Perioperative costs of local or regional anesthesia versus general anesthesia in the outpatient setting: a systematic review of recent literature

Abstract Background and objectives: In this systematic review, we carried out an assessment of perioperative costs of local or regional anesthesia versus general anesthesia in the ambulatory setting. Methods: A systematic literature search was conducted to find relevant data on costs and cost-effectiveness analyses of anesthesia regimens in outpatients, regardless of the medical procedure they underwent. The hypothesis was that local or regional anesthesia has a lower economic impact on hospital costs in the outpatient setting. The primary outcome was the average total cost of anesthesia calculated on perioperative costs (drugs, staff, resources used). Results: One-thousand-six-hundred-ninety-eight records were retrieved, and 28 articles including 27,581 patients were selected after reviewing the articles. Data on the average total costs of anesthesia and other secondary outcomes (anesthesia time, recovery time, time to home readiness, hospital stay time, complications) were retrieved. Taken together, these findings indicated that local or regional anesthesia is associated with lower average total hospital costs than general anesthesia when performed in the ambulatory setting. Reductions in operating room time and postanesthesia recovery time and a lower hospital stay time may account for this result. Conclusions: Despite the limitations of this systematic review, mainly the heterogeneity of the studies and the lack of cost-effectiveness analysis, the economic impact of the anesthesia regimes on healthcare costs appears to be relevant and should be further evaluated.

Perioperative costs of local or regional anesthesia versus general anesthesia in the outpatient setting: a systematic review of recent literature.

BACKGROUND AND OBJECTIVES: In this systematic review, we carried out an assessment of perioperative costs of local or regional anesthesia versus general anesthesia in the ambulatory setting. METHODS: A systematic literature search was conducted to find relevant data on costs and cost-effectiveness analyses of anesthesia regimens in outpatients, regardless of the medical procedure they underwent. The hypothesis was that local or regional anesthesia has a lower economic impact on hospital costs in the outpatient setting. The primary outcome was the average total cost of anesthesia calculated on perioperative costs (drugs, staff, resources used). RESULTS: One-thousand-six-hundred-ninety-eight records were retrieved, and 28 articles including 27,581 patients were selected after reviewing the articles. Data on the average total costs of anesthesia and other secondary outcomes (anesthesia time, recovery time, time to home readiness, hospital stay time, complications) were retrieved. Taken together, these findings indicated that local or regional anesthesia is associated with lower average total hospital costs than general anesthesia when performed in the ambulatory setting. Reductions in operating room time and postanesthesia recovery time and a lower hospital stay time may account for this result. CONCLUSIONS: Despite the limitations of this systematic review, mainly the heterogeneity of the studies and the lack of cost-effectiveness analysis, the economic impact of the anesthesia regimes on healthcare costs appears to be relevant and should be further evaluated.

A phase I trial of inotuzumab ozogamicin in combination with temsirolimus in patients with relapsed or refractory CD22-positive B-cell non-Hodgkin lymphomas.

This phase I trial evaluated the safety, tolerability, and preliminary activity of inotuzumab ozogamicin in combination with temsirolimus in patients with relapsed/refractory CD22 positive B-cell non-Hodgkin lymphomas. Nineteen patients received at least one dose of both study drugs. Dose-limiting toxicities consisted of thrombocytopenia, hypertriglyceridemia, oral mucositis, clinical deterioration, and the inability to receive at least three doses of temsirolimus during cycle 1. The most common grade ≥3 treatment-related adverse events were thrombocytopenia (n = 8), neutropenia (n = 5), and two patients each hyperphosphatemia, lymphopenia, and hypertriglyceridemia. The recommended phase II dose was inotuzumab ozogamicin 0.8 mg/m2 on day 1 in combination with temsirolimus 10 mg on days 8, 15, and 22 every 28 days. Among 18 patients evaluable, seven (39%) with follicular lymphoma had a partial remission. This drug combination is not possible within a therapeutically useful range of doses due to toxicities. Antitumor activity was observed in heavily pretreated patients (ClinicalTrials.gov, Identifier NCT01535989).

