Predictors of mortality within the first year of initiating antiretroviral therapy in urban and rural Kenya: A prospective cohort study
Autoři:
Rachel A. Silverman aff001; Grace C. John-Stewart aff001; Ingrid A. Beck aff006; Ross Milne aff006; Catherine Kiptinness aff002; Christine J. McGrath aff002; Barbra A. Richardson aff002; Bhavna Chohan aff002; Samah R. Sakr aff009; Lisa M. Frenkel aff002; Michael H. Chung aff001
Působiště autorů:
Department of Epidemiology, University of Washington, Seattle, Washington, United states of America
aff001; Department of Global Health, University of Washington, Seattle, Washington, United states of America
aff002; Department of Population Health Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
aff003; Department of Medicine, University of Washington, Seattle, Washington, United States of America
aff004; Pediatrics, University of Washington, Seattle, Washington, United States of America
aff005; Seattle Children’s Research Institute, Seattle, Washington, United States of America
aff006; Department of Biostatistics, University of Washington, Seattle, Washington, United States of America
aff007; Kenya Medical Research Institute (KEMRI), Nairobi, Kenya
aff008; Coptic Hospital, Nairobi, Kenya
aff009; Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
aff010
Vyšlo v časopise:
PLoS ONE 14(10)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0223411
Souhrn
Introduction
Despite increased treatment availability, HIV-infected individuals continue to start antiretroviral therapy (ART) late in disease progression, increasing early mortality risk.
Materials and methods
Nested prospective cohort study within a randomized clinical trial of adult patients initiating ART at clinics in urban Nairobi and rural Maseno, Kenya, between 2013–2014. We estimated mortality incidence rates following ART initiation and used Cox proportional hazards regression to identify predictors of mortality within 12 months of ART initiation. Analyses were stratified by clinic site to examine differences in mortality correlates and risk by location.
Results
Among 811 participants initiated on ART, the mortality incidence rate within a year of initiating ART was 7.44 per 100 person-years (95% CI 5.71, 9.69). Among 207 Maseno and 612 Nairobi participants initiated on ART, the mortality incidence rates (per 100 person-years) were 12.78 (95% CI 8.49, 19.23) and 5.72 (95% CI 4.05, 8.09). Maseno had a 2.20-fold greater risk of mortality than Nairobi (95% CI 1.29, 3.76; P = 0.004). This association remained [adjusted hazard ratio (HR) = 2.09 (95% CI 1.17, 3.74); P = 0.013] when adjusting for age, gender, education, pre-treatment drug resistance (PDR), and CD4 count, but not when adjusting for BMI. In unadjusted analyses, other predictors (P<0.05) of mortality included male gender (HR = 1.74), age (HR = 1.04 for 1-year increase), fewer years of education (HR = 0.92 for 1-year increase), unemployment (HR = 1.89), low body mass index (BMI<18.5 m/kg2; HR = 4.99), CD4 count <100 (HR = 11.67) and 100–199 (HR = 3.40) vs. 200–350 cells/μL, and pre-treatment drug resistance (PDR; HR = 2.49). The increased mortality risk associated with older age, males, and greater education remained when adjusted for location, age, education and PDR, but not when adjusted for BMI and CD4 count. PDR remained associated with increased mortality risk when adjusted for location, age, gender, education, and BMI, but not when adjusted for CD4 count. CD4 and BMI associations with increased mortality risk persisted in multivariable analyses. Despite similar baseline CD4 counts across locations, mortality risk associated with low CD4 count, low BMI, and PDR was greater in Maseno than Nairobi in stratified analyses.
Conclusions
High short-term post-ART mortality was observed, partially due to low CD4 count and BMI at presentation, especially in the rural setting. Male gender, older age, and markers of lower socioeconomic status were also associated with greater mortality risk. Engaging patients earlier in HIV infection remains critical. PDR may influence short-term mortality and further studies to optimize management will be important in settings with increasing PDR.
Klíčová slova:
Body Mass Index – Death rates – Socioeconomic aspects of health – Kenya – HIV infections – Antimicrobial resistance – Randomized controlled trials
Zdroje
1. World Health Organization (WHO). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommentations for a public health approach. 2013.
2. WHO. Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommenations for a Public Health Approach. 2nd Edition. 2016.
3. WHO. Guideline on When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. 2015.
4. Guthrie BL, Choi RY, Liu AY, Mackelprang RD, Rositch AF, Bosire R, et al. Barriers to antiretroviral initiation in HIV-1-discordant couples. J Acquir Immune Defic Syndr. 2011;58(3):e87–93. doi: 10.1097/QAI.0b013e31822f064e 21826010
5. Ilovi CS, Lule GN, Obel AO, Irimu HM. Correlation of WHO clinical staging with CD4 counts in adult HIV/AIDS patients at Kenyatta National Hospital, Nairobi. East Afr Med J. 2011;88(2):65–70. 24968593
6. Mwangi J, Nganga Z, Lihana R, Lagat N, Kinyua J, Muriuki J, et al. Switch from 200 to 350 CD4 baseline count: what it means to HIV care and treatment programs in Kenya. Pan Afr Med J. 2012;12:80. 23077701
7. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008;22(15):1897–908. doi: 10.1097/QAD.0b013e32830007cd 18784453
8. Yiannoutsos CT, Johnson LF, Boulle A, Musick BS, Gsponer T, Balestre E, et al. Estimated mortality of adult HIV-infected patients starting treatment with combination antiretroviral therapy. Sex Transm Infect. 2012;88 Suppl 2:i33–43.
