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Ibrutinib, an antineoplastic agent tackling chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's Macroglobulinemia, falls under the category of BCS class II drugs, characterized by a puzzling combination of low solubility and high permeability. Its oral bioavailability remains a perplexing challenge, merely reaching 2.9 % due to formidable first-pass metabolism hurdles. In a bid to surmount this obstacle, researchers embarked on a journey to develop ibrutinib-loaded NLCs (Nanostructured Lipid Carriers) using a methodology steeped in complexity: a Design of Experiments (DoE)-based hot melted ultrasonication approach. Despite a plethora of methods for analyzing ibrutinib in various matrices, the absence of a spectrofluorimetric method for assessing it in rat plasma added to the enigma. Thus emerged a spectrofluorimetric method, embodying principles of white analytical chemistry and analytical quality by design, employing a Placket-Burman design for initial method exploration and a central composite design for subsequent refinement. This method underwent rigorous validation in accordance with ICH guidelines, paving the way for its application in scrutinizing the in-vivo pharmacokinetics of ibrutinib-loaded NLCs, juxtaposed against commercially available formulations. Surprisingly, the optimized NLCs exhibited a striking 1.82-fold boost in oral bioavailability, shedding light on their potential efficacy. The environmental impact of this method was scrutinized using analytical greenness tools, affirming its eco-friendly attributes. In essence, the culmination of these efforts has not only propelled advancements in drug bioavailability but also heralded the dawn of a streamlined and environmentally conscious analytical paradigm.
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Adenina , Lipídeos , Piperidinas , Pirimidinas , Espectrometria de Fluorescência , Animais , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/química , Adenina/sangue , Piperidinas/farmacocinética , Piperidinas/química , Piperidinas/sangue , Lipídeos/química , Masculino , Espectrometria de Fluorescência/métodos , Ratos , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/sangue , Portadores de Fármacos/química , Nanoestruturas/química , Pirazóis/farmacocinética , Pirazóis/química , Pirazóis/sangue , Pirazóis/administração & dosagem , Reprodutibilidade dos Testes , Ratos WistarRESUMO
Advancements in recombinant DNA technology have made proteins and peptides available for diagnostic and therapeutic applications, but their effectiveness when taken orally leads to poor patient compliance, requiring clinical administration. Among the alternative routes, transmucosal delivery has the advantage of being noninvasive and bypassing hepato-gastrointestinal clearance. Various mucosal routes-buccal, nasal, pulmonary, rectal, and vaginal-have been explored for delivering these macromolecules. Nanofibers, due to their unique properties like high surface-area-to-volume ratio, mechanical strength, and improved encapsulation efficiency, serve as promising carriers for proteins and peptides. These nanofibers can be tailored for quick dissolution, controlled release, enhanced encapsulation, targeted delivery, and improved bioavailability, offering superior pharmaceutical and pharmacokinetic performance compared to conventional methods. This leads to reduced dosages, fewer side effects, and enhanced patient compliance. Hence, nanofibers hold tremendous potential for protein/peptide delivery, especially through mucosal routes. This review focuses on the therapeutic application of proteins and peptides, challenges faced in their conventional delivery, techniques for fabricating different types of nanofibers and, various nanofiber-based dosage forms, and factors influencing nanofiber generation. Insights pertaining to the precise selection of materials used for fabricating nanofibers and regulatory aspects have been covered. Case studies wherein the use of specific protein/peptide-loaded nanofibers and delivered via oral/vaginal/nasal mucosa for diagnostic/therapeutic use and related preclinical and clinical studies conducted have been included in this review.
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Sistemas de Liberação de Medicamentos , Nanofibras , Feminino , Humanos , Sistemas de Liberação de Medicamentos/métodos , Nanofibras/química , Proteínas , Peptídeos , Preparações FarmacêuticasRESUMO
Pleurocutaneous fistula (PCF) is a pathological communication between the pleural space and subcutaneous tissue. This rare condition occurs as a complication of infection, malignancy, and therapeutic procedures such as tube thoracostomies. PCF is typically confirmed with computed tomography (CT) imaging. There is no current literature describing the post-traumatic causes of PCF. We describe a PCF related to multiple rib fractures and its rapid improvement following the placement of a chest tube. This case emphasizes the importance of prompt CT imaging in trauma patients and radiographically illustrates the progression and resolution of a post-traumatic PCF.
