Systemic review of the robustness of randomized controlled trials for the treatment of cholangiocarcinoma in three domains: survival-inferred fragility index, restricted mean survival time, and the spin effect

Background:The vast majority of patients with cholangiocarcinoma(CC)have advanced disease at diagnosis and are candidates for palliative treatment only.The robustness of the randomized controlled trials regarding the treatment of CC are assessed.Methods:A systematic review of all randomized control trials(RCT)of treatments for both intra-and extrahepatic CC between 2010 and 2020 was performed.The survival-inferred fragility index(SIFI;the minimum number of reassignments of the best survivors between arms that would overturn the statistical outcomes)was calculated.In addition,the gain,or loss,in survival in RCTs was evaluated by the restricted mean survival time(RMST)difference.Finally,the level of spin i.e.,misrepresentation of study outcomes,was measured in inconclusive studies to assess distorted reporting strategies.Results:Out of 6,167 studies retrieved,11 could be retained for full text revision(7 with both intra-and extrahepatic CC,3 with peri-hilar CC,and 1 with peri-hilar or distal CC).Only 3 studies included resected patients(2 with both intra-and extrahepatic CC and 1 with peri-hilar or distal CC).Nine studies investigated systemic chemotherapy(including 3 after surgical resection),one study evaluated photodynamic therapy,and another investigated the use of an endoscopically inserted stent in the biliary tract.The median SIFI was−2[interquartile range(IQR):−6.25,−0.25]across all studies.Overall,the median RMST difference was 0.56 months(IQR:0.10,0.95).Finally,for inconclusive studies,the level of spin was high,moderate,and low in respectively 12.5%,25%,and 62.5% of the studies.Conclusions:RCTs of CC showed a low degree of robustness with a frequent proportion of associated spin.

Fragility of statistically significant findings from randomized clinical trials of surgical treatment of humeral shaft fractures:A systematic review

BACKGROUND Despite recent meta-analyses of randomized controlled trials(RCTs),there remains no consensus regarding the preferred surgical treatment for humeral shaft fractures.The fragility index(FI)is an emerging tool used to evaluate the robustness of RCTs by quantifying the number of participants in a study group that would need to switch outcomes in order to reverse the study conclusions.AIM To investigate the fragility index of randomized control trials assessing outcomes of operative fixation in proximal humerus fractures.METHODS We completed a systematic review of RCTs evaluating the surgical treatment of humeral shaft fractures.Inclusion criteria included:articles published in English;patients randomized and allotted in 1:1 ratio to 2 parallel arms;and dichotomous outcome variables.The FI was calculated for total complications,each complication individually,and secondary surgeries using the Fisher exact test,as previously published.RESULTS Fifteen RCTs were included in the analysis comparing open reduction plate osteosynthesis with dynamic compression plate or locking compression plate,intramedullary nail,and minimally invasive plate osteosynthesis.The median FI was 0 for all parameters analyzed.Regarding individual outcomes,the FI was 0 for 81/91(89%)of outcomes.The FI exceeded the number lost to follow up in only 2/91(2%)outcomes.CONCLUSION The FI shows that data from RCTs regarding operative treatment of humeral shaft fractures are fragile and does not demonstrate superiority of any particular surgical technique.

State fragility and the coronavirus disease 2019(COVID-19)pandemic:an ecologic analysis of data from 146 countries

Background:Global spread and impact of the coronavirus disease 2019(COVID-19)pandemic are determined to a large extent,by resistance to the pandemic and public response of all countries in the world;while a country's resistance and response are in turn determined by its political and socio economic conditions.To inform future disease prevention and control,we analyzed global data to exam the relationship between state vulnerabilities and COVID-19 incidences and deaths.Methods:Vulnerability was measured using the Fragile States Index(FSI).FSI is created by the Fund for Peace to assess levels of fragility for individual countries.Total FSI score and scores for 12 specific indicators were used as the predictor variables.Outcome variables were national cumulative COVID-19 cases and deaths up to September 16,2020,derived from the World Health Organization.Cumulative incidence rates were computed using 2019 National population derived from the World Bank,and case fatality rates were computed as the ratio of deaths/COVID-19 cases.Countries with incomplete data were excluded,yielding a final sample of 146 countries.Multivariate regression was used to examine the association between the predictor and the outcome measures.Results:There were dramatic cross-country variations in both FSI and COVID-19 epidemiological measurements.FSI total scores were negatively associated with both COVID-19 cumulative incidence rates(β=-0.0135,P<0.001)and case fatality rates(β=-0.0147,P<0.05).Of the 12 FSI indicators,three negatively associated with COVID-19 incidences were E1(Economic Decline and Poverty),E3(Human Flight and Brain Drain),and S2(Refugees and Internally Displaced Persons);two positively associated were P1(State Legitimacy)and X1(External Intervention).With regard to association with case fatality rates,C1(Security Apparatus)was positive,and P3(Human Rights and Rule of Law)and X1 was negative.Conclusion:With FSI measures by the Fund of Peace,overall,more fragile countries are less likely to be affected by the COVID-19 pandemic,and even if affected,death rates were lower.However,poor in state legitimacy and lack of external intervention are risk for COVID-19 infection and lack of security apparatus is risky for COVID-19 death.Implications of the study findings are discussed and additional studies are needed to examine the mechanisms underpinning these relationships.

Glass formation,thermal and mechanical properties of ZrCuAlNi bulk metallic glasses

The glass forming ability, thermal and mechanical properties of some Zr Cu Al Ni bulk metallic glasses were analyzed. The compositions of the alloys were theoretically determined with the dense packing and kinetic fragility index models. Cylindrical and conical ingots were produced by copper mould suction-casting under Ar atmosphere. The conical ingots were characterized by means of X-ray diffraction in order to determine the glassy structure. It was found that both alloys have a critical glassy diameter, Dc, of 3 mm. Thermal behaviours were investigated by differential scanning calorimetry at heating rates of 0.5, 0.67 and 0.83 K/s. The gamma parameter γ, supercooled liquid region ΔTx, and reduced glass transition temperature Trg, of the experimentally obtained glasses indicated high glass forming ability. The glassy compositions showed a fragility index of ~40 GPa. The compression test of the investigated alloys was carried out at a strain rate of 0.016 s^-1, obtaining a elastic modulus of ~83 GPa, total deformation of ~5%, yield strength of 1.6 GPa and hardness of 4 GPa. It was concluded that the use of the dense packing and kinetic fragility index models helped to predict glass-forming compositions in the family alloy investigated.