Infusion reactions to adeno-associated virus (AAV)-based gene therapy: Mechanisms, diagnostics, treatment and review of the literature.

The use of adeno-associated virus (AAV) vectors in gene therapy has demonstrated great potential in treating genetic disorders. However, infusion-associated reactions (IARs) pose a significant challenge to the safety and efficacy of AAV-based gene therapy. This review provides a comprehensive summary of the current understanding of IARs to AAV therapy, including their underlying mechanisms, clinical presentation, and treatment options. Toll-like receptor activation and subsequent production of pro-inflammatory cytokines are associated with IARs, stimulating neutralizing antibodies (Nabs) and T-cell responses that interfere with gene therapy. Risk factors for IARs include high titers of pre-existing Nabs, previous exposure to AAV, and specific comorbidities. Clinical presentation ranges from mild flu-like symptoms to severe anaphylaxis and can occur during or after AAV administration. There are no established guidelines for pre- and postadministration tests for AAV therapies, and routine laboratory requests are not standardized. Treatment options include corticosteroids, plasmapheresis, and supportive medications such as antihistamines and acetaminophen, but there is no consensus on the route of administration, dosage, and duration. This review highlights the inadequacy of current treatment regimens for IARs and the need for further research to improve the safety and efficacy of AAV-based gene therapy.

Characteristics of Phase IV Clinical Trials in Oncology: An Analysis Using the ClinicalTrials.gov Registry Data.

The present study analyzed the characteristics of phase IV clinical trials in oncology using data from the ClinicalTrials.gov registry. The included trials were conducted between January 2013 and December 2022 and were examined for key characteristics, including outcome measures, interventions, sample sizes, and study design, different cancer types, and geographic regions. The analysis included 368 phase IV oncology studies. An amount of 50% of these studies examined both safety and efficacy, while 43.5% only reported efficacy outcome measures, and 6.5% only described safety outcome measures. Only 16.9% of studies were powered to detect adverse events with a frequency of 1 in 100. Targeted therapies accounted for the majority of included studies (53.5%), with breast (32.91%) and hematological cancers (25.82%) being the most frequently investigated malignancies. Most phase IV oncology studies lacked sufficient power to detect rare adverse events due to their small sample sizes and instead focused on effectiveness. To ensure that there is no gap in drug safety data collection and detection of rare adverse events due to limited phase IV clinical trials, there is a significant need for additional education and participation by both health care providers and patients in spontaneous reporting processes.

Cell-Free DNA, Neutrophil extracellular traps (NETs), and Endothelial Injury in Coronavirus Disease 2019- (COVID-19-) Associated Acute Kidney Injury.

Introduction: Neutrophil extracellular traps (NETs) release (i.e., NETosis) has been recently implicated in the pathomechanism underlying severe end-organ damage in Coronavirus Disease 2019 (COVID-19) and could present a novel therapeutic target. We aimed to determine whether circulating levels of cell-free DNA (cfDNA), a surrogate for NETosis, may be associated with the development of acute kidney injury (AKI), a major contributor to poor outcomes and mortality in COVID-19. Methods: Blood samples were collected prospectively from adult patients infected with SARS-CoV-2 presenting to the emergency department (ED). Circulating levels of cfDNA were quantified from patients' serum. Further assessment of correlations between cfDNA levels and markers of AKI (i.e., serum creatinine (SCr), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL)), biomarkers of thrombotic microangiopathy and of inflammation in patients' serum was performed. Results: Fifty-one COVID-19 patients were enrolled. cfDNA levels were found to be significantly higher in those who developed severe AKI (p < 0.001) and those needing renal replacement therapy (p = 0.020). cfDNA positively correlated with ED SCr, NGAL, cystatin C, neutrophil count, neutrophil-to-lymphocyte ratio, C3a, C5a, Scb5-9, IL-6, IL-8, IL-10, TNF-α, LDH, CRP, ferritin, and fibrinogen and negatively correlated with ADAMTS13/von-Willebrand factor ratio and lymphocyte count. In a multivariate logistic regression, a one-unit increase in cfDNA value was associated with 4.6% increased odds of severe AKI (OR = 1.046; p = 0.040). Finally, cfDNA significantly correlated with established NETs components, myeloperoxidase, and neutrophil elastase. Conclusion: Intravascular NETosis could be an important contributing factor in the development of microthrombosis and COVID-19-associated AKI. Further research is urgently needed to understand the role of NETosis in COVID-19 and evaluate therapeutic avenues for targeting this process.

