Original article| Volume 142, P119-132, February 2022

Download started.


Sex and Gender Appraisal Tool-Systematic Reviews-2 and Participation-To-Prevalence Ratio assessed to whom the evidence applies in sepsis reviews

  • A Antequera
    Corresponding author: Tel.: (0034) 935537814 fax.: (0034) 935537809.
    Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    Search for articles by this author
  • E Stallings
    Clinical Biostatistics Unit, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Spain
    Search for articles by this author
  • RS Henry
    Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada

    Department of Psychiatry, McGill University, Montreal, Quebec, Canada
    Search for articles by this author
  • J Lopez-Alcalde
    Clinical Biostatistics Unit, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Spain

    Institute for Complementary and Integrative Medicine, University Hospital Zurich and University of Zurich, Zurich, Switzerland

    Universidad Francisco de Vitoria, Pozuelo de Alarcón, Spain
    Search for articles by this author
  • V Runnels
    University of Ottawa, Ottawa, Ontario, Canada
    Search for articles by this author
  • S Tudiver
    Researcher/Consultant - Gender and Health, Ottawa, Ontario, Canada
    Search for articles by this author
  • P Tugwell
    Department of Medicine, and School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada

    Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    WHO Collaborating Centre for Knowledge Translation and Health Technology Assessment in Health Equity, Bruyère Research Institute, Ottawa, Ontario, Canada
    Search for articles by this author
  • V Welch
    Bruyère Research Institute, University of Ottawa, Ottawa, Ontario, Canada

    School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
    Search for articles by this author
Published:November 08, 2021DOI:



      To revise a sex and gender appraisal tool for systematic reviews (SGAT-SR) and apply it to Cochrane sepsis reviews.

      Study design and setting

      The revision process was informed by existing literature on sex, gender, intersectionality, and feedback from an expert advisory board. We revised the items to consider additional factors associated with health inequities and appraised sex and gender considerations using the SGAT-SR-2 and female Participation-to-Prevalence Ratio (PPR) in Cochrane sepsis reviews.


      SGAT-SR-2 consists of 19 questions appraising the review's sections and use of the terms sex and gender. amongst 71 SRs assessed, 50.7% included at least one tool item, the most frequent being the number of participants by sex or gender at included study-level (24/71 reviews). Only four reviews provided disaggregated data for the full set of included trials, while two considered other equity-related factors. Reviews rarely appraised possible similarities and differences across sex and gender. In half of a subset of reviews, female participants were under-represented relative to their share of the sepsis population (PPR<0.8).


      The SGAT-SR-2 tool and the PPR can support the design and appraisal of systematic reviews to assess sex and gender considerations, address to whom evidence applies, and determine future research needs.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Clinical Epidemiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Singer M.
        • Deutschman C.S.
        • Seymour C.W.
        • Shankar-Hari M.
        • Annane D.
        • Bauer M.
        • et al.
        The third international consensus definitions for sepsis and septic shock (Sepsis-3).
        JAMA. 2016; 315: 801
        • Rudd K.E.
        • Johnson S.C.
        • Agesa K.M.
        • Shackelford K.A.
        • Tsoi D.
        • Rhodes Kievlan D.
        • et al.
        Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.
        Lancet. 2020; 395: 200-211
        • World Health Organization. Regional Office for the Western Pacific
        Taking sex and gender into account in emerging infectious disease programmes: an analytical framework.
        WHO Regional Office for the Western Pacific, Manila2011
        • Asai K.
        • Hiki N.
        • Mimura Y.
        • Ogawa T.
        • Unou K.
        • Kaminishi M.
        Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model.
        Shock. 2001; 16: 340-343
        • Beenakker K.G.M.
        • Westendorp R.G.J.
        • De Craen A.J.M.
        • Chen S.
        • Raz Y.
        • Ballieux B.E.P.B.
        • et al.
        Men have a stronger monocyte-derived cytokine production response upon stimulation with the gram-negative stimulus lipopolysaccharide than women: a pooled analysis including 15 study populations.
        J Innate Immun. 2020; 12: 142-153
        • Angele M.K.
        • Pratschke S.
        • Hubbard W.J.
        • Chaudry I.H.
        Gender differences in sepsis: cardiovascular and immunological aspects.
        Virulence. 2014; 5: 12-19
        • De Castro R.
        • Ruiz D.
        • Lavín B.A.
        • Lamsfus J.Á.
        • Vázquez L.
        • Montalban C.
        • et al.
        Cortisol and adrenal androgens as independent predictors of mortality in septic patients.
        PLoS ONE. 2019; 14e0214312
        • Madsen T.E.
        • Napoli A.M.
        The DISPARITY-II study: delays to antibiotic administration in women with severe sepsis or septic shock.
        Acad Emerg Med. 2014; 21: 1499-1502
        • Valentin A.
        • Jordan B.
        • Lang T.
        • Hiesmayr M.
        • Metnitz P.G.H.
        Gender-related differences in intensive care: a multiple-center cohort study of therapeutic interventions and outcome in critically ill patients.
        Crit Care Med. 2003; 31: 1901-1907
      1. National Institute for Health and Care Excellenc. Sepsis: recognition,assessment and early management (NICE Guideline 51). 2016. Available at Accessed October 16, 2020.

