Therapeutics and Clinical Risk Management最新文献

Background: The activities of tissue establishments are constantly and rapidly evolving. The development of a new type of allograft, full-thickness acellular dermal matrix, with high mechanical properties to be used in tendon repair surgeries and abdominal wall reconstruction, has determined the need for quality by design process in order to assess evidence of quality, safety and efficacy. The EuroGTPII methodologies were specifically tailored to perform the risk assessment, identify and suggest tests in order to mitigate the potential risk consequences of a novel tissue preparation implementation.

Methods: The new allograft and associated preparation processes were assessed using the EuroGTP methodologies and characterized to properly evaluate the novelty (Step 1), identify and quantify the potential risks and risk consequences (Step 2), and define the extent of pre-clinical and clinical assessments required to mitigate the risks identified in the assessment (Step 3).

Results: Four risk consequences associated with the preparation process were identified: (i) implant failure related with tissue procurement and the reagents used during the decellularization protocol; (ii) unwanted immunogenicity related with the processing; (iii) disease transmission linked with the processing, reagents used, reduction in the reliability of microbiology testing and the storage conditions; and (iv) toxicity related to the reagents used and handling of the tissue during clinical application. The outcome of the risk assessment was a low level of risk. Nevertheless, it determined the need for a series of risk mitigation strategies proposed to reduce each individual risk and to provide additional evidence of the safety and efficacy of full-thickness acellular dermal matrix grafts.

Conclusion: EuroGTPII methodologies allow us to identify the risks and ensure the correct definition of pre-clinical assessments required to address and mitigate the potential risk consequences, before proceeding with clinical use of the new allografts in patients.

Purpose: To evaluate the accuracy of mixed reality (MR)-guided visualization technology for spinal puncture (MRsp).

Methods: MRsp involved the following three steps: 1. Lumbar spine computed tomography (CT) data were obtained to reconstruct virtual 3D images, which were imported into a HoloLens (2nd gen). 2. The patented MR system quickly recognized the spatial orientation and superimposed the virtual image over the real spine in the HoloLens. 3. The operator performed the spinal puncture with structural information provided by the virtual image. A posture fixation cushion was used to keep the subjects' lateral decubitus position consistent. 12 subjects were recruited to verify the setup error and the registration error. The setup error was calculated using the first two CT scans and measuring the displacement of two location markers. The projection points of the upper edge of the L3 spinous process (L3↑), the lower edge of the L3 spinous process (L3↓), and the lower edge of the L4 spinous process (L4↓) in the virtual image were positioned and marked on the skin as the registration markers. A third CT scan was performed to determine the registration error by measuring the displacement between the three registration markers and the corresponding real spinous process edges.

Results: The setup errors in the position of the cranial location marker between CT scans along the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) axes of the CT bed measured 0.09 ± 0.06 cm, 0.30 ± 0.28 cm, and 0.22 ± 0.12 cm, respectively, while those of the position of the caudal location marker measured 0.08 ± 0.06 cm, 0.29 ± 0.18 cm, and 0.18 ± 0.10 cm, respectively. The registration errors between the three registration markers and the subject's real L3↑, L3↓, and L4↓ were 0.11 ± 0.09 cm, 0.15 ± 0.13 cm, and 0.13 ± 0.10 cm, respectively, in the SI direction.

Conclusion: This MR-guided visualization technology for spinal puncture can accurately and quickly superimpose the reconstructed 3D CT images over a real human spine.

Objective: This study aimed to evaluate the safety and efficacy of liver venous deprivation (LVD) following transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).

Methods: Between January 2021 and December 2022, HCC patients indicated for hepatectomy with initial insufficient future liver remnant (FLR) underwent LVD after TACE to induce preoperative liver hypertrophy.

Results: Twenty-seven HCC patients with a median age of 55 years underwent LVD. No TACE or LVD procedure-associated complications occurred, except for 1 case presenting with grade A liver failure after LVD (then recovered after 7 days). The FLR volume was 29.3% (interquartile range [IQR] = 7.5) and 48.9% (IQR = 8.6) of the total liver volume before and after LVD, respectively (p < 0.001). The degree of hypertrophy and FLR hypertrophy rate were 14.8% (IQR = 8.4) and 55.2% (IQR = 36.7), respectively. All 27 patients demonstrated sufficient FLR after LVD (24 patients at three weeks post-LVD, one at six weeks, and two at ten weeks), but only 21 patients accepted surgery. Postoperative histopathology showed 16 patients with cirrhosis and five with mild fibrosis (F1, F2). One patient presented with severe intraoperative bleeding due to damage of left hepatic vein and developed grade C liver failure, then died on day 32 postoperation.