Early prediction of COVID-19-associated acute kidney injury: Are serum NGAL and serum Cystatin C levels better than serum creatinine?

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with a high risk of acute kidney injury (AKI), often requiring renal replacement therapy (RRT). Serum Cystatin C (sCysC) and serum Neutrophil Gelatinase-Associated Lipocalin (sNGAL) are emerging biomarkers for kidney injury, and were suggested to be superior to serum creatinine (sCr) in several clinical settings. Moreover, elevated sCysC is associated with disease severity and mortality in COVID-19. We aimed to assess the utility of sCysC and sNGAL for predicting COVID-19-associated AKI, need for RRT, and need for intensive care unit (ICU) admission, when measured at presentation to the emergency department (ED). METHODS: Patients presenting to the ED with laboratory-confirmed COVID-19 were included. The primary outcome was development of COVID-19-associated AKI, while the secondary outcomes were need for RRT and ICU admission. RESULTS: Among 52 COVID-19 patients, 22 (42.3%) developed AKI with 8/22 (36.4%) requiring RRT. Both sCr and sCysC demonstrated excellent performance for predicting AKI (AUC, 0.86 and 0.87, respectively) and need for RRT (AUC, 0.94 and 0.95, respectively). sNGAL displayed acceptable performance for predicting AKI (AUC, 0.81) and need for RRT (AUC, 0.87). CONCLUSIONS: SCr and sCysC measured at ED presentation are both highly accurate predictors of AKI and need for RRT, whereas sNGAL demonstrated adequate diagnostic performance. While sCyC was previously shown to be superior to sCr as a diagnostic biomarker of kidney injury in certain etiologies, our findings demonstrate that sCr is comparable to sCyC in the context of predicting COVID-19-associated AKI. Given the high sensitivity of these biomarkers for predicting the need for RRT, and as sCysC is associated with mortality in COVID-19 patients, we recommend their measurement for enabling risk stratification and early intervention.

Analysis of the Different Lymphatic Drainage Patterns during Sentinel Lymph Node Biopsy for Skin Melanoma.

In the last two decades, studies of lymphoscintigraphy imaging in lymphatic mapping reported an extreme heterogeneity of skin lymphatic drainage of some skin area, in contrast with the previous scientific literature. The aim of this study was to investigate the presence of any correlations between the topographical location of cutaneous melanoma and the topographical location of sentinel lymph nodes. Data from 165 patients undergoing sentinel lymph node biopsy between January 2013 and May 2021 were analyzed, demonstrating that melanomas in the Lumbar region presented a significant more heterogeneous drainage by site than those in the Scapular region (p < 0.01) and that melanomas in the Subscapular region were significantly more heterogeneous by laterality (unilateral vs. bilateral) than those in the Scapular region (p < 0.05). Results of this study supported the evidence of multiple lymphatic drainage as regards the sentinel node biopsy performed in skin melanoma located on the dorsal subscapular region and lumbar region. For this reason, the association of preoperative lymphoscintigraphy with another imaging evaluation is needed in these critical cutaneous areas. Recent technical developments enabling fluorescence lymphography together with indocyanine green have significantly improved the visualization of lymphatic drainage patterns at a microscopic level. In the preoperative phase, any doubt can be resolved by associating the SPET-CT scan to lymphoscintigraphy, while during the intraoperative phase, an additional evaluation with indocyanine green can be performed in doubtful cases. The aim of the duplex lymphatic mapping (pre and/or intraoperative) is an accurate search of sentinel nodes, in order to reduce the rate of false negatives.

Is body temperature mass screening a reliable and safe option for preventing COVID-19 spread?

With the ongoing coronavirus disease 2019 (COVID-19) pandemic continuing worldwide, mass screening of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection is a cornerstone of strategies for limiting viral spread within communities. Although mass screening of body temperature with handheld, non-contact infrared thermometers and thermal imagine scanners is now widespread in a kaleidoscope of social and healthcare settings for the purpose of detecting febrile individuals bearing SARS-CoV-2 infection, this strategy carries some drawbacks, which will be highlighted and discussed in this article. These caveats basically include high rate of asymptomatic SARS-CoV-2 infections, the challenging definition of "normal" body temperature, variation of measured values according to the body district, false negative cases due to antipyretics, device inaccuracy, impact of environmental temperature, along with the low specificity of this symptom for screening COVID-19 in patients with other febrile conditions. Some pragmatic suggestions will also be endorsed for increasing accuracy and precision of mass screening of body temperature. These encompass the regular assessment of body temperature (possibly twice) with validated devices, which shall be constantly monitored over time and used following manufacturer's instructions, the definition of a range of "normal" body temperatures in the local population, patients interrogation on usual body temperature, measurement standardization of one body district, allowance of sufficient environmental acclimatization before temperature check, integration with contact history and other clinical information, along with exclusion of other causes of increased body temperature. We also endorse the importance of individual and primary care physician's regular and repeated check of personal body temperature.