        • Rhodes A.
        • Evans L.E.
        • Alhazzani W.
        • Levy M.M.
        • Antonelli M.
        • Ferrer R.
        • et al.
        Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016.
        Crit Care Med. 2017; 45: 486-552
        • Institute of Gender and Health, CIHR
        What a difference sex and gender make: a gender, sex and health research casebook.
        Canadian Institutes of Health Research, Ottawa2012. (Available at Accessed October 16, 2020)
      2. Statistics Canada. Sex of person. Available at: Accessed November 27, 2020.

        • American Psychological Association
        Guidelines for psychological practice with transgender and gender nonconforming people.
        Am Psychol. 2015; 70: 832-864
        • Cools M.
        • Nordenström A.
        • Robeva R.
        • Hall J.
        • Westerveld P.
        • Flück C.
        • et al.
        Caring for individuals with a difference of sex development (DSD): a consensus statement.
        Nat Rev Endocrinol. 2018; 14: 415-429
        • Krieger N.
        Genders, sexes, and health: what are the connections - and why does it matter?.
        Int J Epidemiol. 2003; 32: 652-657
        • Springer K.W.
        • Mager Stellman J.
        • Jordan-Young R.M
        Beyond a catalogue of differences: a theoretical frame and good practice guidelines for researching sex/gender in human health.
        Soc Sci Med. 2012; 74: 1817-1824
        • Liu K.A.
        • Mager N.A.D.
        Women's involvement in clinical trials: historical perspective and future implications.
        Pharm Pract (Granada). 2016; 14: 708
      3. Guidance document: considerations for inclusion of women in clinical trials and analysis of sex differences. Health Canada 2013. Available at Accessed April 7, 2021.

      4. U.S. Food and Drug Administration. Enhancing the diversity of clinical trial populations. Eligibility criteria, enrollment practices, and trial designs guidance for industry. US Food Drug Adm 2020. Available at Accessed September 7, 2021.

        • Hammarström A.
        • Hensing G.
        How gender theories are used in contemporary public health research.
        Int J Equity Health. 2018; 17: 34
        • Brabete A.C.
        • Greaves L.
        • Hemsing N.
        • Stinson J.
        Sex- and gender-based analysis in cannabis treatment outcomes: a systematic review.
        Int J Environ Res Public Health. 2020; 17: 872
      5. Incorporating intersectional gender analysis into research on infectious diseases of poverty: a toolkit for health researchers.
        World Health Organization, Geneva2020
        • Leopold S.S.
        • Beadling L.
        • Dobbs M.B.
        • Gebhardt M.C.
        • Lotke P.A.
        • Manner P.A.
        • et al.
        Fairness to all: gender and sex in scientific reporting.
        Clin Orthop Relat Res. 2014; 472: 391-392
        • Clayton J.A.
        • Tannenbaum C.
        Reporting sex, gender, or both in clinical research?.
        JAMA - J Am Med Assoc. 2016; 316: 1863-1864
        • Heidari S.
        • Babor T.F.
        • De Castro P.
        • Tort S.
        • Curno M.
        Sex and gender equity in research: rationale for the SAGER guidelines and recommended use.
        Res Integr Peer Rev. 2016; 1: 2. h
        • Ovseiko P.V.
        • Greenhalgh T.
        • Adam P.
        • Grant J.
        • Hinrichs-Krapels S.
        • Graham K.E.
        • et al.
        A global call for action to include gender in research impact assessment.
        Heal Res Policy Syst. 2016; 14: 50
      6. International Committee of Medical Journal Editor. Recommendations for the conduct, reporting, editing, and publication of scholarly work in medical journals Available at Accessed November 27, 2020.

