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  1. Boyle E, Healy D, Hill AD, O'Connell PR, Kerin M, McHugh S, et al.
    Ir J Med Sci, 2013 Sep;182(3):337-43.
    PMID: 23242574 DOI: 10.1007/s11845-012-0882-x
    INTRODUCTION: The national junior doctor recruitment crisis prompts an appraisal of medical student attitudes to different career pathways. The purpose of this study was to perform a national review of surgical career intentions of Irish final year medical students.

    METHODS: Ethical and institutional approval was obtained at each study location. A questionnaire was designed and distributed to final year students. Domains assessed included demographics, career plans and reasons associated. Anonymised responses were collated and evaluated. Categorical data were compared with Fisher's exact test.

    RESULTS: Responses were obtained from 342 students in four medical schools of whom 78.6% were undergraduates. Over half (53%) were Irish, with Malaysia, Canada and the USA the next most common countries of origin. Only 18% of students intended to pursue surgery, with 60% stating they did not plan to, and 22% undecided. Of those who plan not to pursue surgery, 28% were unsure about a speciality but the most common choices were medicine (39%), general practice (16%) and paediatrics (8%). Reasons for not picking a career in surgery included long hours and the unstructured career path. Suggestions to improve uptake included earlier and more practical exposure to surgery, improved teaching/training and reduction in working hours.

    CONCLUSIONS: In this study 18% of final year medical students identified surgery as their chosen career pathway. Although lifestyle factors are significant in many students' decision, perceived quality and duration of surgical training were also relevant and are modifiable factors which, if improved could increase interest in surgery as a career.

  2. Dresen E, Lee ZY, Hill A, Notz Q, Patel JJ, Stoppe C
    Nutr Clin Pract, 2023 Feb;38(1):46-54.
    PMID: 36156315 DOI: 10.1002/ncp.10914
    In 1747, an important milestone in the history of clinical research was set, as the Scottish surgeon James Lind conducted the first randomized controlled trial. Lind was interested in scurvy, a severe vitamin C deficiency which caused the death of thousands of British seamen. He found that a dietary intervention with oranges and lemons, which are rich in vitamin C by nature, was effective to recover from scurvy. Because of its antioxidative properties and involvement in many biochemical processes, the essential micronutrient vitamin C plays a key role in the human biology. Moreover, the use of vitamin C in critical illness-a condition also resulting in death of thousands in the 21st century-has gained increasing interest, as it may restore vascular responsiveness to vasoactive agents, ameliorate microcirculatory blood flow, preserve endothelial barriers, augment bacterial defense, and prevent apoptosis. Because of its redox potential and powerful antioxidant capacity, vitamin C represents an inexpensive and safe antioxidant, with the potential to modify the inflammatory cascade and improve clinical outcomes of critically ill patients. This narrative review aims to update and provide an overview on the role of vitamin C in the human biology and in critically ill patients, and to summarize current evidence on the use of vitamin C in diverse populations of critically ill patients, in specific focusing on patients with sepsis and coronavirus disease 2019.
  3. Patel JJ, Ortiz-Reyes A, Dhaliwal R, Clarke J, Hill A, Stoppe C, et al.
    Crit Care Med, 2022 Mar 01;50(3):e304-e312.
    PMID: 34637420 DOI: 10.1097/CCM.0000000000005320
    OBJECTIVES: To conduct a systematic review and meta-analysis to evaluate the impact of IV vitamin C on outcomes in critically ill patients.

    DATA SOURCES: Systematic search of MEDLINE, EMBASE, CINAHL, and the Cochrane Register of Controlled Trials.

    STUDY SELECTION: Randomized controlled trials testing IV vitamin C in critically ill patients.

    DATA ABSTRACTION: Two independent reviewers abstracted patient characteristics, treatment details, and clinical outcomes.

    DATA SYNTHESIS: Fifteen studies involving 2,490 patients were identified. Compared with placebo, IV vitamin C administration is associated with a trend toward reduced overall mortality (relative risk, 0.87; 95% CI, 0.75-1.00; p = 0.06; test for heterogeneity I2 = 6%). High-dose IV vitamin C was associated with a significant reduction in overall mortality (relative risk, 0.70; 95% CI, 0.52-0.96; p = 0.03), whereas low-dose IV vitamin C had no effect (relative risk, 0.94; 95% CI, 0.79-1.07; p = 0.46; test for subgroup differences, p = 0.14). IV vitamin C monotherapy was associated with a significant reduction in overall mortality (relative risk, 0.64; 95% CI, 0.49-0.83; p = 0.006), whereas there was no effect with IV vitamin C combined therapy. No trial reported an increase in adverse events related to IV vitamin C.