A systematic review and meta-analysis of iliocapsularis muscle: an important landmark in orthopedic surgery.

PURPOSE: Iliocapsularis (IC) is a small muscle overlying the capsule of the hip joint. Although recent attention is being given to this muscle by orthopedic surgeons who encounter it during the anterior approach to total hip arthroplasty, little is known about its anatomical features. The aim of this study was to review the anatomy of IC, and describe its' origin, insertion, blood supply, innervation, muscle fiber characteristics and size. The function, clinical relevance and comparative anatomy of IC were also appraised. METHODS: Using Evidence-Based Anatomy methodology, electronic databases were searched with the terms "iliocapsularis", "iliacus minor", "iliotrochantericus", and "ilioinfratrochantericus" to identify eligible studies. RESULTS: Six studies (n = 287 lower limbs) examining the anatomy of IC were included. The pooled prevalence (PP) of the IC was 98.7% (95% CI 96.5-100.0). It arises from the inferior facet of the anterior inferior iliac spine (AIIS) and attaches inferior to the lesser trochanter. Attached to the anteromedial capsule along its entire length, IC has the largest capsular contribution of any of the hip muscles (73.8 ± 27.3 × 16.1 ± 4.4 mm). Thus, it is an important landmark in anterior surgical approaches to the hip joint. CONCLUSION: The anatomy of IC is becoming more relevant with the increasing use of anterior approaches to hip surgery. With attachments to the AIIS, the lesser trochanter as well as the length of the capsule, this muscle is an important landmark in total hip arthroplasty. LEVEL OF EVIDENCE: Level V.

A systematic review and meta-analysis of variants of the branches of the superior mesenteric artery: the Achilles heel of right hemicolectomy with complete mesocolic excision?

AIM: Dissection with subsequent ligation and resection of arteries at their origin (central vascular ligation) is essential for adequate oncological resection during right hemicolectomy with complete mesocolic excision. This technique is technically demanding due to the highly variable arterial pattern of the right colon. Therefore, this study aims to provide a comprehensive evidence-based assessment of the arterial vascular anatomy of the right colon. METHODS: A thorough systematic literature search through September 2020 was conducted on the electronic databases PubMed, Scopus and Web of Science to identify studies eligible for inclusion. Data were extracted and pooled into a meta-analysis using MetaXl software. RESULTS: A total of 41 studies (n = 4691 patients) were included. The ileocolic artery (ICA), right colic artery (RCA) and middle colic artery (MCA) were present in 99.7% (95% CI 99.4%-99.8%), 72.6% (95% CI 61.3%-82.5%) and 96.9% (95% CI 94.2%-98.8%) respectively of patients. Supernumerary RCA and MCA were observed in 3.2% and 11.4% respectively of all cases. The RCA shared a common trunk with the ICA and MCA in 13.2% and 17.7% respectively of patients. A retro-superior mesenteric vein course of the ICA and RCA was observed in 55.1% and 11.4% respectively of all cases. CONCLUSION: The vascular anatomy of the right colon displays several notable variations, namely the absence of some branches (RCA absent in 27.4% of cases), supernumerary branches, common trunks, and retro-superior mesenteric vein courses. These variations should be taken into consideration during right hemicolectomy with complete mesocolic excision to ensure adequate oncological resection while minimizing intra-operative complications.

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis: A Review.

Importance: The COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST. Observations: VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk. Conclusions and Relevance: Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

Surgical anatomy of the accessory middle colic artery: a meta-analysis with implications for splenic flexure cancer surgery.