Phase I Dose-Escalation Study of the Dual PI3K-mTORC1/2 Inhibitor Gedatolisib in Combination with Paclitaxel and Carboplatin in Patients with Advanced Solid Tumors.

PURPOSE: This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel. PATIENTS AND METHODS: Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m2 on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression. RESULTS: Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0-2). Median number of administered cycles was 6 (range, 2-16). Dose-limiting toxicities occurred in 4 patients: 2 (cycle 2 delay due to G2-G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m2 on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results. CONCLUSIONS: Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.

P1245 Polymorphic Variants of HSD3B1 Gene Confer Different Outcome in Specific Subgroups of Patients Infected With SARS-CoV-2.

Introduction: Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the androgen receptor (AR), through ACE2 receptor and TMPRSS2, to enter nasal and upper airways epithelial cells. Genetic analyses revealed that HSD3B1 P1245C polymorphic variant increases dihydrotestosterone production and upregulation of TMPRSS2 with respect to P1245A variant, thus possibly influencing SARS-CoV-2 infection. Our aim was to characterize the HSD3B1 polymorphism status and its potential association with clinical outcomes in hospitalized patients with COVID-19 in Southern Switzerland. Materials and Methods: The cohort included 400 patients hospitalized for COVID-19 during the first wave between February and May 2020 in two different hospitals of Canton Ticino. Genomic DNA was extracted from formalin-fixed paraffin-embedded tissue blocks, and HSD3B1 gene polymorphism was evaluated by Sanger sequencing. Statistical associations were verified using different test. Results: HSD3B1 polymorphic variants were not associated with a single classical factor related to worse clinical prognosis in hospitalized patients with SARS-CoV-2. However, in specific subgroups, HSD3B1 variants played a clinical role: intensive care unit admission was more probable in patients with P1245C diabetes compared with P1245A individuals without this comorbidity and death was more associated with hypertensive P1245A>C cases than patients with P1245A diabetes without hypertension. Discussion: This is the first study showing that HSD3B1 gene status may influence the severity of SARS-CoV-2 infection. If confirmed, our results could lead to the introduction of HSD3B1 gene status analysis in patients infected with SARS-CoV-2 to predict clinical outcome.

Prevalence of microhematuria in renal colic and urolithiasis: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aims to investigate the prevalence of microhematuria in patients presenting with suspected acute renal colic and/or confirmed urolithiasis at the emergency department. METHODS: A comprehensive literature search was conducted to find relevant data on prevalence of microhematuria in patients with suspected acute renal colic and/or confirmed urolithiasis. Data from each study regarding study design, patient characteristics and prevalence of microhematuria were retrieved. A random effect-model was used for the pooled analyses. RESULTS: Forty-nine articles including 15'860 patients were selected through the literature search. The pooled microhematuria prevalence was 77% (95%CI: 73-80%) and 84% (95%CI: 80-87%) for suspected acute renal colic and confirmed urolithiasis, respectively. This proportion was much higher when the dipstick was used as diagnostic test (80 and 90% for acute renal colic and urolithiasis, respectively) compared to the microscopic urinalysis (74 and 78% for acute renal colic and urolithiasis, respectively). CONCLUSIONS: This meta-analysis revealed a high prevalence of microhematuria in patients with acute renal colic (77%), including those with confirmed urolithiasis (84%). Intending this prevalence as sensitivity, we reached moderate values, which make microhematuria alone a poor diagnostic test for acute renal colic or urolithiasis. Microhematuria could possibly still important to assess the risk in patients with renal colic.

Diagnostic performance of 18F-FDG PET/CT in patients with spinal infection: a systematic review and a bivariate meta-analysis.