    CONCLUSIONS: IV vitamin C administration appears safe and may be associated with a trend toward reduction in overall mortality. High-dose IV vitamin C monotherapy may be associated with improved overall mortality, and further randomized controlled trials are warranted.

  4. Patel JJ, Hill A, Lee ZY, Heyland DK, Stoppe C
    Crit Care Med, 2022 Sep 01;50(9):1371-1379.
    PMID: 35853198 DOI: 10.1097/CCM.0000000000005602
    OBJECTIVES: Concise definitive review of how to read and critically appraise a systematic review.

    DATA SOURCES: None.

    STUDY SELECTION: Current literature describing the conduct, reporting, and appraisal of systematic reviews and meta-analyses.

    DATA EXTRACTION: Best practices for conducting, reporting, and appraising systematic review were summarized.

    DATA SYNTHESIS: A systematic review is a review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant original research, and to collect and analyze data from the studies that are included in the review. Critical appraisal methods address both the credibility (quality of conduct) and rate the confidence in the quality of summarized evidence from a systematic review. The A Measurement Tool to Assess Systematic Reviews-2 tool is a widely used practical tool to appraise the conduct of a systematic review. Confidence in estimates of effect is determined by assessing for risk of bias, inconsistency of results, imprecision, indirectness of evidence, and publication bias.

    CONCLUSIONS: Systematic reviews are transparent and reproducible summaries of research and conclusions drawn from them are only as credible and reliable as their development process and the studies which form the systematic review. Applying evidence from a systematic review to patient care considers whether the results can be directly applied, whether all important outcomes have been considered, and if the benefits are worth potential harms and costs.

  5. Henry JC, Wong LY, Reyes AM, Jin JZ, Ferguson MK, Yip CH, et al.
    Front Health Serv, 2023;3:1096144.
    PMID: 37609518 DOI: 10.3389/frhs.2023.1096144
    OBJECTIVES: There is a lack of evidence-based guidelines for enhancing global surgical care delivery. We propose a set of recommendations to serve as a framework to guide surgical quality improvement and scale-up initiatives in low and middle income countries (LMICs).

    METHODS: From January-December 2019, we reviewed the available literature and their application toward LMIC settings. The first initiative was the establishment of Best Practices Recommendations intended to summarize best-level evidence around quality improvement processes that have shown to decrease morbidity and mortality in LMICs. The GRADE level of evidence and strength of the recommendation were assigned in accordance with the WHO handbook for guidelines development. The second initiative was the scale-up of principles and practices by establishing international expert consensus on the optimal organization of surgical services in LMICs using a modified Delphi methodology.

    RESULTS: Recommendations for three topic areas were established: reducing surgical site infections, improving quality of trauma systems, and interventions to reduce maternal and perinatal mortality. 27 studies were included in a quantitative synthesis and meta-analysis for interventions reducing surgical site infections, 27 studies for interventions improving the quality of trauma systems, and 14 studies for interventions reducing maternal and perinatal mortality. Using Delphi methodology, an international expert panel established consensus that district hospitals should place the highest priority on developing surgical services for low complexity, high volume conditions. At the national level, emergency and essential surgical care should be integrated within national Universal Health Coverage frameworks.

    CONCLUSIONS: This project fills a critical cap in the rapidly developing field of global surgery: gathering evidence-based, practical, and cost-effective solutions that will serve as a guide for the efficient planning and allocation of resources necessary to promote quality and safe essential surgical services in LMICs.

  6. Stoppe C, Lee ZY, Lew CCH, Hill A, Ortiz-Reyes A, Heyland DK, et al.
    Crit Care Med, 2022 Sep 01;50(9):e720-e721.
    PMID: 35984061 DOI: 10.1097/CCM.0000000000005600
  7. Notz Q, Lee ZY, Menger J, Elke G, Hill A, Kranke P, et al.
    Crit Care, 2022 01 19;26(1):23.
    PMID: 35045885 DOI: 10.1186/s13054-022-03896-3
    BACKGROUND: Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients.

    METHODS: A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed.

    RESULTS: 1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] - 6.88; 95% CI - 11.27, - 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD - 3.53; 95% CI - 6.16, - 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care.

    CONCLUSION: Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact. Trial registration PROSPERO international prospective database of systematic reviews (CRD42021259238).