AIM: Surgical resection of splenic flexure cancers (SFCs) is technically demanding due to the complex regional anatomy, characterized by the presence of embryological adhesions, close proximity to the pancreas and spleen, and a highly heterogeneous arterial supply and lymphatic drainage. The accessory middle colic artery (AMCA) is increasingly being recognized as an important source of blood supply to the splenic flexure. The aim of this study is to determine the prevalence and anatomical features of the AMCA. METHOD: A systematic search of the scientific literature was conducted on PubMed and Embase from inception to November 2020 to identify potentially eligible studies. Data were extracted and prevalence was pooled into a meta-analysis using MetaXL and Meta-Analyst software. RESULTS: A total of 16 studies (n = 2203 patients) were included. The pooled prevalence (PP) of the AMCA was 25.4% (95% CI 18.1-33.4). Its prevalence was higher in patients without a left colic artery (LCA) (PP = 83.2%; 95% CI 70.4-93.1). The commonest origin for the AMCA was the superior mesenteric artery (PP = 87.9%; 95% CI 86.4-90.7). The AMCA shared a common trunk/gave rise to pancreatic branches in 23.1% of cases (95% CI 15.3-31.9). CONCLUSION: The AMCA contributes to the vascularization of the splenic flexure in approximately 25% of individuals, and may be an important feeder artery to SFCs, especially in the absence of a LCA. Preoperative identification of this artery is important to ensure optimal surgery for SFC and minimize complications.

Laparoscopic surgery during the COVID-19 pandemic: detection of SARS-COV-2 in abdominal tissues, fluids, and surgical smoke.

BACKGROUND: There are still concerns over the safety of laparoscopic surgery in coronavirus disease 2019 (COVID-19) patients due to the potential risk of viral transmission through surgical smoke/laparoscopic pneumoperitoneum. METHODS: We performed a systematic review of currently available literature to determine the presence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in abdominal tissues or fluids and in surgical smoke. RESULTS: A total of 19 studies (15 case reports and 4 case series) comprising 29 COVID-19 patients were included. The viral RNA was positively identified in 11 patients (37.9%). The samples that tested positive include the peritoneal fluid, bile, ascitic fluid, peritoneal dialysate, duodenal wall, and appendix. Similar samples, together with the omentum and abdominal subcutaneous fat, tested negative in the other patients. Only one study investigated SARS-COV-2 RNA in surgical smoke generated during laparoscopy, reporting negative findings. CONCLUSIONS: There are conflicting results regarding the presence of SARS-COV-2 in abdominal tissues and fluids. No currently available evidence supports the hypothesis that SARS-COV-2 can be aerosolized and transmitted through surgical smoke. Larger studies are urgently needed to corroborate these findings.

Congenital Anomalies of the Tracheobronchial Tree: A Meta-Analysis and Clinical Considerations.

BACKGROUND: The aim of this study was to determine the prevalence and anatomic features of major tracheobronchial anomalies. METHODS: Major electronic databases were systematically searched to identify eligible studies. Data were extracted and pooled into a meta-analysis. The primary outcome was the prevalence of major tracheobronchial anomalies, specifically tracheal bronchus (TB) and accessory cardiac bronchus (ACB). Secondary outcomes included the origin and types of TB and ACB. RESULTS: A total of 27 studies (n = 119,695 patients) were included. A TB was present in 0.99% (95% confidence interval, 0.67 to 1.37) of patients, and an ACB was present in 0.14% (95% confidence interval, 0.09 to 0.20). The overall prevalence of TB was higher in imaging than in operative studies (1.81% vs 0.82%). It was also higher in pediatric (2.55%) than in adult studies (0.50%). Patients with other congenital anomalies were 15 times more likely to have a TB (odds ratio 14.89; 95% confidence interval, 7.09 to 31.22). The most common origin of TBs was from the trachea (81.42%), primarily from the right side (96.43%). The most common origin of ACBs was from the intermediate bronchus (74.32%). The ACBs terminated as blind-ending diverticulum in two thirds of cases. CONCLUSIONS: Major tracheobronchial anomalies are present in approximately 1% of the population, although the prevalence is higher among pediatric patients and patients with accompanying congenital anomalies. Although rare, major tracheobronchial anomalies can be associated with significant respiratory morbidities and present challenges during airway management in surgical and critical care patients. Establishing a preoperative diagnosis of these variations is essential for planning and implementing an appropriate airway management strategy to minimize attendant complications.

The inferior intercavernous sinus: An anatomical study with application to trans-sphenoidal approaches to the pituitary gland.