PURPOSE: Diagnosis of spinal infection (SI) is challenging and usually requires multiple tests. We aimed to perform a systematic review and a bivariate meta-analysis on the diagnostic role of 18F-FDG PET/CT in patients with SI. METHODS: A comprehensive literature search of studies published through February 2019 in PubMed/MEDLINE and Cochrane library databases was carried out. Studies investigating the diagnostic performance of 18F-FDG PET/CT in patients with SI were eligible for inclusion in the qualitative analysis. For the quantitative analysis, pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR-) and diagnostic odds ratio (DOR) of 18F-FDG PET/CT in patients with suspected SI were calculated on a per examination-based analysis. Pooled data were presented with 95% confidence intervals (95% CI). RESULTS: Twenty-six articles (833 patients) using 18F-FDG PET/CT were eligible for the qualitative analysis. Twelve studies (396 patients) were selected for the meta-analysis. Overall, 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment. The bivariate meta-analysis on 18F-FDG PET/CT in patients with suspected SI provided the following results: sensitivity 94.8% (95% CI 88.9-97.6%) and specificity 91.4% (95% CI 78.2-96.9%). The pooled LR+, LR- and DOR were 4.7 (95% CI 2.9-7.7), 0.11 (95% CI 0.07-0.16) and 63.4 (95% CI 28.9-139), respectively. No significant heterogeneity or publication bias was found. CONCLUSION: 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and can be used in patients in which MRI cannot be performed or is non-diagnostic or inconclusive. Several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment in patients with SI. Overall, larger multicentre and prospective studies and cost-effectiveness analyses are warranted.

Radiolabelled choline versus PSMA PET/CT in prostate cancer restaging: a meta-analysis.

Both radiolabelled choline and prostate specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) could be used in patients with biochemical recurrent prostate cancer (BRPCa). We aimed to perform a meta-analysis about the head-to-head comparison of detection rate (DR) between these methods in BRPCa. A comprehensive literature search of studies listed in PubMed/MEDLINE, EMBASE and Cochrane library databases through October 2018 and regarding the head-to-head comparison of DR between radiolabelled choline and PSMA PET/CT in BRPCa was carried out. Overall pooled DR was calculated on a per patient-based analysis; subgroup analyses taking into account different prostate-specific antigen (PSA) cut-off values were performed. Five studies (257 BRPCa patients) were included. The meta-analysis provided the following overall DR: 56% [95% confidence interval (95% CI): 37-75%] for radiolabelled choline PET/CT and 78% (95% CI: 70-84%) for radiolabelled PSMA PET/CT. Significant difference of DR was found only in patients with PSA ≤ 1 ng/ml [the DR of radiolabelled choline and PSMA PET/CT were 27% (95% CI: 17-39%) and 54% (95% CI: 43-65%), respectively]. Radiolabelled PSMA PET/CT proved to be clearly superior in detecting BRPCa lesions at low PSA levels (≤ 1 ng/ml) when compared to radiolabelled choline PET/CT. On the other hand, the superiority of radiolabelled PSMA PET/CT was less evident in patients with PSA > 1 ng/ml. More studies and in particular cost-effectiveness analyses comparing these imaging methods are warranted.

Detection rate of unknown primary tumour by using somatostatin receptor PET/CT in patients with metastatic neuroendocrine tumours: a meta-analysis.