9. Gupta A, Nadkarni G, Yang WT, Chandrasekhar A, Gupte N, Bisson GP, et al. Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis. PLoS One. 2011;6(12):e28691. doi: 10.1371/journal.pone.0028691 22220193
10. Geng EH, Odeny TA, Lyamuya RE, Nakiwogga-Muwanga A, Diero L, Bwana M, et al. Estimation of mortality among HIV-infected people on antiretroviral treatment in East Africa: a sampling based approach in an observational, multisite, cohort study. Lancet HIV. 2015;2(3):e107–16. doi: 10.1016/S2352-3018(15)00002-8 26424542
11. Beckham SW, Beyrer C, Luckow P, Doherty M, Negussie EK, Baral SD. Marked sex differences in all-cause mortality on antiretroviral therapy in low- and middle-income countries: a systematic review and meta-analysis. J Int AIDS Soc. 2016;19(1):21106. doi: 10.7448/IAS.19.1.21106 27834182
12. Mee P, Collinson MA, Madhavan S, Kabudula C, Gomez-Olive FX, Kahn K, et al. Determinants of the risk of dying of HIV/AIDS in a rural South African community over the period of the decentralised roll-out of antiretroviral therapy: a longitudinal study. Glob Health Action. 2014;7(1):24826.
13. Damtew B, Mengistie B, Alemayehu T. Survival and determinants of mortality in adult HIV/Aids patients initiating antiretroviral therapy in Somali Region, Eastern Ethiopia. Pan Afr Med J. 2015;22:138. doi: 10.11604/pamj.2015.22.138.4352 26889319
14. Siika AM, Wools-Kaloustian K, Mwangi AW, Kimaiyo SN, Diero LO, Ayuo PO, et al. Risk factors for death in HIV-infected adult African patients receiving anti-retroviral therapy. East Afr Med J. 2010;87(11):443–51. 23457806
15. Flynn AG, Anguzu G, Mubiru F, Kiragga AN, Kamya M, Meya DB, et al. Socioeconomic position and ten-year survival and virologic outcomes in a Ugandan HIV cohort receiving antiretroviral therapy. PLoS One. 2017;12(12):e0189055. doi: 10.1371/journal.pone.0189055 29244807
16. O’Brien D, Spelman T, Greig J, McMahon J, Ssonko C, Casas E, et al. Risk factors for mortality during antiretroviral therapy in older populations in resource-limited settings. J Int AIDS Soc. 2016;19(1):20665. doi: 10.7448/IAS.19.1.20665 26782169
17. Pinoges L, Schramm B, Poulet E, Balkan S, Szumilin E, Ferreyra C, et al. Risk factors and mortality associated with resistance to first-line antiretroviral therapy: multicentric cross-sectional and longitudinal analyses. J Acquir Immune Defic Syndr. 2015;68(5):527–35. doi: 10.1097/QAI.0000000000000513 25585301
18. Boender TS, Hoenderboom BM, Sigaloff KC, Hamers RL, Wellington M, Shamu T, et al. Pretreatment HIV drug resistance increases regimen switches in sub-Saharan Africa. Clin Infect Dis. 2015;61(11):1749–58. doi: 10.1093/cid/civ656 26240203
19. National AIDS Control Council. Kenya AIDS Response Progress Report. Ministry of Health. 2016.
20. Cawley C, McRobie E, Oti S, Njamwea B, Nyaguara A, Odhiambo F, et al. Identifying gaps in HIV policy and practice along the HIV care continuum: evidence from a national policy review and health facility surveys in urban and rural Kenya. Health Policy Plan. 2017;32(9):1316–26. doi: 10.1093/heapol/czx091 28981667
21. Mberu BU, Haregu TN, Kyobutungi C, Ezeh AC. Health and health-related indicators in slum, rural, and urban communities: a comparative analysis. Glob Health Action. 2016;9(1):33163.
22. Kenya National Bureau of Statistics, Ministry of Health/Kenya, National AIDS Control Council/Kenya, Kenya Medical Research Institute, Population NCf, Development/Kenya. Kenya Demographic and Health Survey 2014. Rockville, MD, USA; 2015.
23. Feikin DR, Olack B, Bigogo GM, Audi A, Cosmas L, Aura B, et al. The burden of common infectious disease syndromes at the clinic and household level from population-based surveillance in rural and urban Kenya. PLoS One. 2011;6(1):e16085. doi: 10.1371/journal.pone.0016085 21267459
24. Katz MA, Lebo E, Emukule G, Njuguna HN, Aura B, Cosmas L, et al. Epidemiology, seasonality, and burden of influenza and influenza-like illness in urban and rural Kenya, 2007–2010. J Infect Dis. 2012;206 Suppl 1:S53–60.
25. Verani JR, