Antimicrobial resistance (AMR) is a world-wide public health threat that is projected to lead to 10 million annual deaths globally by 2050. The AMR public health issue has led to the development of action plans to combat AMR, including improved antimicrobial stewardship, development of new antimicrobials, and advanced monitoring. The National Antimicrobial Resistance Monitoring System (NARMS) led by the United States (U.S) Food and Drug Administration along with the U.S. Centers for Disease Control and U.S. Department of Agriculture has monitored antimicrobial resistant bacteria in retail meats, humans, and food animals since the mid 1990's. NARMS is currently exploring an integrated One Health monitoring model recognizing that human, animal, plant, and environmental systems are linked to public health. Since 2020, the U.S. Environmental Protection Agency has led an interagency NARMS environmental working group (EWG) to implement a surface water AMR monitoring program (SWAM) at watershed and national scales. The NARMS EWG divided the development of the environmental monitoring effort into five areas: (i) defining objectives and questions, (ii) designing study/sampling design, (iii) selecting AMR indicators, (iv) establishing analytical methods, and (v) developing data management/analytics/metadata plans. For each of these areas, the consensus among the scientific community and literature was reviewed and carefully considered prior to the development of this environmental monitoring program. The data produced from the SWAM effort will help develop robust surface water monitoring programs with the goal of assessing public health risks associated with AMR pathogens in surface water (e.g., recreational water exposures), provide a comprehensive picture of how resistant strains are related spatially and temporally within a watershed, and help assess how anthropogenic drivers and intervention strategies impact the transmission of AMR within human, animal, and environmental systems.
Spaceflight induces molecular, cellular, and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet, current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools, and protocols. Here, we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular, and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, plus Axiom and Polaris. The SOMA resource represents a >10-fold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiome data sets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation, and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific murine data sets. Leveraging the datasets, tools, and resources in SOMA can help accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation, and countermeasures data for upcoming lunar, Mars, and exploration-class missions.
In this experimental study, we combine drop impact into porous media and onto a single fiber to study drop impact into fiber arrays inspired by mammalian fur coats. In our 3D-printed arrays, we vary the packing density, fiber alignment, strand cross-section, and wettability. Drops impact fibers fixed at both ends, penetrating over short periods of time by momentum and laterally spreading throughout the array. Using image analysis, we measure penetration depth and wetted width into the array. Impact Weber number and intrinsic porosity define penetration, retraction, and rebound regimes. On average, at an impact Weber number of ≈80, staggered fibers reduce penetration by 24% in hydrophilic fibers and 34% in hydrophobic fibers, and the penetration reduction percentage is expected to increase with increasing Weber number. Our results indicate that as density grows toward the density of mammalian pelts, penetration will reach a maximum value independent of drop impact velocity, thereby providing an effective rain barrier. Hydrophilicity at the densities we test, 50-150 strands/cm2, aids fiber array resistance to dynamic penetration by impacting drops through the promotion of lateral drop spreading and inhibition of drop fragmentation. Conversely, hydrophobic fibers best resist low-speed wicking. The fraction of a drop that infiltrates hydrophilic and hydrophobic fibers is nearly identical for a fixed Weber number because lateral spreading restricts the penetration depth into hydrophilic fibers but does not restrict mass infiltration. Above a critical Weber number, the entire drop mass penetrates fiber arrays regardless of strand wettability.
PURPOSE: The development of acute kidney injury (AKI) after the acute respiratory distress syndrome (ARDS) reduces the chance of organ recovery and survival. The purpose of this study was to examine the AKI rate and attributable mortality in ARDS patients. METHODS: We performed an individual patient-data analysis including 10 multicenter randomized controlled trials conducted over 20 years. We employed a Super Learner ensemble technique, including a time-dependent analysis, to estimate the adjusted risk of AKI. We calculated the mortality attributable to AKI using an inverse probability of treatment weighting estimator integrated with the Super Learner. RESULTS: There were 5148 patients included in this study. The overall incidence of AKI was 43.7% (n = 2251). The adjusted risk of AKI ranged from 38.8% (95% confidence interval [CI], 35.7 to 41.9%) in ARMA, to 55.8% in ROSE (95% CI, 51.9 to 59.6%). 37.1% recovered rapidly from AKI, with a significantly lower recovery rate in recent trials (P < 0.001). The 90-day excess in mortality attributable to AKI was 15.4% (95% CI, 12.8 to 17.9%). It decreased from 25.4% in ARMA (95% CI, 18.7 to 32%), to 11.8% in FACTT (95% CI, 5.5 to 18%) and then remained rather stable over time. The 90-day overall excess in mortality attributable to acute kidney disease was 28.4% (95% CI, 25.3 to 31.5%). CONCLUSIONS: The incidence of AKI appears to be stable over time in patients with ARDS enrolled in randomized trials. The development of AKI remains a significant contributing factor to mortality. These estimates are essential for designing future clinical trials for AKI prevention or treatment.
With the improvement in the detection of congenital heart disease in fetal life, fetal cardiac interventions are pushing the envelope in hopes of either altering the natural history of disease or improving survival in certain high-risk lesions. These interventions include fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome, fetal atrial septoplasty with or without atrial septal stenting for hypoplastic left heart syndrome and variants with intact or severely restrictive atrial septum, and fetal pulmonary valvuloplasty for severe pulmonary stenosis or pulmonary atresia with intact ventricular septum. This review discusses their indications, technical aspects, and outcomes based on available literature.
Fetal Heart , Heart Defects, Congenital , Humans , Heart Defects, Congenital/surgery , Pregnancy , Female , Fetal Heart/surgery , Ultrasonography, Prenatal/methods , Cardiac Surgical Procedures/methods , Pulmonary Atresia/surgery , Fetal Diseases/surgery , Fetal Diseases/diagnosis , Treatment Outcome
Phospholipids are asymmetrically distributed at the plasma membrane. This asymmetric lipid distribution is transiently altered during calcium-regulated exocytosis but the impact of this transient remodeling on presynaptic function is currently unknown. As PhosphoLipid SCRamblase 1 (PLSCR1) randomizes phospholipid distribution between the two leaflets of the plasma membrane in response to calcium activation, we set out to determine its role in neurotransmission. We report here that PLSCR1 is expressed in cerebellar granule cells (GrCs) and that PLSCR1-dependent phosphatidylserine egress occurred at synapses in response to neuron stimulation. Synaptic transmission is impaired at GrC Plscr1 -/- synapses and both PS egress and synaptic vesicle endocytosis are inhibited in Plscr1 -/- cultured neurons from male and female mice, demonstrating that PLSCR1 controls phospholipid asymmetry remodeling and synaptic vesicle retrieval following neurotransmitter release. Altogether, our data reveal a novel key role for PLSCR1 in synaptic vesicle recycling and provide the first evidence that phospholipid scrambling at the plasma membrane is a prerequisite for optimal presynaptic performance.Significance statement During calcium-regulated exocytosis, phospholipids like phosphatidylserine (PS) undergo dynamic remodeling. Phospholipid Scramblase-1 (PLSCR1) belongs to a family of proteins able to randomize lipids at the cell surface in response to intracellular Ca2+ increases. Whether PLSCR1 and PS egress have a role during neurotransmission is unknown. We show that PLSCR1 expression is restricted to specific brain regions capable of sustaining neurotransmission during high firing rates. In the absence of PLSCR1, synaptic transmission is impaired, and both PS egress and synaptic vesicle endocytosis are hindered. This study highlights the pivotal role of PLSCR1 in regulating optimal presynaptic performance by redistributing phospholipid at the plasma membrane to control compensatory endocytosis.
Personal names are a universal feature of human language, yet few analogues exist in other species. While dolphins and parrots address conspecifics by imitating the calls of the addressee, human names are not imitations of the sounds typically made by the named individual. Labelling objects or individuals without relying on imitation of the sounds made by the referent radically expands the expressive power of language. Thus, if non-imitative name analogues were found in other species, this could have important implications for our understanding of language evolution. Here we present evidence that wild African elephants address one another with individually specific calls, probably without relying on imitation of the receiver. We used machine learning to demonstrate that the receiver of a call could be predicted from the call's acoustic structure, regardless of how similar the call was to the receiver's vocalizations. Moreover, elephants differentially responded to playbacks of calls originally addressed to them relative to calls addressed to a different individual. Our findings offer evidence for individual addressing of conspecifics in elephants. They further suggest that, unlike other non-human animals, elephants probably do not rely on imitation of the receiver's calls to address one another.
The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self-controlled estimates were adjusted using negative cases (external "control" DOAC users with the same outcomes but co-dispensings for non-interacting AHDs or ASMs). Signal thresholds were set based on P-values and false discovery rate q-values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self-controlled assessments with q-value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the P-value threshold and no signals from the q-value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with P-value thresholds yielded 3 3DI and 26 DDI signals following self-control, as well as 4 3DI signals following adjustment. No 3DI signals met the q-value threshold. The presented self- and externally-controlled approach aimed to advance paradigms for real-world higher order drug interaction screening among high-susceptibility populations with pre-existent DDI risk.