  8. Lee ZY, Chin Han Lew C, Stoppe C, Hill A, Ortiz-Reyes A, Dhaliwal R, et al.
    Crit Care Med, 2022 Aug 01;50(8):e691-e693.
    PMID: 35838267 DOI: 10.1097/CCM.0000000000005573
  9. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Füreder W, et al.
    Blood, 2019 02 07;133(6):530-539.
    PMID: 30510080 DOI: 10.1182/blood-2018-09-876136
    Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (-76.8% vs -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.
  10. Jin J, Akau Ola S, Yip CH, Nthumba P, Ameh EA, de Jonge S, et al.
    World J Surg, 2021 10;45(10):2993-3006.
    PMID: 34218314 DOI: 10.1007/s00268-021-06208-y
    BACKGROUND: Morbidity and mortality in surgical systems in low- and middle-income countries (LMICs) remain high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to improve peri-operative outcomes.

    METHODS: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country surgical systems was conducted according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC, occurred in a surgical setting, and measured the effect of an implementation and its impact. The primary outcome was mortality, and secondary outcomes were rates of rates of hospital-acquired infection (HAI) and surgical site infections (SSI). Prospero Registration: CRD42020171542.

    RESULT: Of 38,273 search results, 31 studies were included in a qualitative synthesis, and 28 articles were included in a meta-analysis. Implementation of multimodal bundled interventions reduced the incidence of HAI by a relative risk (RR) of 0.39 (95%CI 0.26 to 0.59), the effect of hand hygiene interventions on HAIs showed a non-significant effect of RR of 0.69 (0.46-1.05). The WHO Safe Surgery Checklist reduced mortality by RR 0.68 (0.49 to 0.95) and SSI by RR 0.50 (0.33 to 0.63) and antimicrobial stewardship interventions reduced SSI by RR 0.67 (0.48-0.93).

    CONCLUSION: There is evidence that a number of quality improvement processes, interventions and structural changes can improve mortality, HAI and SSI outcomes in the peri-operative setting in LMICs.

  11. Jin J, Akau'ola S, Yip CH, Nthumba P, Ameh EA, de Jonge S, et al.
    World J Surg, 2021 07;45(7):1982-1998.
    PMID: 33835217 DOI: 10.1007/s00268-021-06065-9
    BACKGROUND: Trauma mortality in low- and middle-income countries (LMICs) remains high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to decrease trauma mortality.

    METHODS: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country trauma systems was conducted from November 1989 to August 2020 according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC population according to World Bank Income Classification, occurred in a trauma setting, and measured the effect of implementation and its impact. The primary outcome was trauma mortality.

    RESULTS: Of 37,575 search results, 30 studies were included from 15 LMICs covering five WHO regions in a qualitative synthesis. Twenty-seven articles were included in a meta-analysis. Implementing a pre-hospital trauma system reduced overall trauma mortality by 45% (risk ratio (RR) 0.55, 95% CI 0.4 to 0.75). Training first responders resulted in an overall decrease in mortality (RR 0.47, 95% CI 0.28 to 0.78). In-hospital trauma training with certified courses resulted in a reduction of mortality (RR 0.71, 95% CI 0.62 to 0.78). Trauma audits and trauma protocols resulted in varying improvements in trauma mortality.

    CONCLUSION: There is evidence that quality improvement processes, interventions, and structure can improve mortality in the trauma systems in LMICs.

  12. Henry JA, Reyes AM, Ameh E, Yip CH, Nthumba P, Mehes M, et al.
    BMJ Open, 2023 Jan 24;13(1):e062687.
    PMID: 36693687 DOI: 10.1136/bmjopen-2022-062687
    OBJECTIVES: To develop consensus statements regarding the regional-level or district-level distribution of surgical services in low and middle-income countries (LMICs) and prioritisation of service scale-up.

    DESIGN: This work was conducted using a modified Delphi consensus process. Initial statements were developed by the International Standards and Guidelines for Quality Safe Surgery and Anesthesia Working Group of the Global Alliance for Surgical, Obstetric, Trauma and Anesthesia Care (G4 Alliance) and the International Society of Surgery based on previously published literature and clinical expertise. The Guidance on Conducting and REporting DElphi Studies framework was applied.

    SETTING: The Working Group convened in Suva, Fiji for a meeting hosted by the Ministry of Health and Medical Services to develop the initial statements. Local experts were invited to participate. The modified Delphi process was conducted through an electronically administered anonymised survey.