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Every year, nearly 60,000 hospitalizations occur in the United States due to chronic pancreatitis (CP). CP can cause severe chronic abdominal pain, pancreatic insufficiency, and increased risk of pancreatic cancer. While venous thrombotic complications are common, arterial thrombotic events are rarely reported in CP. This report describes a case of a 43-year-old female who presented with severe worsening abdominal pain due to CP. Diagnostic imaging disclosed thrombosis of superior mesenteric artery (SMA) and celiac artery (CA) with acute bowel wall changes reflecting ischemic changes, resulting in acute-on-chronic mesenteric ischemia. Endovascular stent placement relieved the ischemia with the resolution of pain. Arterial thrombosis should be considered as a diagnostic possibility when patients with CP present with a significant change in symptoms. Importantly, the case demonstrates that endovascular treatment with stent placement can relieve ischemia and resolve symptoms in patients with CP.
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Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been proven to be an effective means of decreasing COVID-19 mortality, hospitalization rates, and transmission. One of the vaccines deployed worldwide is ChAdOx1 nCoV-19, which uses an adenovirus vector to drive the expression of the original SARS-CoV-2 spike on the surface of transduced cells. Using cryo-electron tomography and subtomogram averaging, we determined the native structures of the vaccine product expressed on cell surfaces in situ. We show that ChAdOx1-vectored vaccines expressing the Beta SARS-CoV-2 variant produce abundant native prefusion spikes predominantly in one-RBD-up conformation. Furthermore, the ChAdOx1-vectored HexaPro-stabilized spike yields higher cell surface expression, enhanced RBD exposure, and reduced shedding of S1 compared to the wild type. We demonstrate in situ structure determination as a powerful means for studying antigen design options in future vaccine development against emerging novel SARS-CoV-2 variants and broadly against other infectious viruses.
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NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis and other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) and other diseases. Structural similarities between NOX's have complicated development of specific inhibitors. Here, we report development of NCATS-SM7270, a small molecule optimized from GSK2795039, that inhibited NOX2 in primary human and mouse granulocytes. NCATS-SM7270 specifically inhibited NOX2 and had reduced inhibitory activity against xanthine oxidase in vitro. We also studied the role of several NOX isoforms during mild TBI (mTBI) and demonstrated that NOX2 and, to a lesser extent, NOX1 deficient mice are protected from mTBI pathology, whereas injury is exacerbated in NOX4 knockouts. Given the pathogenic role played by NOX2 in mTBI, we treated mice transcranially with NCATS-SM7270 after injury and revealed a dose-dependent reduction in mTBI induced cortical cell death. This inhibitor also partially reversed cortical damage observed in NOX4 deficient mice following mTBI. These data demonstrate that NCATS-SM7270 is an improved and specific inhibitor of NOX2 capable of protecting mice from NOX2-dependent cell death associated with mTBI.
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Lesões Encefálicas Traumáticas , NADPH Oxidases , Humanos , Camundongos , Animais , NADPH Oxidase 2/genética , Espécies Reativas de Oxigênio/metabolismo , NADPH Oxidase 4 , NADPH Oxidases/metabolismo , Lesões Encefálicas Traumáticas/tratamento farmacológico , NADPH Oxidase 1/genéticaRESUMO
Preclinical pharmacokinetics (PK) and In Vitro ADME properties of GS-441524, a potential oral agent for the treatment of Covid-19, were studied. GS-441524 was stable in vitro in liver microsomes, cytosols, and hepatocytes of mice, rats, monkeys, dogs, and humans. The plasma free fractions of GS-441524 were 62-78% across all studied species. The in vitro transporter study results showed that GS-441524 was a substrate of MDR1, BCRP, CNT3, ENT1, and ENT2; but not a substrate of CNT1, CNT2, and ENT4. GS-441524 had a low to moderate plasma clearance (CLp), ranging from 4.1 mL/min/kg in dogs to 26 mL/min/kg in mice; the steady state volume distribution (Vdss) ranged from 0.9 L/kg in dogs to 2.4 L/kg in mice after IV administration. Urinary excretion appeared to be the major elimination process for GS-441524. Following oral administration, the oral bioavailability was 8.3% in monkeys, 33% in rats, 39% in mice, and 85% in dogs. The PK and ADME properties of GS-441524 support its further development as an oral drug candidate.