        • Edwards J.R.
        The peaceful coexistence of ethics and quantitative research.
        J Bus Ethics. 2020; 167: 31-40
        • Day S.
        • Mason R.
        • Lagosky S.
        • Rochon P.A.
        Integrating and evaluating sex and gender in health research.
        Heal Res Policy Syst. 2016; 4: 75
        • Welch V.
        • Doull M.
        • Yoganathan M.
        • Jull J.
        • Boscoe M.
        • Coen S.E.
        • et al.
        Reporting of sex and gender in randomized controlled trials in Canada: a cross-sectional methods study.
        Res Integr Peer Rev. 2017; 2: 15
        • Sugimoto C.R.
        • Ahn Y.Y.
        • Smith E.
        • Macaluso B.
        • Larivière V.
        Factors affecting sex-related reporting in medical research: a cross-disciplinary bibliometric analysis.
        Lancet. 2019; 393: 550-559
        • López-Alcalde J.
        • Stallings E.
        • Cabir Nunes S.
        • Fernández Chávez A.
        • Daheron M.
        • Bonfill Cosp X.
        • et al.
        Consideration of sex and gender in Cochrane reviews of interventions for preventing healthcare-associated infections: a methodology study.
        BMC Health Serv Res. 2019; 19: 169
        • Adisso É.L.
        • Zomahoun H.T.V.
        • Gogovor A.
        • Légaré F.
        Sex and gender considerations in implementation interventions to promote shared decision making: a secondary analysis of a Cochrane systematic review.
        PLoS ONE. 2020; 15e0240371
        • Antequera A.
        • Madrid-Pascual O.
        • Solà I.
        • Roy-Vallejo E.
        • Petricola S.
        • Plana M.N.
        • et al.
        Female under-representation in sepsis studies: a bibliometric analysis of systematic reviews and guidelines.
        J Clin Epidemiol. 2020; 126: 26-36
        • Welch V.A.
        • Akl E.A.
        • Pottie K.
        • Ansari M.T.
        • Briel M.
        • Christensen R.
        • et al.
        GRADE equity guidelines 3: considering health equity in GRADE guideline development: rating the certainty of synthesized evidence.
        J Clin Epidemiol. 2017; 90: 76-83
        • Welch V.
        • Petticrew M.
        • Tugwell P.
        • Moher D.
        • O'Neill J.
        • Waters E.
        • et al.
        PRISMA-Equity 2012 extension: reporting guidelines for systematic reviews with a focus on health equity.
        PLoS Med. 2012; 9e1001333
        • Tannenbaum C.
        • Day D.
        Age and sex in drug development and testing for adults.
        Pharmacol Res. 2017; 121: 83-93
        • Day S.
        • Mason R.
        • Tannenbaum C.
        • Rochon P.A.
        Essential metrics for assessing sex & gender integration in health research proposals involving human participants.
        PLoS ONE. 2017; 12e0182812
        • Hankivsky O.
        • Grace D.
        • Hunting G.
        • Giesbrecht M.
        • Fridkin A.
        • Rudrum S.
        • et al.
        An intersectionality-based policy analysis framework: critical reflections on a methodology for advancing equity.
        Int J Equity Health. 2014; 13: 1-16
        • Evans T.
        • Brown H.
        Road traffic crashes: operationalizing equity in the context of health sector reform.
        Inj Control Saf Promot. 2003; 10: 11-12
        • Oliver S.
        • Dickson K N.M
        Getting started with a review.
        (editor)in: Gough D Oliver S Thomas J E An introd. to syst. rev.2nd ed. SAGE Publications, London2012
        • O'Neill J.
        • Tabish H.
        • Welch V.
        • Petticrew M.
        • Pottie K.
        • Clarke M.
        • et al.
        Applying an equity lens to interventions: using PROGRESS ensures consideration of socially stratifying factors to illuminate inequities in health.
        J Clin Epidemiol. 2014; 67: 56-64
        • Higgins J.P.T.
        • Green S.
        • Sally E.
        Cochrane collaboration. cochrane handbook for systematic reviews of interventions.
        Wiley-Blackwell, 2019
        • Romero B.
        • Fry M.
        • Roche M.
        The impact of evidence-based sepsis guidelines on emergency department clinical practice: a pre-post medical record audit.
        J Clin Nurs. 2017; 26: 3588-3596
        • Cronshaw H.L.
        • Daniels R.
        • Bleetman A.
        • Joynes E.
        • Sheils M.
        Impact of the surviving sepsis campaign on the recognition and management of severe sepsis in the emergency department: are we failing?.
        Emerg Med J. 2011; 28: 670-675
        • Damiani E.
        • Donati A.
        • Serafini G.
        • Rinaldi L.
        • Adrario E.
        • Pelaia P.
        • et al.
        Effect of performance improvement programs on compliance with sepsis bundles and mortality: a systematic review and meta-analysis of observational studies.
