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STUDY DESIGN: Retrospective cohort. PURPOSE: To assess preoperative arm pain severity influence on postoperative patient-reported outcomes measures (PROMs) and minimal clinically important difference (MCID) achievement following single-level anterior cervical discectomy and fusion (ACDF). OVERVIEW OF LITERATURE: There is evidence that preoperative symptom severity can affect postoperative outcomes. Few have evaluated this association between preoperative arm pain severity and postoperative PROMs and MCID achievement following ACDF. METHODS: Individuals undergoing single-level ACDF were identified. Patients were grouped by preoperative Visual Analog Scale (VAS) arm ≤8 vs. >8. PROMs collected preoperatively and postoperatively included VAS-arm/VAS-neck/Neck Disability Index (NDI)/12-item Short Form (SF-12) Physical Composite Score (PCS)/SF-12 mental composite score (MCS)/Patient-Reported Outcomes Measurement Information System physical function (PROMIS-PF). Demographics, PROMs, and MCID rates were compared between cohorts. RESULTS: A total of 128 patients were included. The VAS arm ≤8 cohort significantly improved for all PROMs excepting VAS arm at 1-year/2-years, SF-12 MCS at 12-weeks/1-year/2-years, and SF-12 PCS/PROMIS-PF at 6-weeks, only (p ≤0.021, all). The VAS arm >8 cohort significantly improved for VAS neck at all timepoints, VAS arm from 6-weeks to 1-year, NDI from 6-weeks to 6-months, and SF-12 MCS/PROMIS-PF at 6-months (p ≤0.038, all). Postoperatively, the VAS arm >8 cohort had higher VAS-neck (6 weeks/6 months), VAS-arm (12 weeks/6 months), NDI (6 weeks/6 months), lower SF-12 MCS (6 weeks/6 months), SF-12 PCS (6 months), and PROMISPF (12 weeks/6 months) (p ≤0.038, all). MCID achievement rates were higher among the VAS arm >8 cohort for the VAS-arm at 6-weeks/12-weeks/1-year/overall and NDI at 2 years (p ≤0.038, all). CONCLUSIONS: Significance in PROM score differences between VAS arm ≤8 vs. >8 generally dissipated at the 1-year and 2-year timepoint, although higher preoperative arm pain patients suffered from worse pain, disability, and mental/physical function scores. Furthermore, clinically meaningful rates of improvement were similar throughout the vast majority of timepoints for all PROMs studied.
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BACKGROUND: Existing literature has not yet evaluated the impact of postoperative length of stay (LOS) on patient-reported outcome measures (PROMs) and minimum clinically important difference (MCID) in patients undergoing anterior lumbar interbody fusion (ALIF). The authors investigates the influence of postoperative LOS following ALIF on PROMs and MCID achievement rates. METHODS: A single-surgeon database was retrospectively reviewed for patients undergoing single-level ALIF. The following 2 cohorts were studied: patients with LOS <45 hours and patients with LOS ≥45 hours. The following PROMs were recorded at preoperative and 6-week, 12-week, 6-month, 1-year, and 2-year postoperative timepoints: visual analog scale (VAS) back and leg, Oswestry Disability Index (ODI), 12-item short form (SF-12) physical composite score (PCS), and patient-reported outcome measurement information system physical function. MCID achievement was compared by LOS grouping using χ 2 analysis. The rates of complications by LOS grouping and the relative risk among demographic and perioperative characteristics for a longer hospital stay of ≥45 hours were calculated. RESULTS: A total of 52 subjects were included in each cohort. LOS ≥45 hours demonstrated worse ODI at 6 weeks and SF-12 PCS preoperative and at 12 weeks (P ≤ 0.026, all). LOS <45 hours demonstrated greater MCID rates for all PROMs except VAS back (P ≤ 0.004, all). Postoperative urinary retention (POUR), fever, and total complications (P ≤ 0.003, all) were associated with increased LOS. Diabetes (P = 0.037), preoperative VAS neck ≥7 (P = 0.012), and American Society of Anesthesiologists classification ≥2 (P = 0.003) served as preoperative risk factors for postoperative stay ≥45 hours. CONCLUSION: Following single-level ALIF, patients with shorter LOS demonstrated significantly greater overall MCID achievement for most PROMs. POUR, fever, and total complications were associated with longer LOS and greater blood loss. Diabetes and higher preoperative leg pain were identified as risk factors for longer LOS. CLINICAL RELEVANCE: Patients undergoing ALIF with shorter LOS had greater MCID achievement for disability, physical function, and leg pain outcomes. Patients with greater preoperative leg pain and diabetes may be at risk for longer LOS.