PURPOSE: The high diagnostic performance of somatostatin receptor positron emission tomography with computed tomography (PET/CT) in neuroendocrine tumours (NETs) was demonstrated by several articles. However, only some studies evaluated the detection rate (DR) of this imaging method in patients with metastatic NETs and unknown primary tumours (CUP-NETs). Therefore, we aimed to perform a meta-analysis to add evidence-based data in this setting. METHODS: A comprehensive computer literature search of studies listed in PubMed/MEDLINE, EMBASE, and Cochrane library databases through December 2018 and regarding the use of somatostatin receptor PET/CT in patients with CUP-NETs was carried out. Pooled DR of CUP-NETs by using somatostatin receptor PET/CT was calculated. A pooled analysis evaluating the percentage of change of management by using somatostatin receptor PET/CT in these patients was also performed. RESULTS: Twelve studies on the use of somatostatin receptor PET/CT in detecting CUP-NETs in 383 metastatic patients were included. The meta-analysis of all these studies provided the following DR on a per patient-based analysis: 56% (95% confidence interval (95% CI): 48-63%). Moderate heterogeneity among the selected studies was found (I2 = 50%), whereas a significant publication bias was excluded by Egger's test (p = 0.45). The most common primary tumour sites were the bowel and the pancreas. A change of management by using somatostatin receptor PET/CT was demonstrated in 20% (95% CI: 10-33%) of patients with CUP-NET. CONCLUSIONS: Somatostatin receptor PET/CT is very useful in detecting CUP-NETs in patients with metastatic disease. More studies on the change of management by using this imaging method in this setting are needed.

Correlation between PSA kinetics and PSMA-PET in prostate cancer restaging: A meta-analysis.

BACKGROUND: Serum prostate-specific antigen (PSA) may predict the risk of positive positron emission tomography/computed tomography with radiolabelled prostate-specific membrane antigen (PSMA-PET/CT) in patients with biochemical recurrent prostate cancer (BRPCa). However, to date, there are no clear data regarding the correlation between PSA kinetics and PSMA-PET findings. We performed a systematic review and meta-analysis to provide evidence-based data in this setting. METHODS: A comprehensive literature search of studies published through October 2018 in PubMed/MEDLINE, EMBASE and Cochrane library databases was performed. A meta-analysis to establish the detection rate (DR) of PSMA-PET using different cut-off values of PSA doubling time (PSAdt) and a pooled analysis to establish whether shorter PSAdt may predict positive PSMA-PET results was performed in patients with BRPCa. RESULTS: Twelve articles were included in the systematic review, and eight articles (including about 1400 patients) were selected for the meta-analysis. The pooled DR including 95% confidence intervals (95%CI) of PSMA-PET in restaging prostate cancer (PCa) patients was 72% (95%CI:60%-82%), increasing to 83% (95%CI:75%-90%) when PSAdt was ≤6 months and decreasing to 60% (95%CI:37%-80%) when PSAdt was >6 months, without a statistical significant difference. PSAdt ≤6 months may predict the positive result of PSMA-PET (pooled odds ratio: 3.22; 95%CI:1.17-8.88). Statistical heterogeneity among the included studies was found. CONCLUSIONS: PSA kinetics, and in particular shorter PSAdt, may be predictor of PSMA-PET positivity in patients with BRPCa. Further larger studies in this setting are warranted.

Impact of 18F-FDG PET/CT in Staging Patients With Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Background: Molecular imaging methods are currently used in the management of patients with lung cancer. Compared to non-small cell lung cancer, less data are available about the impact of molecular imaging using fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in staging patients with small cell lung cancer (SCLC). Performing a systematic review and meta-analysis, we aimed to provide quantitative data about the impact of 18F-FDG PET/CT in staging SCLC. Methods: A comprehensive literature search of studies on the use of 18F-FDG PET/CT in patients with SCLC was performed. Three different databases were screened (PubMed/MEDLINE, EMBASE, and Cochrane library databases) until June 2019. Only articles describing the impact of 18F-FDG PET/CT in staging patients with SCLC were selected. A pooled analysis evaluating the change of binary SCLC staging (limited-stage vs. extensive-stage disease) using 18F-FDG PET/CT was carried out. Results: Nine articles including 721 patients with SCLC were included in the systematic review. Compared to conventional staging, a superior diagnostic accuracy of 18F-FDG PET/CT was found. A change of binary SCLC staging using 18F-FDG PET/CT was demonstrated in 15% (95% confidence interval, 9-21%) of patients with SCLC. Currently, it is not clearly demonstrated that the use of 18F-FDG PET/CT for staging may improve the survival outcome of patients with SCLC. Conclusions: 18F-FDG PET/CT is a useful molecular imaging method for staging patients with SCLC because it can change the management in a significant number of patients. More large prospective studies and cost-effectiveness analyses on the impact of 18F-FDG PET/CT in staging patients with SCLC are needed.

