The Feinstein Institutes for Medical Research comprise the research arm of Northwell Health. Feinstein is home to 50 research labs, 2,500 clinical research studies, and 5,000 professional and support staff. Feinstein scientists conduct research in molecular medicine, genetics, cancer, brain research, mental health, autoimmunity and bioelectronic medicine, among others. Feinstein is the laboratory and faculty home of the Elmezzi Graduate School of Molecular Medicine. Students without an MD degree may earn a PhD in molecular medicine via the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, as part of the medical school's MD/PhD or PhD programs.The Feinstein Institutes acquired assets from the closing of the Picower Institute for Medical Research, founded in 1991 by Anthony Cerami and funded by Jeffry Picower. In 2001 the institute's funding was withdrawn and it closed; in 2002 it was acquired by The Institute for Medical Research at North Shore-LIJ. In 2005 board member Leonard Feinstein, co-founder of Bed Bath & Beyond, made a $25 million gift that led to its renaming The Feinstein Institute for Medical Research. In 2016, Feinstein and his wife, Susan, committed another $25 million.[citation needed]In 2019, Feinstein comprised 5 institutes:Feinstein publishes two open-access, international peer-reviewed medical journals in partnership with BioMed Central, part of Springer Nature: Molecular Medicine and Bioelectronic Medicine.The Feinstein Institutes bestow two major academic awards: the Anthony Cerami Award in Translational Medicine, starting in 2013, and the Ross Prize in Molecular Medicine.
OBJECTIVE:A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN:Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING:Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS:A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS:A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS:A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.
OBJECTIVE:Using a hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust the HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. METHODS:This observational study included patients (N = 2,010) across the Systemic Lupus International Collaborating Clinics, Wisconsin, international, and French studies who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified an HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for the Systemic Lupus Erythematosus Disease Activity Index 2000 [score ≥6]). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. RESULTS:Among 1,842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ-related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1,150 ng/mL and 1.7-fold higher with the cumulative HCQ dose per 1,000-g increase. Blood levels ≥1,150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1,150 ng/mL). CONCLUSION:The therapeutic reference range for HCQ blood level monitoring is 750 to <1,150 ng/mL. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.
OBJECTIVE:This study aimed to compare the performance of the Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL), British Isles Lupus Assessment Group Index (BILAG), and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in detecting the clinician's perception of improvement and worsening disease and identifying patients requiring treatment escalation. METHODS:This was a prospective, observational study conducted at four centers. Adults with systemic lupus erythematosus were evaluated at a baseline and follow-up visit. Disease activity was assessed using SLEDAI, BILAG, and LFA-REAL at both visits by the same physician. At the follow-up visit, the Clinician Global Impression of Change (CGIC) was recorded to classify patients as improved, worsened, or unchanged. Receiver operating characteristic curve analysis was used to evaluate each instrument in detecting clinician-rated change gauged by CGIC with optimal cut-off points determined using the Youden Index. RESULTS:Of the 163 patients enrolled, 145 (89%) completed a follow-up visit. Based on CGIC, 23% improved, 16% worsened, and 61% remained stable. For detecting CGIC-defined improvement, LFA-REAL had an area under the curve (AUC) of 0.85 (95% confidence interval [CI] 0.77-0.92), compared to 0.75 (95% CI 0.66-0.85) for BILAG and 0.74 (95% CI 0.64-0.84) for SLEDAI. For CGIC-defined worsening, AUCs were 0.86 (95% CI 0.77-0.96), 0.79 (95% CI 0.67-0.90), and 0.76 (95% CI 0.66-0.87). Of those with CGIC-defined worsening, eight (35%) required treatment escalation. LFA-REAL identified a difference of ≥10 mm in all eight of these patients, compared to four by BILAG and two by SLEDAI. CONCLUSION:LFA-REAL showed comparable performance relative to SLEDAI and BILAG in detecting clinician-rated change. There was a statistically significant advantage over SLEDAI for detection of improvement. These findings support its utility as a metric for disease activity in clinical practice and research.
Objective: To assess the clinical use of the UltraScore balloon in a real-world setting. Methods: This is a prospective, multicenter, single-arm, real-world study to assess the clinical use of the UltraScore balloon for the treatment of stenotic lesions of the superficial femoral artery (SFA), popliteal and below-the-knee (BTK) arteries. A total of 350 subjects were treated with the study device and follow-up was performed at hospital discharge, 30 days, and 6 and 12 months post-index procedure. The primary endpoints were technical success and optimal PTA, defined as ≤30% residual stenosis without major flow-limiting dissection. Secondary endpoints included rate of bail-out stenting, freedom from target lesion revascularization (TLR), freedom from major amputation and clinical improvement measurements. Results: Technical success was 100% and optimal PTA was 72.8%. The rate of bail-out stenting was 4.0%; freedom from TLR was 100% at 30 days, 93.5% at 6 months and 88.2% at 12 months. Freedom from major amputation was 97.4% at 30 days, 94.7% at 6 months and 93.4% at 12 months. Conclusions: This study supports the feasibility and potential clinical utility of the UltraScore balloon when used during the endovascular treatment of stenotic and calcified lesions in the SFA, popliteal and BTK arteries.
Sepsis and rheumatoid arthritis (RA) are distinct yet mechanistically related conditions commonly driven by dysregulated inflammatory responses. Here, we explored the counterintuitive hypothesis that an epitope from a deleterious anti-tetranectin (TN) antibody (mAb9) could hold unforeseen therapeutic potential. By mapping mAb9’s epitope to P2 (residues 55–70), a region crucial for TN’s protective functions, we developed P2-1, a water-soluble derivative as a targeted therapy. We then employed animal models of sepsis (cecal ligation and puncture) and arthritis (collagen antibody-induced arthritis) to evaluate the therapeutic effects of P2, P2-1, and a procathepsin L (pCTS-L)-neutralizing antibody by assessing septic survival, arthritis severity, pain sensitivity, and joint tissue histology. In parallel, we utilized a surface plasmon resonance (SPR) assay and computational modeling to examine the P2-1/high mobility group box 1 (HMGB1) interaction. Finally, we elucidate the effect of P2-1 on the HMGB1-induced release of pCTS-L and other cytokines and chemokines using primary human peripheral blood mononuclear cells (PBMCs). P2-1 significantly improved survival and reduced systemic inflammation in a sepsis model, and attenuated arthritis severity and pain sensitivity in an RA model, even with therapeutic administration after disease onset. Mechanistically, P2-1 exhibited high-affinity binding to HMGB1 and selectively suppressed HMGB1-induced cathepsin L (Ctsl) mRNA upregulation and pCTS-L secretion from human immune cells, crucially without perturbing other HMGB1-induced cytokines and chemokines. We further validated pCTS-L as a therapeutic target by demonstrating that a neutralizing antibody conferred potent antiarthritic effects, reducing joint inflammation, pain, and structural damage. Our findings introduce a paradigm-shifting drug discovery strategy that transforms insights from harmful antibody action into targeted therapeutics for the HMGB1-pCTS-L axis. This approach not only delivers P2-1 as a potent therapy but also establishes pCTS-L as a crucial mediator in inflammatory diseases such as sepsis and RA.