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The etiologies of several cardiovascular, inflammatory, neurological, hereditary disorders, cancer, and infectious diseases have implicated changes in the genetic set up or genetic mutations as the root cause. Nucleic acid based therapeutics (NBTs) is a new class of biologics that are known to regulate gene expression at the transcriptional and post-transcriptional level. The NBTs include oligonucleotides, nucleosides, antisense RNA, small interfering RNAs, micro RNA etc. In recent times, this new category of biologics has found enormous potential in the management of cardiovascular, inflammatory, neurological disorders, cancer, infectious diseases and organ transplantation. However, the delivery of NBTs is highly challenging in terms of target specificity (intracellular delivery), mononuclear phagocyte system uptake, stability and biodistribution. Additionally, management of the above mentioned disorders require regular and intrusive therapy making non-invasive routes preferable in comparison to invasive routes like parenteral. The nasal route is garnering focus in delivery of NBTs to the brain in the management of several CNS disorders due to the associated merits such as non-invasiveness, possibility of chronic delivery, improved patient compliance, avoidance of hepatic and gastrointestinal metabolism as well as ability to bypass the BBB. Hence in recent times, this route has been sought by the reserachers as an alternative to parenteral therapy for the delivery of several NBTs. This review shall focus on an array of NBTs delivered through nasal route, their challenges, applications and opportunities. The novel delivery systems for incorporating NBTs; their targeting strategies shall be critically reviewed. The challenges towards regulatory approvals and commercialization shall also be discussed at large. Comparison of learnings derived from the success and barriers in nasal delivery of NBTs will help in identification of futuristic opportunities for their translation from bench to bedside.
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OBJECTIVE: This study evaluated postoperative AKI severity and its relation to short- and long-term patient outcomes. DESIGN: A retrospective, single-center cohort study of patients undergoing surgery from January 2015 to May 2020. SETTING: An urban, academic medical center. PATIENTS: Adult patients undergoing elective, non-cardiac surgery at our institution with a postoperative length of stay (LOS) of at least 24 h were included. Patients were included in 1-year mortality analysis if their procedure occurred prior to June 2019. INTERVENTIONS: None. MEASUREMENTS: Postoperative AKI was identified and staged using the Kidney Disease Improving Global Outcomes definitions. The outcomes analyzed were in-hospital mortality, LOS, total cost of the surgical hospitalization, and 1-year mortality. MAIN RESULTS: Of the 8887 patients studied, 648 (7.3%) had postoperative AKI. AKI was associated with severity-dependent increases in all outcomes studied. Patients with AKI had rates of in-hospital mortality of 2.0%, 3.8%, and 12.5% for stage 1, 2, and 3 AKI compared to 0.3% for patients without AKI. Mean total costs of the surgical hospitalization were $23,896 (SD $23,736) for patients without AKI compared to $33,042 (SD $27,115), $39,133 (SD $34,006), and $73,216 ($82,290) for patients with stage 1, 2, and 3 AKI, respectively. In the 6729 patients who met inclusion for 1-year mortality analysis, AKI was also associated with 1-year mortality rates of 13.9%, 19.4%, and 22.7% compared to 5.2% for patients without AKI. In multivariate models, stage 1 AKI patients still had a higher probability of 1-year mortality (OR 1.9, 95% CI 1.3-2.6, p < 0.001) in addition to $4391 of additional costs when compared to patients without AKI (95% CI $2498-$6285, p < 0.001). CONCLUSIONS: All stages of postoperative AKI were associated with increased LOS, surgical hospitalization costs, in-hospital mortality, and 1-year mortality. These findings suggest that patients with even a low-grade or stage 1 AKI are at higher risk for short- and long-term complications.