        PLoS ONE. 2015; 10e0125827
        • Doull M.
        • Runnels V.E.
        • Tudiver S.
        • Boscoe M.
        Appraising the evidence: applying sex- and gender-based analysis (SGBA) to Cochrane systematic reviews on cardiovascular diseases.
        J Womens Health (Larchmt). 2010; 19: 997-1003
        • Tudiver S.
        • Boscoe M.
        • Runnels V.E .DM
        Challenging “dis-ease”: sex, gender and systematic reviews in health. In: what a difference sex and gender make: a gender, sex and health research casebook, Ottawa: canadian Institutes of Health Research.
        Institute of Gender and Health. 2012; : 25-33
        • Antequera A.
        • Stallings E.
        • Lopez-Alcalde J.
        • Welch V.A.
        Modifying and applying an appraisal tool to sex-and gender-based analysis in Cochrane systematic reviews on sepsis: a methodology study.
        Protocol. 2020; (
        • Chakravartty D.
        • Wiseman C.L.
        • Cole D.C.
        Differential environmental exposure among non-Indigenous Canadians as a function of sex/gender and race/ethnicity variables: a scoping review.
        Can J Public Health. 2014; 105: e438-e444
        • Runnels V.
        • Tudiver S.
        • Doull M.
        • Boscoe M.
        The challenges of including sex/gender analysis in systematic reviews: a qualitative survey.
        Syst Rev. 2014; 3: 33
        • McGregor A.J.
        • Hasnain M.
        • Sandberg K.
        • Morrison M.F.
        • Berlin M.
        • Trott J.
        How to study the impact of sex and gender in medical research: a review of resources.
        Biol Sex Differ. 2016; 7: 46
        • Tannenbaum C.
        • Norris C.M.
        • McMurtry M.S.
        Sex-specific considerations in guidelines generation and application.
        Can J Cardiol. 2019; 35: 598-605
        • Doull M.
        • Welch V.
        • Puil L.
        • Runnels V.
        • Coen S.E.
        • Shea B.
        • et al.
        Development and evaluation of “briefing notes” as a novel knowledge translation tool to aid the implementation of sex/gender analysis in systematic.
        PLoS ONE. 2014; 9e110786
        • Antequera Martín A.M.
        • Barea Mendoza J.A.
        • Muriel A.
        • Sáez I.
        • Chico-Fernández M.
        • Estrada-Lorenzo J.M.
        • et al.
        Buffered solutions versus 0.9% saline for resuscitation in critically ill adults and children.
        Cochrane Database Syst Rev. 2019; 7CD012247
        • Poon R.
        • Khanijow K.
        • Umarjee S.
        • Fadiran E.
        • Yu M.
        • Zhang L.
        • et al.
        Participation of women and sex analyses in late-phase clinical trials of new molecular entity drugs and biologics approved by the FDA in 2007-2009.
        J Women's Heal. 2013; 22: 604-616
        • Scott P.E.
        • Unger E.F.
        • Jenkins M.R.
        • Southworth M.R.
        • McDowell T.-.Y.
        • Geller R.J.
        • et al.
        Participation of women in clinical trials supporting fda approval of cardiovascular drugs.
        J Am Coll Cardiol. 2018; 71: 1960-1969
        • Martin G.S.
        • Mannino D.M.
        • Eaton S.
        • Moss M.
        The Epidemiology of Sepsis in the United States from 1979 through 2000.
        N Engl J Med. 2003; 348: 1546-1554
        • Sakr Y.
        • Jaschinski U.
        • Wittebole X.
        • Szakmany T.
        • Lipman J.
        • Ñamendys-Silva S.A.
        • et al.
        Sepsis in intensive care unit patients: worldwide data from the intensive care over nations audit.
        Open Forum Infect Dis. 2018; 5: ofy313
        • Lukacs S.L.
        • Schrag S.J.
        Clinical sepsis in neonates and young infants, United States, 1988-2006.
        J Pediatr. 2012; 160
        • Weiss S.L.
        • Fitzgerald J.C.
        • Pappachan J.
        • Wheeler D.
        • Jaramillo-Bustamante J.C.
        • Salloo A.
        • et al.
        Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study.
        Am J Respir Crit Care Med. 2015; 191: 1147-1157
        • Dramowski A.
        • Cotton M.F.
        • Rabie H.
        • Whitelaw A.
        Trends in paediatric bloodstream infections at a South African referral hospital.
        BMC Pediatr. 2015; 15: 33
        • Vekaria-Hirani V.
        • Kumar R.
        • Musoke R.N.
        • Wafula E.M.
        • Chipkophe I.N.
        Prevalence and management of septic shock among children admitted at the Kenyatta National Hospital, longitudinal survey 2019.
        Int J Pediatr. 2019; 20191502963
      7. Centers for Disease Control and Prevention. Sepsis, Data & Reports. 2019. Available at Accessed February 26, 2020.