PURPOSE: A previously published method for MRI-based transfer function assessment makes use of the so-called transceive phase assumption (TPA). This limits its applicability to shorter leads and/or lower field strengths. A new method is presented where the background electric field is determined from both B 1 + $$ {\mathrm{B}}_1^{+} $$ - and B 1 - $$ {\mathrm{B}}_1^{-} $$ -field distributions, avoiding the TPA and making it more generally applicable. THEORY AND METHODS: These B 1 $$ {\mathrm{B}}_1 $$ -distributions are determined from a spoiled gradient echo multiflip angle acquisition. From the separated B 1 $$ {\mathrm{B}}_1 $$ -components the background electrical field and the induced current are computed. Further improvement is achieved by recasting the B 1 $$ {\mathrm{B}}_1 $$ -field model as a "magnitude squared least squares" problem. The proposed reconstruction method is used to determine transfer functions of various copper wire lengths up to 40 cm inside an elliptical ASTM phantom. The method is first tested on EM-simulated data and subsequently phantom and bench measurements are used to determine transfer functions experimentally. RESULTS: In silica reconstructions demonstrate the validity of the proposed B 1 $$ {\mathrm{B}}_1 $$ -field model resulting in highly accurate reconstructed B 1 $$ {\mathrm{B}}_1 $$ -fields, currents, incident electric fields and transfer functions. The experimental results show slight deviations in the field model, however, resulting transfer functions are accurately determined with high similarity to simulations and comparable to bench measurements. CONCLUSION: A more generally applicable method for MRI-based transfer function assessment is presented. The proposed method circumvents phase assumptions making it applicable for longer objects and/or higher field strengths. Additional improvements are implemented in the B 1 $$ {\mathrm{B}}_1 $$ -mapping method and the solution algorithm.
OBJECTIVE: Tibial tubercle avulsion fractures (TTAFs) represent 0.4% to 2.7% of pediatric physeal injuries. These injuries are thought to confer a risk of acute compartment syndrome (ACS), and these patients are often admitted for compartment monitoring and, in many cases, undergo prophylactic fasciotomy. This study sought to review our institution's experience with TTAF and associated compartment syndrome in pediatric patients. METHODS: All patients aged 8 to 18 years with TTAF at our institution from January 1, 2017 to January 1, 2023 were retrospectively reviewed. Patient demographics, injury mechanism, fracture morphology, and postinjury course were reviewed. ACS was diagnosed by clinical exam or necessitating therapeutic compartment fasciotomy. RESULTS: A total of 49 TTAFs in 47 patients were included in the final analysis. The mean age was 14.5 ± 1.2 years (range: 11 to 17), and males were significantly older than females (14.6 ± 1.1 vs 13.3 ± 1.3 y, P = 0.01). The average body mass index was 27.1 ± 7.0, and males had a significantly lower body mass index than females (26.3 ± 6.5 vs 34.1 ± 8.5, P = 0.03). Basketball was the most common mechanism of injury (49%), followed by soccer (13%), football (11%), trampoline (6%), fall (6%), jumping (4%), lacrosse (4%), running (4%), and softball (2%). The Ogden fracture types were as follows: I: 10%; II: 16%; III: 41%; IV: 24%; V: 8%. Thirty-four patients (69%) were admitted to the hospital for at least one night after presentation. Forty-six (96%) underwent surgical fixation an average of 3.5 days after injury. No patients developed ACS during their post-injury or postoperative course. Three patients underwent the removal of hardware. No other complications were observed. The average follow-up duration was 238 days. CONCLUSIONS: The results of this study suggest that the risk of ACS in pediatric patients with TTAF may be small enough to allow for same-day discharge after diagnosis or operative management in patients deemed to be sufficiently low risk by clinical judgment. LEVEL OF EVIDENCE: Level III-retrospective comparative study.
Complement-mediated hemolytic uremic syndrome (CM-HUS) is a thrombotic microangiopathy characterized by germline variants or acquired antibodies to complement proteins and regulators. Building upon our prior experience with the modified Ham (mHam) assay for ex vivo diagnosis of complementopathies, we have developed an array of cell-based complement "biosensors'' by selective removal of complement regulatory proteins (CD55 and CD59, CD46, or a combination thereof) in an autonomously bioluminescent HEK293 cell line. These biosensors can be used as a sensitive method for diagnosing CM-HUS and monitoring therapeutic complement blockade. Using specific complement pathway inhibitors, this model identifies IgM-driven classical pathway stimulus during both acute disease and in many patients during clinical remission. This provides a potential explanation for ~50% of CM-HUS patients who lack an alternative pathway "driving" variant and suggests at least a subset of CM-HUS is characterized by a breakdown of IgM immunologic tolerance. Key Points: CM-HUS has a CP stimulus driven by polyreactive IgM, addressing the mystery of why 40% of CM-HUS lack complement specific variantsComplement biosensors and the bioluminescent mHam can be used to aid in diagnosis of CM-HUS and monitor complement inhibitor therapy.