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Injúria Renal Aguda , Complicações Pós-Operatórias , Injúria Renal Aguda/etiologia , Adulto , Estudos de Coortes , Mortalidade Hospitalar , Humanos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Cytochrome P450 (CYP) 3A7 is one of the major xenobiotic metabolizing enzymes in human embryonic, fetal, and newborn liver. CYP3A7 expression has also been observed in a subset of the adult population, including pregnant women, as well as in various cancer patients. The characterization of CYP3A7 is not as extensive as other CYPs, and health authorities have yet to provide guidance towards DDI assessment. To identify potential CYP3A7-specific molecules, we used a P450-Glo CYP3A7 enzyme assay to screen a library of â¼5,000 compounds, including FDA-approved drugs and drug-like molecules, and compared these screening data with that from a P450-Glo CYP3A4 assay. Additionally, a subset of 1,000 randomly selected compounds were tested in a metabolic stability assay. By combining the data from the qHTS P450-Glo and metabolic stability assays, we identified several chemical features important for CYP3A7 selectivity. Halometasone was chosen for further evaluation as a potential CYP3A7-selective inhibitor using molecular docking. From the metabolic stability assay, we identified twenty-two CYP3A7-selective substrates over CYP3A4 in supersome setting. Our data shows that CYP3A7 has ligand promiscuity, much like CYP3A4. Furthermore, we have established a large, high-quality dataset that can be used in predictive modeling for future drug metabolism and interaction studies.
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The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure-activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of in vitro drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human phase 1 clinical trial.
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Núcleo Celular , Neoplasias , Biomarcadores/metabolismo , Nucléolo Celular/metabolismo , Nucléolo Celular/patologia , Núcleo Celular/metabolismo , Humanos , Neoplasias/metabolismo , Pirimidinas , PirróisRESUMO
Silibinin (SB) is shown to have an anticancer properties. However, its clinical therapeutic effects have been restricted due to its low water solubility and poor absorption after oral administration. The aim of this study was to develop SB-loaded PCL/Pluronic F68 nanoparticles for pulmonary delivery in the treatment of lung cancer. A modified solvent displacement process was used to make nanoparticles, which were then lyophilized to make inhalation powder, Nanoparticles were characterized with DSC, FTIR,SEM and In vitro release study. Further, a validated HPLC method was developed to investigate the Biodistribution study, pharmacokinetic parameters. Poly Caprolactone PCL / Pluronic F68 NPs showed the sustained release effect up to 48 h with an emitted (Mass median Aerodynamic diameter)MMAD and (Geometric size distribution)GSD were found to be 4.235 ±0.124 and 1.958±1.23 respectively. More specifically, the SB Loaded PCL/Pluronic F 68 NPs demonstrated long circulation and successful lung tumor-targeting potential due to their cancer-targeting capabilities. SB Loaded PCL/Pluronic F68 NPs significantly inhibited tumour growth in lung cancer-induced rats after inhalable administration. In a pharmacokinetics study, PCL/ Pluronic F68 NPs substantially improved SB bioavailability, with a more than 4-fold rise in AUC when compared to IV administration. These findings indicate that SB-loaded PCL/PluronicF68 nanoparticles may be a successful lung cancer therapy delivery system.
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Neoplasias Pulmonares , Nanopartículas , Animais , Caproatos , Portadores de Fármacos/uso terapêutico , Lactonas , Neoplasias Pulmonares/tratamento farmacológico , Poloxâmero , Poliésteres/farmacologia , Ratos , Silibina , Distribuição TecidualRESUMO
Currently, approximately 80,000 chemicals are used in commerce. Most have little-to-no toxicity information. The U.S. Toxicology in the 21st Century (Tox21) program has conducted a battery of in vitro assays using a quantitative high-throughput screening (qHTS) platform to gain toxicity information on environmental chemicals. Due to technical challenges, standard methods for providing xenobiotic metabolism could not be applied to qHTS assays. To address this limitation, we screened the Tox21 10,000-compound (10K) library, with concentrations ranging from 2.8 nM to 92 µM, using a p53 beta-lactamase reporter gene assay (p53-bla) alone or with rat liver microsomes (RLM) or human liver microsomes (HLM) supplemented with NADPH, to identify compounds that induce p53 signaling after biotransformation. Two hundred and seventy-eight compounds were identified as active under any of these three conditions. Of these 278 compounds, 73 gave more potent responses in the p53-bla assay with RLM, and 2 were more potent in the p53-bla assay with HLM compared with the responses they generated in the p53-bla assay without microsomes. To confirm the role of metabolism in the differential responses, we re-tested these 75 compounds in the absence of NADPH or with heat-attenuated microsomes. Forty-four compounds treated with RLM, but none with HLM, became less potent under these conditions, confirming the role of RLM in metabolic activation. Further evidence of biotransformation was obtained by measuring the half-life of the parent compounds in the presence of microsomes. Together, the data support the use of RLM in qHTS for identifying chemicals requiring biotransformation to induce biological responses.