        • Breederveld R.S.
        • Tuinebreijer W.E.
        Recombinant human growth hormone for treating burns and donor sites.
        Cochrane Database Syst Rev. 2014; 2014CD008990
        • Li D.
        • Li X.
        • Cui W.
        • Shen H.
        • Zhu H.
        • Xia Y.
        Liberal versus conservative fluid therapy in adults and children with sepsis or septic shock.
        Cochrane Database Syst Rev. 2018; 12: CD01059
        • Martí-Carvajal A.J.
        • Solà I.
        • Gluud C.
        • Lathyris D.
        • Anand V.
        Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients.
        Cochrane Database Syst Rev. 2012; CD004388
        • Warttig S.
        • Alderson P.
        • Evans D.J.W.
        • Lewis S.R.
        • Kourbeti I.S.
        • Smith A.F.
        Automated monitoring compared to standard care for the early detection of sepsis in critically ill patients.
        Cochrane Database Syst Rev. 2018; 6CD012404
        • Shah P.S.
        • Kaufman D.A.
        Antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants.
        Cochrane Database Syst Rev. 2009; CD006449
        • Paul M.
        • Lador A.
        • Grozinsky-Glasberg S.
        • Leibovici L.
        Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.
        Cochrane Database Syst Rev. 2014; 2014CD003344
        • Annane D.
        • Bellissant E.
        • Bollaert P.E.
        • Briegel J.
        • Keh D.
        • Kupfer Y.
        • et al.
        Corticosteroids for treating sepsis in children and adults.
        Cochrane Database Syst Rev. 2019; 12CD002243
        • Borthwick E.M.J.
        • Hill C.J.
        • Rabindranath K.S.
        • Maxwell A.P.
        • McAuley D.F.
        • Blackwood B.
        High-volume haemofiltration for sepsis in adults.
        Cochrane Database Syst Rev. 2017; 1CD008075
        • Szakmany T.
        • Hauser B.
        • Radermacher P.
        N-acetylcysteine for sepsis and systemic inflammatory response in adults.
        Cochrane Database Syst Rev. 2012; 2012CD006616
        • Johnson S.M.
        • Karvonen B.S.
        • Phelps C.L.
        • Nader S.
        • Sanborn B.M.
        Assessment of analysis by gender in the cochrane reviews as related to treatment of cardiovascular disease.
        J Women's Heal. 2003; 12: 449-457
        • Petkovic J.
        • Trawin J.
        • Dewidar O.
        • Yoganathan M.
        • Tugwell P.
        • Welch V.
        Sex/gender reporting and analysis in Campbell and Cochrane systematic reviews: a cross-sectional methods study.
        Syst Rev. 2018; 7: 113
        • Schiebinger L.
        • Leopold S.S.
        • Miller V.M.
        Editorial policies for sex and gender analysis.
        Lancet. 2016; 388: 2841-2842
        • Wandschneider L.
        • Batram-Zantvoort S.
        • Razum O.
        • Miani C.
        Representation of gender in migrant health studies – a systematic review of the social epidemiological literature.
        Int J Equity Health. 2020; 19: 181
        • Reisner S.L.
        • Poteat T.
        • Keatley J.A.
        • Cabral M.
        • Mothopeng T.
        • Dunham E.
        • et al.
        Global health burden and needs of transgender populations: a review.
        Lancet. 2016; 388: 412-436
        • Marshall Z.
        • Welch V.
        • Minichiello A.
        • Swab M.
        • Brunger F.
        • Kaposy C.
        Documenting research with transgender, nonbinary, and other gender diverse (trans) individuals and communities: introducing the global trans research evidence map.
        Transgender Heal. 2019; 4: 68-80
        • Tadiri C.P.
        • Raparelli V.
        • Abrahamowicz M.
        • Kautzy-Willer A.
        • Kublickiene K.
        • Herrero M.T.
        • et al.
        Methods for prospectively incorporating gender into health sciences research.
        J Clin Epidemiol. 2021; 129: 191-197
        • Scott P.E.
        • Unger E.F.
        • Jenkins M.R.
        • Southworth M.R.
        • McDowell T.-.Y.Y.
        • Geller R.J.
        • et al.
        Participation of women in clinical trials supporting FDA approval of cardiovascular drugs.
        J Am Coll Cardiol. 2018; 71: 1960-1969
        • Curno M.J.
        • Rossi S.
        • Hodges-Mameletzis I.
        • Johnston R.
        • Price M.A.
        • Heidari S.
        A systematic review of the inclusion (or exclusion) of women in HIV research: from clinical studies of antiretrovirals and vaccines to cure strategies.
        J Acquir Immune Defic Syndr. 2016; 71: 181-188
        • Feldman S.
        • Ammar W.
        • Lo K.
        • Trepman E.
        • Van Zuylen M.
        • Etzioni O.
        Quantifying sex bias in clinical studies at scale with automated data extraction.
        JAMA Netw Open. 2019; 2
        • García-Olmos L.
        • Salvador C.H.
        • Alberquilla Á.
        • Lora D.
        • Carmona M.
        • García-Sagredo P.
        • et al.
        Comorbidity patterns in patients with chronic diseases in general practice.
        PLoS ONE. 2012; 7: e32141
        • Schafer I.
        • von Leitner E.C.
        • Schon G.
        • Koller D.
        • Hansen H.
        • Kolonko T.
        • et al.
        Multimorbidity patterns in the elderly - a new approach of disease clustering.
        PLoS ONE. 2010; 5: e15941
        • Adrie C.
        • Azoulay E.
        • Francais A.
        • Clec'h C.
        • Darques L.
        • Schwebel C.
        • et al.
        Influence of gender on the outcome of severe sepsis: a reappraisal.
        Chest. 2007; 132: 1786-1793
        • Van Spall H.G.C.
        • Toren A.
        • Kiss A.
        • Fowler R.A.
        Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.
        J Am Med Assoc. 2007; 297: 1233-1240
      8. Guidance document: considerations for inclusion of women in clinical trials and analysis of sex differences-Canada. Ottawa: Canada; 2013. Available at Accessed April 1, 2021.