Polarization of drift-Alfvén waves, defined as the ratio of electrostatic to electromagnetic fluctuations, has remained unmeasurable in fusion plasmas for decades, despite its pivotal role in understanding wave dynamics and their impact on plasmas. We report the first measurements of drift-Alfvén wave polarization in a hot, magnetically confined plasma. The breakthrough is enabled by a novel methodology developed from gyrokinetic theory, utilizing fluctuations of electron temperature and density. Analysis of data from the DIII-D tokamak reveals that the waves above the geodesic acoustic mode frequency exhibit dominant electromagnetic polarization, whereas lower-frequency waves show a mix of electromagnetic and electrostatic polarization, indicating a strong coupling between shear Alfvén waves and drift-acoustic waves.
Organic synthesis often requires multiple steps where a functional group (FG) is concealed from reaction by a protecting group (PG). Common PGs include N-carbobenzyloxy (Cbz or Z) of amines and tert-butyloxycarbonyl (OtBu) of acids. An essential step is the removal of the PG, but this often requires excess reagents, extensive time and can have low % yield. An overarching goal of biocatalysis is to use "green" or "enzymatic" methods to catalyse chemical transformations. One under-utilised approach is the use of "deprotectase" biocatalysts to selectively remove PGs from various organic substrates. The advantage of this methodology is the exquisite selectivity of the biocatalyst to only act on its target, leaving other FGs and PGs untouched. A number of deprotectase biocatalysts have been reported but they are not commonly used in mainstream synthetic routes. This study describes the construction of a cascade to deprotect doubly-protected amino acids. The well known Bacillus BS2 esterase was used to remove the OtBu PG from various amino acid substrates. The more obscure Sphingomonas Cbz-ase (amidohydrolase) was screened with a range of N-Cbz-modified amino acid substrates. We then combined both the BS2 and Cbz-ase together for a 1 pot, 2 step deprotection of the model substrate CBz-L-Phe OtBu to produce the free L-Phe. We also provide some insight into the residues involved in substrate recognition and catalysis using docked ligands in the crystal structure of BS2. Similarly, a structural model of the Cbz-ase identifies a potential di-metal binding site and reveals conserved active site residues. This new biocatalytic cascade should be further explored for its application in chemical synthesis.
BACKGROUND: A sport-related concussion (SRC) is a common injury that affects multiple clinical domains such as cognition, balance, and nonspecific neurobehavioral symptoms. Although multidimensional clinical assessments of concussion are widely accepted, there remain limited empirical data on the nature and clinical utility of distinct clinical profiles identified by multimodal assessments. PURPOSE: Our objectives were to (1) identify distinct clinical profiles discernible from acute postinjury scores on the Sport Concussion Assessment Tool (SCAT), composed of a symptom checklist, a cognitive assessment (Standardized Assessment of Concussion), and a balance assessment (Balance Error Scoring System), and (2) evaluate the clinical utility of the identified profiles by examining their association with injury characteristics, neuropsychological outcomes, and clinical management-related outcomes. STUDY DESIGN: Cohort study (Prognosis); Level of evidence, 2. METHODS: Up to 7 latent profiles were modeled for 1885 collegiate athletes and/or military cadets who completed the SCAT at 0 to 12 hours after an injury. Chi-square tests and general linear models were used to compare identified profiles on outcomes at 12 to 72 hours after the injury. Kaplan-Meier analysis was used to investigate associations between clinical profiles and time to return to being asymptomatic and to return to play. RESULTS: There were 5 latent profiles retained: low impairment (65.8%), high cognitive impairment (5.4%), high balance impairment (5.8%), high symptom severity (16.4%), and global impairment (6.5%). The latent profile predicted outcomes at 12 to 72 hours in expectable ways (eg, the high balance impairment profile demonstrated worse balance at 12 to 72 hours after the injury). Time to return to being asymptomatic and to return to play were different across profiles, with the high symptom severity and global impairment profiles experiencing the longest recovery and the high balance impairment profile experiencing an intermediate-length recovery (vs low impairment profile). CONCLUSION: An SRC is a heterogeneous injury that presents in varying ways clinically in the acute injury period and results in different recovery patterns. These data support the clinical prognostic value of diverse profiles of impairment across symptom, cognitive, and balance domains. By identifying distinct profiles of an SRC and connecting them to differing outcomes, the findings support more evidence-based use of accepted multimodal clinical assessment strategies for SRCs.
Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits V Ì O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.
BACKGROUND: Sleeve gastrectomy (SG) is an effective treatment option for patients with obesity. Robotic sleeve gastrectomy (RSG) is reported to have worse short-term patient outcomes compared to laparoscopic SG (LSG), but prior studies may not have accounted for evolving technology, including stapler utilization. OBJECTIVE: This study compared RSG and LSG outcomes over different time periods. SETTING: Academic Hospital. MATERIAL AND METHODS: The 2015 to 2021 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Project (MBSAQIP) databases were used. Matched cohort analyses compared adverse outcomes within 30 days for the 2015-2018 and 2019-2021 cohorts. Bivariate and regression models compared cohorts using Stata/MP 17.0. RESULTS: Seven hundred sixty-eight thousand and sixty-nine SG were analyzed. Over the 7-year study period, all patient outcomes, operation length (OL), and length of stay (LOS) trended downward for RSG, except surgical site infection (SSI). In the 2015-2018 cohort, leak was significantly higher with RSG (OR 1.53), and OL and LOS longer (p < 0.001). In the 2019-2021 cohort which corelated with a significant increase in robotic cases, leak (OR 1.36), SSI (OR 1.46), and morbidity (OR 1.11) were higher with RSG. While the mean difference in OL and LOS decreased between the two time periods, they remain longer for RSG (p < 0.001). CONCLUSION: While RSG and LSG are safe with similar mortality, RSG continues to be associated with higher rates of morbidity, leak, and SSI, as well as longer OL, hospital LOS, and higher cost. The study is limited by the ability to account for the impact of surgeon experience and stapler utilization on outcomes.
Metastasis to the brain is a frequent complication of advanced melanoma. Historically, patients with melanoma brain metastasis (MBM) have had dismal outcomes, but outcomes have improved with the development of more effective treatments, including stereotactic radiosurgery and effective immune and targeted therapies. Despite these advances, MBM remains a leading cause of death from this disease, and many therapies show decreased efficacy against these tumors compared with extracranial metastases. This differential efficacy may be because of recently revealed unique molecular and immune features of MBMs-which may also provide rational new therapeutic strategies.
Hereditary haemorrhagic telangiectasia is a genetic condition of abnormal blood vessel formation resulting from an imbalance of pro- and anti-angiogenic products of the transforming growth factor ß/bone morphogenetic protein signalling pathway which contributes to vascular remodelling and maintenance. Hepatic vascular malformations are common although less frequently symptomatic, but may result in high-output cardiac failure, portal hypertension and biliary ischaemia. Whilst the understanding of the genetic and cell signalling pathways that are the hallmark of hereditary haemorrhagic telangiectasia have been clarified, there remain challenges in therapy for these patients. Only patients with symptomatic hepatic vascular malformations require treatment, with most (63%) responding to first-line medical therapy. For non-responders, bevacizumab is effective in reducing cardiac output in those with heart failure secondary to hepatic vascular malformations as well as other manifestations of the disease. Although liver transplantation is the only curative option, optimal timing is critical. Novel anti-angiogenetic drugs and those that target aberrant cell signalling pathway are being explored.
Fetal posterior communicating artery (PComA) is a variant of the cerebral vasculature.1 Woven endobridge (WEB) embolization carries a good safety profile as treatment for ruptured wide neck PComA aneurysms, without the need for antiplatelet therapy. However, the reported occlusion rates are not optimal.2 Flow diversion is suboptimal in treating aneurysms originating from fetal PComA.3 Here we present a case of a 78-year-old female patient with a history of ruptured right fetal PComA aneurysm with wide base. It was initially treated with WEB embolization at an outside hospital. After WEB implantation, the initial follow-up of cerebral angiogram (6 months later) demonstrated a neck recurrence measuring 6 × 3 mm. Approximately 1 year after the initial treatment, pipeline embolization was performed and patient was placed on antiplatelet therapy since. Follow-up images demonstrated a 6 mm × 4 mm persistent neck remnant. Her care was transferred to our institution. Cerebral angiogram obtained 36 months post-WEB implantation showed growth of the neck remnant measuring 9 × 8.5 mm. The WEB device was found to be folded in the aneurysmal fundus. Given this was a growing recurrent previously ruptured fetal PComA aneurysm with a pipeline stent in the internal carotid artery the decision was made to retreat with microsurgical clipping; carotid access at the neck was required for proximal control. We achieved complete aneurysm obliteration through a minimal invasive approach. The patient gave informed consent for surgery and video recording. Institutional Review Board approval was deemed unnecessary.
