenous pacemakers, they are associated with an estimated 15 % complication rate at three years. Driven by the advantages over traditional transvenous pacemakers including a lack of transvenous leads, resistance to infection, and ease of implantation, the number of leadless pacemakers placed annually in the United States has dramatically increased since their initial approval. While current iterations of leadless pacemakers lack the versatility offered by transvenous devices, recent advances in leadless pacing offer an increasingly diverse range of therapeutic options. This review will discuss the past, present, and future emerging technologies, and strategies in leadless pacing.

Somatic Loss-of-Function PIK3R1 and Activating Non-hotspot PIK3CA Mutations Associated with Capillary Malformation with Dilated Veins (CMDV).

Common capillary malformations are red vascular skin lesions, most commonly associated with somatic activating GNAQ or GNA11 mutations. We focused on capillary malformations lacking such a mutation to identify previously unreported genetic causes. We used targeted next-generation sequencing on 82 lesions. Bioinformatic analysis allowed the identification of 9 somatic pathogenic variants in PIK3R1 and PIK3CA, encoding for the regulatory and catalytic subunits of phosphoinositide 3-kinase, respectively. Recharacterization of these lesions unraveled a common phenotype: a pale capillary malformation associated with visible dilated veins. Primary endothelial cells from 2 PIK3R1-mutated lesions were isolated, and PI3k-Akt-mTOR and RAS-RAF-MAPK signaling were assessed by western blot. This unveiled an abnormal increase in Akt phosphorylation, effectively reduced by PI3K pathway inhibitors, such as mTOR, Akt, and PIK3CA inhibitors. The effects of mutant PIK3R1 were further studied using zebrafish embryos. Endothelium-specific expression of PIK3R1 mutants resulted in abnormal development of the posterior capillary-venous plexus. In summary, capillary malformation associated with visible dilated veins emerges as a clinical entity associated with somatic pathogenic variants in PIK3R1 or PIK3CA (nonhotspot). Our findings suggest that the activated Akt signaling can be effectively reversed by PI3K pathway inhibitors. In addition, the proposed zebrafish model holds promise as a valuable tool for future drug screening aimed at developing patient-tailored treatments.

Sediment discharge from Greenland's marine-terminating glaciers is linked with surface melt.

Sediment discharged from the Greenland Ice Sheet delivers nutrients to marine ecosystems around Greenland and shapes seafloor habitats. Current estimates of the total sediment flux are constrained by observations from land-terminating glaciers only. Addressing this gap, our study presents a budget derived from observations at 30 marine-margin locations. Analyzing sediment cores from nine glaciated fjords, we assess spatial deposition since 1950. A significant correlation is established between mass accumulation rates, normalized by surface runoff, and distance down-fjord. This enables calculating annual sediment flux at any fjord point based on nearby marine-terminating outlet glacier melt data. Findings reveal a total annual sediment flux of 1.324 + /- 0.79 Gt yr-1 over the period 2010-2020 from all marine-terminating glaciers to the fjords. These estimates are valuable for studies aiming to understand the basal ice sheet conditions and for studies predicting ecosystem changes in Greenland's fjords and offshore areas as the ice sheet melts and sediment discharge increase.