OBJECTIVES: The inferior intercavernous sinus is located below the pituitary gland in the sella turcica. Its presence has been controversial among anatomists because it is not always found on radiological imaging or during cadaveric dissections; however, it is becoming a better-known structure in the neurosurgical and radiological fields, specifically with respect to transsphenoidal surgery. Therefore, the present study was performed to better elucidate this structure at the skull base. PATIENTS AND METHODS: Fifty adult, latex injected cadavers underwent dissection. The presence or absence of the inferior cavernous sinus was evaluated and when present, measurements of its width and length were made. Its connections with other intradural venous sinuses were also documented. RESULTS: An inferior intercavernous sinus was identified in 26 % of specimens. In all specimens, it communicated with the left and right cavernous sinus. The average width and length were 3 mm and 9.5 mm, respectively. In the sagittal plane, the inferior intercavernous sinus was positioned anteriorly in 31 %, at the nadir of the sella turcica in 38 %, and slightly posterior to the nadir of the sella turcica in 31 %. In two specimens (15.4 %), the sinus was plexiform in its shape. In one specimen a diploic vein connected the basilar venous plexus to the inferior intercavernous sinus on its deep surface. CONCLUSION: An improved understanding of the variable anatomy of the inferior intercavernous sinus is important in pathological, surgical, and radiological cases.

Mitral Valve Replacement Using Subvalvular Apparatus: A Systematic Review and Meta-Analysis.

BACKGROUND: To assess clinical outcomes among participants undergoing mitral valve replacement with preservation of subvalvular apparatus. METHODS: Electronic databases, including PubMed, Embase, Science Direct, World of Science, Scopus, Biosis, SciElo and Cochrane library, were probed using an extensive search strategy. Studies that reported at least one clinical outcome, such as morbidity, mortality, early 30-day mortality, myocardial failure, survival, late cerebrovascular events, length of stay, or major operative complications (stroke, prolonged ventilation, and reoperation for bleeding, renal failure, and sternal infection) were considered for inclusion. Data was extracted and pooled into a meta-analysis in RevMan (version 5.3) using a random-effects model. RESULTS: A total of 21 studies with 5,106 participants (age range: 27.3-69.2 years) were included in this meta-analysis. Preservation of the subvalvular apparatus during MVR significantly reduces the risk of long-term mortality (OR: 0.46; 95% CI: 0.33-0.64), but not early mortality (OR: 0.76; 95% CI: 0.12-4.93). No significant difference ejection fraction was observed (SMD: 0.10; 95% CI: -0.44-0.64). Similarly, there was no significant difference in the risk of stroke, renal failure, and pneumonia between C-MVR and in the control group. CONCLUSION: MVR with the preservation of subvalvular apparatus improves clinical outcomes, such as long-term mortality, hospital length of stay, pneumonia, and bleeding. There is no significant difference in the risk of stroke, renal failure, or ICU length of stay. However, there is very limited data available with respect to bleeding, sepsis, and nosocomial infections.

Laboratory abnormalities in children with mild and severe coronavirus disease 2019 (COVID-19): A pooled analysis and review.

Limited data exists to-date on the laboratory findings in children with COVID-19, warranting the conduction of this study, in which we pool the currently available literature data on the laboratory findings seen in children with mild and severe COVID-19. Following an extensive literature search, we identified 24 eligible studies, including a total of 624 pediatric cases with laboratory-confirmed COVID-19, which report data on 27 different biomarkers. We then performed a meta-analysis to calculate the pooled prevalence estimates (PPE) for these laboratory abnormalities in mild COVID-19. As data was too limited for children with severe COVID-19 to allow pooling, results were presented descriptively in a summary of findings table. Our data show an inconsistent pattern of change in the leukocyte index of mild and severe cases of COVID-19 in children. Specifically, changes in leukocyte counts were only observed in 32% of the mild pediatric cases (PPE: 13% increase, 19% decrease). In mild disease, creatine kinase-MB (CK-MB) was frequently elevated, with a PPE of 33%. In severe disease, c-reactive protein (CRP), procalcitonin (PCT), and lactate dehydrogenase (LDH) were frequently elevated. Based on data obtained from early COVID-19 studies, leukocyte indices in children appear inconsistent, differing from those reported in adults that highlight specific leukocyte trends. This brings into question the utility and reliability of such parameters in monitoring disease severity in the pediatric population. Instead, we suggest physicians to serially monitor CRP, PCT, and LDH to track the course of illness in hospitalized children. Finally, elevated CK-MB in mild pediatric COVID-19 cases is indicative of possible cardiac injury. This highlights the importance of monitoring cardiac biomarkers in hospitalized patients and the need for further investigation of markers such as cardiac troponin in future studies.