Conclusion: LVD following TACE seems to be a safe, effective, and feasible method of inducing significant FLR regeneration in HCC, even in well-selected cirrhotic livers. Comparative studies with a large patient population and multicenter data are needed for further evaluation.

Accumulation of aberrant proteins in the heart causes cardiac amyloidosis, an uncommon and complicated illness. It can be classified into two main types: light chain (AL) and transthyretin (ATTR). The diagnosis of cardiac amyloidosis is challenging due to its non-specific clinical presentation and lack of definitive diagnostic tests. Diagnostic accuracy has increased with the advent of modern imaging methods, including cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Depending on the severity of cardiac amyloidosis, a number of treatments may be attempted and specified according to the subtype of amyloidosis and the presence of complications. However, there are still significant challenges in treating this condition due to its complexity and lack of effective treatments. The prognosis for patients with cardiac amyloidosis is poor. Despite recent advances in diagnosis and treatment, there is still a need for more effective treatments to improve outcomes for patients with this condition. Therefore, we aim to review the current and future therapeutics reported in the literature and among ongoing clinical trials recruiting patients with CA.

Objective: To investigate the correlation between serum parathyroid hormone (PTH) levels and in-hospital major adverse cardiovascular events (MACE) in patients with acute ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI), and establish a risk prediction model based on parameters such as PTH for in-hospital MACE.

Methods: This observational retrospective study consecutively enrolled 340 patients who underwent primary PCI for STEMI between January 2016 and December 2020, divided into a MACE group (n=92) and a control group (n=248). The least absolute shrinkage and selection operator (LASSO) and logistic regression analyses were used to determine the risk factors for MACE after primary PCI. The rms package in R-studio statistical software was used to construct a nomogram, to detect the line chart C-index, and to draw a calibration curve. The decision curve analysis (DCA) method was used to evaluate the clinical application value and net benefit.

Results: Correlation analysis revealed that PTH level positively correlated with the occurrence of in-hospital MACE. Receiver operating characteristic curve analyses revealed that PTH had a good predictive value for in-hospital MACE. Multivariate logistic regression analysis indicated that Killip class II-IV, and FBG were independently associated with in-hospital MACE after primary PCI. A nomogram model was constructed using the above parameters. The model C-index was 0.894 and the calibration curve indicated that the model was well calibrated. The DCA curve suggested that the nomogram model was better than TIMI score model in terms of net clinical benefit.

Conclusion: Serum PTH levels in patients with STEMI are associated with in-hospital MACE after primary PCI, and the nomogram risk prediction model based on PTH demonstrated good predictive ability with obvious clinical practical value.

Purpose: Levothyroxine is a common prescribed drug. Many medications and food, however, can interfere with its bioavailability. The aim of this review was to summarize the medications, food and beverages that interact with levothyroxine and to assess their effects, mechanisms and treatments.

Methods: A systematic review on interfering substances that interact with levothyroxine was performed. Web of Science, Embase, PubMed, the Cochrane library, grey literature from other sources and the lists of references were searched for human studies comparing the levothyroxine efficacy with and without interfering substances. The patient characteristics, drug classes, effects and mechanism were extracted. The NHLBI study quality assessment tools and the JBI critical appraisal checklist were used to assess the quality of included studies.

Results: A total of 107 articles with 128 studies were included. Drugs interactions were revealed in calcium and iron supplements, proton pump inhibitors, bile acid sequestrants, phosphate binders, sex hormones, anticonvulsants and other drugs. Some food and beverage could also induce malabsorption. Proposed mechanisms included direct complexing, alkalization, alteration of serum thyroxine-binding globulin levels and acceleration of levothyroxine catabolism via deiodination. Dose adjustment, administration separation and discontinuation of interfering substances can eliminate the interactions. Liquid solutions and soft-gel capsules could eliminate the malabsorption due to chelation and alkalization. The qualities of most included studies were moderate.

Conclusion: Lots of medications and food can impair the bioavailability of levothyroxine. Clinicians, patients and pharmaceutical companies should be aware of the possible interactions. Further well-designed studies are needed to provide more solid evidence on treatment and mechanisms.