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BACKGROUND: Increased morbidity associated with obesity imposes a greater financial burden on companies that provide insurance to their employees. Few studies have investigated the relationship between body mass index (BMI) and patient-reported outcome measures (PROMs) for minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) in the workers' compensation (WC) population. METHODS: WC patients who underwent a primary, single-level MIS TLIF were included/grouped according to BMI: nonobese (<30 kg/m2); obese I (≥30, <35 kg/m2); severe + morbid (≥35). PROMs were collected pre- and postoperatively: visual analog scale (VAS), Oswestry Disability Index (ODI), 12-Item Short Form (SF-12) physical composite score (PCS), and Patient-Reported Outcome Measurement Information System physical function (PROMIS-PF). BMI predictive power grouping on PROMs was evaluated using simple linear regression. Established minimum clinically important difference values were used to compute achievement rates across PROMs using logistic regression. RESULTS: A total of 116 nonobese, 70 obese I, and 61 severe + morbid patients were included. Demographics among BMI grouping significantly differed in gender, hypertensive status, and American Society of Anesthesiologists score (P ≤ 0.037, all). Operative time was significantly different in perioperative values among BMI grouping (P ≤ 0.001). Increased BMI was significantly associated with greater VAS back at 12 weeks and 2 years (P ≤ 0.026, all), greater ODI preoperatively at 12 weeks and 6 months (P ≤ 0.015, all), and decreased PROMIS-PF at 12 weeks (P ≤ 0.011, all). Mean PROMs between obese I and severe + morbid cohorts differed in SF-12 PCS at 12 weeks, only (P = 0.050). ODI overall was the only parameter for which minimum clinically important difference was achieved among BMI cohorts (P ≤ 0.023). CONCLUSION: WC patients with increased BMI were more likely to develop significant back pain and disability at numerous postoperative timepoints compared with nonobese individuals. Our findings highlight the weight management importance within WC population to minimize back pain and disability following MIS TLIF, but provide a sense of reassurance with comparable clinical improvement regardless of BMI. CLINICAL RELEVANCE: When considering the effect of weight, surgeons may incorporate these findings in managing patient expectations in the WC population undergoing lumbar spine surgery.
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OBJECTIVE: To determine the association between patient-reported depressive symptoms and patient satisfaction following minimally invasive lumbar decompression. METHODS: Primary, single-level/multilevel minimally invasive lumbar decompression was identified. Patient-reported outcome measures (PROMs) collected preoperatively/postoperatively included visual analog scale back/leg, Oswestry Disability Index, 9-Item Patient Health Questionnaire (PHQ-9), and 12-Item Short Form Mental Composite Score (SF-12 MCS). Patients rated current satisfaction level (0-10) with back/leg pain and disability. A paired Student's t-test compared each postoperative PROM score to its preoperative baseline. At each timepoint, patients were categorized by PHQ-9 and SF-12 MCS scores. One-way analysis of variance compared patient satisfaction with back/leg pain and disability among PHQ-9 subgroups. The Student's t-test for independent samples compared patient satisfaction between SF-12 MCS subgroups. Analysis of covariance (ANCOVA) assessed differences in satisfaction between depression subgroups while controlling for preoperative/postoperative values in corresponding PROMs. RESULTS: 193 patients were included. All PROMs demonstrated significant postoperative improvement from 6-weeks through 2-years (P < 0.001, all), except PHQ at 9 2-years (P = 0.874). Mean satisfaction scores ranged from 6.9-7.9 (back pain), 7.3-8.0 (leg pain), and 7.6-8.0 (disability). Satisfaction with back/leg pain and disability significantly differed among PHQ-9 subgroups at all postoperative timepoints (P < 0.001, all). Accounting for baseline and current pain/disability values, ANCOVA revealed differences between PHQ-9 subgroups only in satisfaction with back pain at 2 years (P < 0.001), leg pain at 12 weeks/1 year/2 years (P ≤ 0.047, all), and disability at 6 months/2 years (P ≤ 0.049, both). Satisfaction differed between SF-12 MCS subgroups at all timepoints (P ≤ 0.047), except back pain 6 months (P = 0.263). Accounting for baseline and postoperative pain/disability, ANCOVA revealed differences in satisfaction between SF-12 MCS groups only for back/leg pain at 2 years (P ≤ 0.001, both). CONCLUSIONS: Independent effect of depression at long-term follow-up was significant. This highlights the importance of understanding the interaction between physical and mental health outcomes to optimize patients' perceptions of surgical outcomes.