        • Duan-Porter W.
        • Goldstein K.M.
        • McDuffie J.R.
        • Hughes J.M.
        • Clowse M.E.B.
        • Klap R.S.
        • et al.
        Reporting of sex effects by systematic reviews on interventions for depression, diabetes, and chronic pain.
        Ann Intern Med. 2016; 165: 184-193
        • Rerkasem A.
        • Orrapin S.
        • Howard D.P.J.
        • Rerkasem K.
        Carotid endarterectomy for symptomatic carotid stenosis.
        Cochrane Database Syst Rev. 2020; 9CD001081
      9. Benstoem C., Kalvelage C., Breuer T., Heussen N., Marx G., Stoppe C., et al. Ivabradine as adjuvant treatment for chronic heart failure 2020;11:CD013004.

      10. Julian Higgins, Toby Lasserson, Jackie Chandler, David Tovey, James Thomas, Ella Flemyng RC. Methodological Expectations of Cochrane Intervention Reviews (MECIR). Standards for the conduct and reporting of new Cochrane Intervention Reviews, reporting of protocols and the planning, conduct and reporting of updates 2021.

        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        PLOS Med. 2021; 18e1003583
        • Atal I.
        • Trinquart L.
        • Ravaud P.
        • Porcher R.
        A mapping of 115,000 randomized trials revealed a mismatch between research effort and health needs in non–high-income regions.
        J Clin Epidemiol. 2018; 98: 123-132
        • Yaffe J.
        • Montgomery P.
        • Hopewell S.
        • Shepard L.D.
        Empty reviews: a description and consideration of cochrane systematic reviews with no included studies.
        PLoS ONE. 2012; 7: e36626