Introduction: Non-high-density-lipoprotein cholesterol (non-HDL-C) is a secondary therapeutic target in cardiovascular diseases and is used for residual risk assessment in patients with coronary artery syndrome (ACS). This study was designed to determine the association between non-HDL-C in patients with prior coronary artery bypass graft (CABG) with ACS and clinical outcomes.

Methods: We retrospectively analyzed 468 patients with prior CABG with ACS and categorized them into two groups based on the median non-HDL-C level. The primary endpoints were major adverse cardiovascular events (MACEs), including cardiovascular death and recurrent myocardial infarction. Kaplan-Meier curves, Cox proportional-hazard regressions, and restricted cubic splines were used to determine the association between non-HDL-C and MACEs. The discrimination and reclassification of the nomogram based on non-HDL-C were assessed using time-dependent receiver operating characteristic (ROC) curves and net reclassification improvement (NRI).

Results: During the average follow-up time of 744.5 days, non-HDL-C was independently associated with the occurrence of MACEs (hazard ratio [HR] = 5.01, 95% confidence interval [CI] = 1.65-15.24; p = 0.005) after adjusting for other lipid parameters. The spline curves indicated a linear relationship between non-HDL-C and MACEs (p-nonlinear: 0.863). The time-dependent areas under the ROC curves of prior-CABG-ACS nomograms containing non-HDL regarding MACEs in two consecutive years were 91.7 (95% CI: 85.5-97.9) and 91.5 (95% CI: 87.3-95.7), respectively. The NRI analysis indicated that the prior-CABG-ACS model improved the reclassification ability for 1- and 2-year MACEs (22.4% and 7%, p < 0.05, respectively).

Discussion: Non-HDL is independently associated with the risk of MACEs in patients with prior CABG with ACS. The prior-CABG-ACS nomogram based on non-HDL-C and five convenient variables generates valid and stable predictions of MACE occurrence.

The Bardet Biedl syndrome (BBS) is a rare inherited disorder considered a model of non-motile ciliopathy. It is in fact caused by mutations of genes encoding for proteins mainly localized to the base of the cilium. Clinical features of BBS patients are widely shared with patients suffering from other ciliopathies, especially autosomal recessive syndromic disorders; moreover, mutations in cilia-related genes can cause different clinical ciliopathy entities. Besides the best-known clinical features, as retinal degeneration, learning disabilities, polydactyly, obesity and renal defects, several additional clinical signs have been reported in BBS, expanding our understanding of the complexity of its clinical spectrum. The present review aims to describe the current knowledge of BBS i) pathophysiology, ii) clinical manifestations, highlighting both the most common and the less described features, iii) current and future perspective for treatment.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.

Purpose: To evaluate visual and refractive outcomes of customized photorefractive keratectomy (PRK) in subjects with persistent subepithelial corneal opacities secondary to adenoviral epidemic keratoconjunctivitis (EKC).

Patients and methods: Prospective study, which recruited patients with persistent and visually-significant post-EKC corneal opacities unresponsive to prolonged topical therapy (6 months or more). Outcome measures: uncorrected and best-corrected distance visual acuity, subjective refractive astigmatism, keratometric astigmatism, spherical equivalent, minimum corneal thickness, and corneal morphological irregularity index. Subjects were followed for 12 months post-treatment.

Results: Eighteen eyes of 18 patients aged between 32 and 75 years treated with topography-guided transepithelial PRK with iRes excimer laser (iVIS Technologies, Taranto, Italy) from June 2020 to July 2021. After 12 months, the mean UDVA improved from 1.0±0.00LogMAR pre-op to 0.15±0.154LogMAR, and the mean CDVA improved from 0.4±0.41LogMAR pre-op to 0.0±0.00LogMAR. With respect to UDVA, all treated eyes (100%) showed an improvement of 6 ETDRS lines or more and with respect to CDVA, 9 out of 18 eyes (50%) showed an improvement of 6 ETDRS lines or more. The mean ablation depth was 54.7±5.9μm. A statistically significant improvement was observed in all topographic indices. No infiltrate recurrence, post-treatment corneal haze, ocular hypertension or other side effects were observed throughout the follow-up period.

Conclusion: Topography-guided PRK could be considered an effective and safe treatment option to improve visual acuity in patients affected by persistent and visually-significant subepithelial corneal infiltrates caused by EKC.