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Satisfação do Paciente , Fusão Vertebral , Dor nas Costas/cirurgia , Descompressão , Humanos , Vértebras Lombares/cirurgia , Saúde Mental , Resultado do TratamentoRESUMO
BACKGROUND: As a result of increased practicality and decreased costs and radiation, interest has increased in intraoperative ultrasonography (iUS) in spinal surgery applications; however, few studies have provided a robust overview of its use in spinal surgery. We synthesize findings of existing literature on use of iUS in navigation, pedicle screw placement, and identification of anatomy during spinal interventions. METHODS: PRISMA guidelines were used in this systematic review. Studies were identified through PubMed, Scopus, and Google Scholar databases using the search string. Abstracts mentioning iUS in spine applications were included. On full-text review, exclusion criteria were implemented, including outdated studies or those with weak topic relevance or statistical power. On elimination of duplicates, multireviewer screening for eligibility, and citation search, 44 articles were analyzed. RESULTS: Navigation using iUS is safe, effective, and economical. iUS registration accuracy and success are within clinically acceptable limits for image-guided navigation. Pedicle screw instrumentation with iUS is precise, with a favorable safety profile. Anatomic landmarks are reliably identified with iUS, and surgeons are overwhelmingly successful in neural or vascular tissue identification with iUS modalities, including standard B mode, Doppler, and contrast-enhanced ultrasonography. iUS use in traumatic reduction of fractures properly identifies anatomic structures, intervertebral disc space, and vasculature. CONCLUSIONS: iUS eliminates radiation, decreases costs, and provides sufficient accuracy and reliability in identification of anatomic and neurovascular structures in various spinal surgery settings.
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Parafusos Pediculares , Fusão Vertebral , Cirurgia Assistida por Computador , Humanos , Reprodutibilidade dos Testes , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/cirurgia , UltrassonografiaRESUMO
Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydropyrrolone analogs leading to the identification of potent pan-Pim inhibitor 28 with improved potency, solubility, and drug-like properties. Compound 28 demonstrated on-target Pim activity in an in vivo pharmacodynamic assay with significant inhibition of BAD phosphorylation in KMS-12-BM multiple myeloma tumors for 16 h postdose. In a 2-week mouse xenograft model, daily dosing of compound 28 resulted in 33% tumor regression at 100 mg/kg.
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Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirróis/uso terapêutico , Quinazolinonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Feminino , Humanos , Camundongos SCID , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Relação Estrutura-Atividade , Suínos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.
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Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirróis/farmacologia , Quinazolinonas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Pirróis/administração & dosagem , Pirróis/química , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization and developed a series of 13-membered macrocycles. The structure-activity relationships of the macrocyclic linker were systematically explored, leading to the identification of 9c as a potent, subnanomolar inhibitor of Pim-1 and -2. This molecule also potently inhibited Pim kinase activity in KMS-12-BM, a multiple myeloma cell line with relatively high endogenous levels of Pim-1/2, both in vitro (pBAD IC50 = 25 nM) and in vivo (pBAD EC50 = 30 nM, unbound), and a 100 mg/kg daily dose was found to completely arrest the growth of KMS-12-BM xenografts in mice.
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High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole-thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound's potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55nM and 0.28nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50=150nM). This compound had moderate clearance and bioavailability in rat (CL=2.42L/kg/h; %F=24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74µM (18µg/mL) when dosed at 10, 30, 100 and 200mg/kg po in mice.
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Oxidiazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Cristalografia por Raios X , Descoberta de Drogas , Estrutura Molecular , Oxidiazóis/químicaRESUMO
The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.
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Indazóis/química , Indazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Descoberta de Drogas , Humanos , Relação Estrutura-AtividadeRESUMO
This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.
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Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/prevenção & controle , Colágeno , Cães , Desenho de Fármacos , Descoberta de Drogas , Histamina , Indicadores e Reagentes , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Moleculares , Prurido/induzido quimicamente , Prurido/prevenção & controle , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos , Receptores Histamínicos H4 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossínteseRESUMO
γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aß42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aß42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described.
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Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Picolinas/farmacologia , Doença de Alzheimer/enzimologia , Amidas/química , Animais , Células HEK293 , Humanos , Picolinas/química , Ratos , Ratos Sprague-DawleyRESUMO
This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.