The role of serum neuron-specific enolase in patients with prostate cancer: a systematic review of the recent literature.

In this systematic review, we evaluated the value of serum concentrations of neuron-specific enolase (NSE) in patients with prostate cancer (PCa) in order to clarify the possible role of NSE in the diagnosis, management, treatment and monitoring of PCa. A comprehensive search of the recent literature was conducted to find relevant data on the role of NSE in PCa. Two hundred and eighty-two records were revealed, and 19 articles including 1,772 patients with PCa (either confirmed or suspected) were selected. After reviewing the articles, the major result was that elevated serum NSE appears to correlate with prognosis in advanced PCa, particularly in patients with progressive and metastatic castration-resistant PCa. Based on the existing literature, the role of serum NSE in PCa patients should be further evaluated.

The outcome of prostate cancer patients treated with curative intent strongly depends on survival after metastatic progression.

BACKGROUND: Five-year survival in patients with localized prostate cancer (PCa) is nearly 100%, but metastatic disease still remains incurable. Clinical management of metastatic patients has become increasingly complex as novel therapeutic strategies have emerged. This study aims at evaluating the impact of the first metastatic progression on the outcome of PCa patients treated with curative intent. METHODS: The analysis was conducted using data of 913 cases of localized PCa diagnosed between 2000 and 2014. All patients were treated with curative surgery (N = 382) or radiotherapy (N = 531) with or without adjuvant therapy. All metastases were radiologically documented. The prognostic impact of the first site of metastasis on metastasis-free survival (MFS) and PCa-specific survival (PCaSS) was investigated by univariate and multivariate analyses. RESULTS: One hundred and thirty-six (14.9%) patients developed a metastatic hormone-sensitive PCa and had a median PCaSS of 50.4 months after first metastatic progression. Bone (N = 50, 36.8%) and LN or locoregional (N = 52, 38.2%) metastases occurred more frequently with a median PCaSS of 39.7 and 137 months respectively (p < 0.0001). Seven patients developed visceral metastasis only (5.1%; liver, lung, brain) and 27 (19.9%) concurrent metastases; this last group was associated with the worst survival with a median value of only 17 months. Thus, each subgroup exhibited a survival after metastasis significantly different from each other. In multivariate analysis the site of the first metastasis was an independent prognostic factor for PCaSS along with Gleason score at diagnosis. The correlation between survival and first site of metastasis was confirmed separately for each therapy subgroup. Median metastasis-free survival from primary diagnosis to first metastasis was not correlated with the first site of metastasis. CONCLUSIONS: In non-metastatic PCa patients treated with curative intent, the PCa-specific survival time depends on the time after metastatic progression rather than the time from diagnosis to metastasis. Moreover, the site of first metastasis is an independent prognostic factor for PCaSS. Our data confirm that the first metastatic event may confer a differential prognostic impact and may help in identifying patient at high risk of death supporting the treatment-decision making process following metastatic progression.

The proliferation marker Ki67, but not neuroendocrine expression, is an independent factor in the prediction of prognosis of primary prostate cancer patients.