    PARTICIPANTS: Expert LMIC surgeons were nominated for participation in the modified Delphi process based on criteria developed by the Working Group.

    PRIMARY OUTCOME MEASURES: The consensus panel voted on statements regarding the organisation of surgical services, principles for scale-up and prioritisation of scale-up. Statements reached consensus if there was ≥80% agreement among participants.

    RESULTS: Fifty-three nominated experts from 27 LMICs voted on 27 statements in two rounds. Ultimately, 26 statements reached consensus and comprise the current recommendations. The statements covered three major themes: which surgical services should be decentralised or regionalised; how the implementation of these services should be prioritised; and principles to guide LMIC governments and international visiting teams in scaling up safe, accessible and affordable surgical care.

    CONCLUSIONS: These recommendations represent the first step towards the development of international guidelines for the scaling up of surgical services in LMICs. They constitute the best available basis for policymaking, planning and allocation of resources for strengthening surgical systems.

  13. Lee ZY, Dresen E, Lew CCH, Bels J, Hill A, Hasan MS, et al.
    Crit Care, 2024 Jan 06;28(1):15.
    PMID: 38184658 DOI: 10.1186/s13054-023-04783-1
    BACKGROUND: A recent large multicentre trial found no difference in clinical outcomes but identified a possibility of increased mortality rates in patients with acute kidney injury (AKI) receiving higher protein. These alarming findings highlighted the urgent need to conduct an updated systematic review and meta-analysis to inform clinical practice.

    METHODS: From personal files, citation searching, and three databases searched up to 29-5-2023, we included randomized controlled trials (RCTs) of adult critically ill patients that compared higher vs lower protein delivery with similar energy delivery between groups and reported clinical and/or patient-centred outcomes. We conducted random-effect meta-analyses and subsequently trial sequential analyses (TSA) to control for type-1 and type-2 errors. The main subgroup analysis investigated studies with and without combined early physical rehabilitation intervention. A subgroup analysis of AKI vs no/not known AKI was also conducted.

    RESULTS: Twenty-three RCTs (n = 3303) with protein delivery of 1.49 ± 0.48 vs 0.92 ± 0.30 g/kg/d were included. Higher protein delivery was not associated with overall mortality (risk ratio [RR]: 0.99, 95% confidence interval [CI] 0.88-1.11; I2 = 0%; 21 studies; low certainty) and other clinical outcomes. In 2 small studies, higher protein combined with early physical rehabilitation showed a trend towards improved self-reported quality-of-life physical function measurements at day-90 (standardized mean difference 0.40, 95% CI - 0.04 to 0.84; I2 = 30%). In the AKI subgroup, higher protein delivery significantly increased mortality (RR 1.42, 95% CI 1.11-1.82; I2 = 0%; 3 studies; confirmed by TSA with high certainty, and the number needed to harm is 7). Higher protein delivery also significantly increased serum urea (mean difference 2.31 mmol/L, 95% CI 1.64-2.97; I2 = 0%; 7 studies).

    CONCLUSION: Higher, compared with lower protein delivery, does not appear to affect clinical outcomes in general critically ill patients but may increase mortality rates in patients with AKI. Further investigation of the combined early physical rehabilitation intervention in non-AKI patients is warranted.

    PROSPERO ID: CRD42023441059.

  14. Ortiz-Reyes L, Lee ZY, Chin Han Lew C, Hill A, Jeschke MG, Turgeon AF, et al.
    Crit Care Med, 2023 Aug 01;51(8):1086-1095.
    PMID: 37114912 DOI: 10.1097/CCM.0000000000005887
    OBJECTIVES: Evidence supporting glutamine supplementation in severe adult burn patients has created a state of uncertainty due to the variability in the treatment effect reported across small and large randomized controlled trials (RCTs). We aimed to systematically review the effect of glutamine supplementation on mortality in severe adult burn patients.

    DATA SOURCES: MEDLINE, Embase, CINAHL, and Cochrane Central were searched from inception to February 10, 2023.

    STUDY SELECTION: RCTs evaluating the effect of enteral or IV glutamine supplementation alone in severe adult burn patients were included.

    DATA EXTRACTION: Two reviewers independently extracted data on study characteristics, burn injury characteristics, description of the intervention between groups, adverse events, and clinical outcomes.