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Ensaios de Triagem em Larga Escala , Proteína Supressora de Tumor p53 , Ativação Metabólica , Animais , Ensaios de Triagem em Larga Escala/métodos , Microssomos Hepáticos , NADP , Ratos , Transdução de SinaisRESUMO
AIM: In the current study, efforts are being made to prepare Inhalable Silibinin loaded solid lipid nanoparticles (SLNs) with narrow size distribution with improved bioavailability. METHODS: SLNs were formulated by high shear homogenisation method SLNs were characterised, including Differential Scanning Calorimetry (DSC), Fourier transform infra-red spectroscopy (FTIR), particle size analysis, entrapment efficiency with Aerodynamic behaviour. The MTT assay was performed against A549 cell line, to measure their anticancer cell activity with In vivo study. RESULTS: Optimized formulation exhibited spherical surface with a mean particle size of 221 ± 1.251 nm, PI of 0.121 ± 0.081, zeta potential of -4.12 ± 0.744. Aerodynamic behaviour such as Mass median aerodynamic diameter (MMAD) and Geometric size distribution (GSD) were found to be 5.487 ± 0.072 and 2.321 ± 0.141 respectively proved formulation is suitable for inhalation. In vitro cellular efficacy against A549 cells, revealed that the optimised formulations were more effective and potent. CONCLUSION: The Inhalable SLNs approach was successfully engineered and administered to the lungs safely without causing any problems.
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Lipídeos , Nanopartículas , Portadores de Fármacos , Lipossomos , Pulmão , Tamanho da Partícula , SilibinaRESUMO
AIMS: With resumption of elective spine surgery services in the UK following the first wave of the COVID-19 pandemic, we conducted a multicentre British Association of Spine Surgeons (BASS) collaborative study to examine the complications and deaths due to COVID-19 at the recovery phase of the pandemic. The aim was to analyze the safety of elective spinal surgery during the pandemic. METHODS: A prospective observational study was conducted from eight spinal centres for the first month of operating following restoration of elective spine surgery in each individual unit. Primary outcome measure was the 30-day postoperative COVID-19 infection rate. Secondary outcomes analyzed were the 30-day mortality rate, surgical adverse events, medical complications, and length of inpatient stay. RESULTS: In all, 257 patients (128 males) with a median age of 54 years (2 to 88) formed the study cohort. The mean number of procedures performed from each unit was 32 (16 to 101), with 118 procedures (46%) done as category three prioritization level. The majority of patients (87%) were low-medium "risk stratification" category and the mean length of hospital stay was 5.2 days. None of the patients were diagnosed with COVID-19 infection, nor was there any mortality related to COVID-19 during the 30-day follow-up period, with 25 patients (10%) having been tested for symptoms. Overall, 32 patients (12%) developed a total of 34 complications, with the majority (19/34) being grade 1 to 2 Clavien-Dindo classification of surgical complications. No patient required postoperative care in an intensive care setting for any unexpected complication. CONCLUSION: This study shows that safe and effective planned spinal surgical services can be restored avoiding viral transmission, with diligent adherence to national guidelines and COVID-19-secure pathways tailored according to the resources of the individual spinal units. Cite this article: Bone Jt Open 2021;2(12):1096-1101.