BACKGROUND: Neuroendocrine markers, which could indicate for aggressive variants of prostate cancer and Ki67 (a well-known marker in oncology for defining tumor proliferation), have already been associated with clinical outcome in prostate cancer. The aim of this study was to investigate the prognostic value of those markers in primary prostate cancer patients. PATIENTS AND METHODS: NSE (neuron specific enolase), ChrA (chromogranin A), Syp (Synaptophysin) and Ki67 staining were performed by immunohistochemistry. Then, the prognostic impact of their expression on overall survival was investigated in 166 primary prostate cancer patients by univariate and multivariate analyses. RESULTS: NSE, ChrA, Syp and Ki67 were positive in 50, 45, 54 and 146 out of 166 patients, respectively. In Kaplan-Meier analysis only diffuse NSE staining (negative vs diffuse, p = 0.004) and Ki67 (≤ 10% vs > 10%, p < 0.0001) were significantly associated with overall survival. Ki67 expression, but not NSE, resulted as an independent prognostic factor for overall survival in multivariate analysis. CONCLUSIONS: A prognostic model incorporating Ki67 expression with clinical-pathological covariates could provide additional prognostic information. Ki67 may thus improve prediction of prostate cancer outcome based on standard clinical-pathological parameters improving prognosis and management of prostate cancer patients.

The Lepidopteran endoribonuclease-U domain protein P102 displays dramatically reduced enzymatic activity and forms functional amyloids.

Hemocytes of Heliothis virescens (F.) (Lepidoptera, Noctuidae) larvae produce a protein, P102, with a putative endoribonuclease-U domain. In previous works we have shown that P102 is involved in Lepidopteran immune response by forming amyloid fibrils, which catalyze and localize melanin deposition around non-self intruders during encapsulation, preventing harmful systemic spreading. Here we demonstrate that P102 belongs to a new class of proteins that, at least in Lepidoptera, has a diminished endoribonuclease-U activity probably due to the lack of two out of five catalytically essential residues. We show that the P102 homolog from Trichoplusia ni (Lepidoptera, Noctuidae) displays catalytic site residues identical to P102, a residual endoribonuclease-U activity and the ability to form functional amyloids. On the basis of these results as well as sequence and structural analyses, we hypothesize that all the Lepidoptera endoribonuclease-U orthologs with catalytic site residues identical to P102 form a subfamily with similar function.

Is human papillomavirus associated with prostate cancer survival?

The role of human papillomavirus (HPV) in prostate carcinogenesis is highly controversial: some studies suggest a positive association between HPV infection and an increased risk of prostate cancer (PCa), whereas others do not reveal any correlation. In this study, we investigated the prognostic impact of HPV infection on survival in 150 primary PCa patients. One hundred twelve (74.67%) patients had positive expression of HPV E7 protein, which was evaluated in tumour tissue by immunohistochemistry. DNA analysis on a subset of cases confirmed HPV infection and revealed the presence of genotype 16. In Kaplan-Meier analysis, HPV-positive cancer patients showed worse overall survival (OS) (median 4.59 years) compared to HPV-negative (median 8.24 years, P = 0.0381). In multivariate analysis age (P < 0.001), Gleason score (P < 0.001), nuclear grading (P = 0.002), and HPV status (P = 0.034) were independent prognostic factors for OS. In our cohort, we observed high prevalence of HPV nuclear E7 oncoprotein and an association between HPV infection and PCa survival. In the debate about the oncogenic activity of HPV in PCa, our results further confirm the need for additional studies to clarify the possible role of HPV in prostate carcinogenesis.

Functional amyloids in insect immune response.

The innate immune system of insects consists of humoural and cellular responses that provide protection against invading pathogens and parasites. Defence reactions against these latter include encapsulation by immune cells and targeted melanin deposition, which is usually restricted to the surface of the foreign invader, to prevent systemic damage. Here we show that a protein produced by haemocytes of Heliothis virescens (Lepidoptera, Noctuidae) larvae, belonging to XendoU family, generates amyloid fibrils, which accumulate in large cisternae of the rough endoplasmic reticulum and are released upon immune challenge, to form a layer coating non-self objects entering the haemocoel. This amyloid layer acts as a molecular scaffold that promotes localised melanin synthesis and the adhesion of immune cells around the non-self intruder during encapsulation response. Our results demonstrate a new functional role for these protein aggregates that are commonly associated with severe human diseases. We predict that insects will offer new powerful experimental systems for studying inducible amyloidogenesis, which will likely provide fresh perspectives for its prevention.