    DATA SYNTHESIS: Random effects meta-analyses were performed to estimate the pooled risk ratio (RR). Trial sequential analyses (TSA) for mortality and infectious complications were performed. Ten RCTs (1,577 patients) were included. We observed no significant effect of glutamine supplementation on overall mortality (RR, 0.65, 95% CI, 0.33-1.28; p = 0.21), infectious complications (RR, 0.83; 95% CI, 0.63-1.09; p = 0.18), or other secondary outcomes. In subgroup analyses, we observed no significant effects based on administration route or burn severity. We did observe a significant subgroup effect between single and multicenter RCTs in which glutamine significantly reduced mortality and infectious complications in singe-center RCTs but not in multicenter RCTs. However, TSA showed that the pooled results of single-center RCTs were type 1 errors and further trials would be futile.

    CONCLUSIONS: Glutamine supplementation, regardless of administration, does not appear to improve clinical outcomes in severely adult burned patients.

  15. Notz Q, Heyland DK, Lee ZY, Menger J, Herrmann J, Chillon TS, et al.
    Intensive Care Med Exp, 2023 Dec 08;11(1):89.
    PMID: 38063975 DOI: 10.1186/s40635-023-00574-8
    BACKGROUND: Recent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment.

    METHODS: Patients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity.

    RESULTS: Two hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes.

    CONCLUSIONS: The identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients.

  16. Cheng AL, Cornelio G, Shen L, Price T, Yang TS, Chung IJ, et al.
    Clin Colorectal Cancer, 2017 06;16(2):e73-e88.
    PMID: 27780749 DOI: 10.1016/j.clcc.2016.08.005
    BACKGROUND: In patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC), outcomes with first-line chemotherapies are improved by adding weekly cetuximab. The APEC study investigated first-line once-every-2-weeks cetuximab plus chemotherapy for patients with KRAS wt mCRC; additional biomarker subgroups were also analyzed.

    PATIENTS AND METHODS: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated.

    RESULTS: In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations.

    CONCLUSION: The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.

  17. Davies TW, Kelly E, van Gassel RJJ, van de Poll MCG, Gunst J, Casaer MP, et al.
    Crit Care, 2023 Nov 20;27(1):450.
    PMID: 37986015 DOI: 10.1186/s13054-023-04729-7
    BACKGROUND: CONCISE is an internationally agreed minimum set of outcomes for use in nutritional and metabolic clinical research in critically ill adults. Clinicians and researchers need to be aware of the clinimetric properties of these instruments and understand any limitations to ensure valid and reliable research. This systematic review and meta-analysis were undertaken to evaluate the clinimetric properties of the measurement instruments identified in CONCISE.

    METHODS: Four electronic databases were searched from inception to December 2022 (MEDLINE via Ovid, EMBASE via Ovid, CINAHL via Healthcare Databases Advanced Search, CENTRAL via Cochrane). Studies were included if they examined at least one clinimetric property of a CONCISE measurement instrument or recognised variation in adults ≥ 18 years with critical illness or recovering from critical illness in any language. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for systematic reviews of Patient-Reported Outcome Measures was used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used in line with COSMIN guidance. The COSMIN checklist was used to evaluate the risk of bias and the quality of clinimetric properties. Overall certainty of the evidence was rated using a modified Grading of Recommendations, Assessment, Development and Evaluation approach. Narrative synthesis was performed and where possible, meta-analysis was conducted.

    RESULTS: A total of 4316 studies were screened. Forty-seven were included in the review, reporting data for 12308 participants. The Short Form-36 Questionnaire (Physical Component Score and Physical Functioning), sit-to-stand test, 6-m walk test and Barthel Index had the strongest clinimetric properties and certainty of evidence. The Short Physical Performance Battery, Katz Index and handgrip strength had less favourable results. There was limited data for Lawson Instrumental Activities of Daily Living and the Global Leadership Initiative on Malnutrition criteria. The risk of bias ranged from inadequate to very good. The certainty of the evidence ranged from very low to high.

    CONCLUSIONS: Variable evidence exists to support the clinimetric properties of the CONCISE measurement instruments. We suggest using this review alongside CONCISE to guide outcome selection for future trials of nutrition and metabolic interventions in critical illness.

    TRIAL REGISTRATION:  PROSPERO (CRD42023438187). Registered 21/06/2023.

  18. Godman B, Hill A, Simoens S, Selke G, Selke Krulichová I, Zampirolli Dias C, et al.
    Expert Rev Pharmacoecon Outcomes Res, 2021 Aug;21(4):527-540.
    PMID: 33535841 DOI: 10.1080/14737167.2021.1884546
    Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems.Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines.Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments.
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