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5-Fluorouracil (5-FU) is the most preferred chemotherapeutic agent in the management of colon cancer but is associated with poor therapeutic efficacy and lack of site specificity. Hence, it was aimed to employ Eudragit S100 surface engineered 5-FU nanostructured lipid carriers for the spatial and temporal release of the drug for the treatment of colon cancer. Hot high-pressure homogenization (HPH) technique was employed in the preparation of 5-FU-NLCs. The optimization of 5-FU-NLCs was performed using a Quality by Design (QbD) approach. A 32 factorial design was employed wherein the relationship between independent variables [amount of oleic acid (X1) and concentration of Tween®80 (X2)] and dependent variables [particle size (Y1) and % entrapment efficiency (Y2)] was studied. Optimized 5-FU-NLCs were surface treated to obtain Eudragit S100-coated 5-FU-NLCs (EU-5-FU-NLCs). The evaluation parameters for 5-FU-NLCs and EU-5-FU-NLCs included surface morphology, particle size, PDI, and zeta potential. In vitro release from EU-5-FU-NLCs revealed a selective and controlled 5-FU release in the colonic region for 24 h. In vitro cytotoxicity (MTT assay) was performed against Caco-2 cancer cells, wherein EU-5-FU-NLCs exhibited a 2-fold greater cytotoxic potential in comparison to a 5-FU solution (5-FU-DS). Oral administration of EU-5-FU-NLCs in Albino Wistar rats depicted a higher Cmax (2.54 folds) and AUC (11 folds) as well as prolonged Tmax (16 folds) and MRT (4.32 folds) compared to 5-FU-DS confirming higher bioavailability along with the spatial and temporal release in the colonic region. Thus, a multifaceted strategy involving abridgement of nanotechnology along with surface engineering is introduced for effective chemotherapy of colon cancer via oral administration of 5-FU with uncompromised safety and higher efficacy.Graphical abstract.
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Neoplasias do Colo , Portadores de Fármacos , Nanoestruturas , Ácidos Polimetacrílicos , Animais , Células CACO-2 , Colo , Neoplasias do Colo/tratamento farmacológico , Fluoruracila , Humanos , Lipídeos , Tamanho da Partícula , RatosRESUMO
INTRODUCTION: Evidence is emerging, suggesting a significant drop in hospital referrals and attendances for various medical conditions due to the COVID-19 pandemic. With the implementation of lockdown rules, road traffic and outdoor activities were expected to drop, thereby reducing the number of high-energy spinal injuries. Critical non-traumatic spinal conditions like spinal tumours, infections, or compressive pathologies, however, should continue to present as before. We assessed all acute spinal referrals to our tertiary spine unit comparing with the acute activity for a similar time frame in the previous year. The aim was to identify any variance in the acute spinal activity, explain reasons for the discrepancy and identify any learning points. MATERIALS: All acute referrals to our tertiary spinal surgery unit made from 01 February 2020 to 30 April 2020 were evaluated. Similar data from the preceding year, i.e. 2019 was evaluated for comparison. Data were analysed for qualitative or quantitative changes in the referral pattern and their subsequent management outcomes. RESULTS: Spinal referral numbers reduced by 46.05% during the time frame of February-April 2020 when compared to the same period in 2019 (p < 0.017). Similarly, numbers of high-energy traumatic presentations reduced by 72% (p < 0.002). Referrals for critical spinal conditions declined by two-thirds for spinal infections and more than a third for spinal tumours. Emergency surgical workload waned by 27%, especially more so during the six-week lockdown duration. CONCLUSION: Reduction in spinal activity, even for critical spinal conditions, during the pandemic is likely due to a combination of factors like patient behaviour, fear of contracting COVID-19 infection during hospital visit, self-isolation advice, availability of a senior decision maker on the frontlines, and changes in healthcare service provisions. The health crisis may provide an opportunity for optimisation of spinal healthcare services both at the referring hospital and at the tertiary centre.
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COVID-19 , Pandemias , Controle de Doenças Transmissíveis , Humanos , Encaminhamento e Consulta , SARS-CoV-2 , Reino Unido/epidemiologiaRESUMO
PURPOSE OF REVIEW: Healthcare is rapidly evolving toward value-focused objectives, integrating outcomes and cost instead of simply volume. Concepts pertaining to Enhanced Recovery After Surgery (ERAS), Lean, and claims-based risk-adjusted databases can be used to optimize value, but the application of Lean principles and risk-adjusted outcomes is poorly described in perioperative medicine in perioperative medicine. RECENT FINDINGS: Lean management and process optimization tools allow the consistent application of a perioperative medical framework of ERAS to improve outcomes. Vizient risk-stratified outcomes are often used by hospitals to measure and compare quality. SUMMARY: Understanding administrative databases and Lean concepts for change management will allow the perioperative physician to better align medical concepts with health system tools for improving quality and reducing cost.
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Recuperação Pós-Cirúrgica Melhorada , Humanos , Assistência PerioperatóriaRESUMO
The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.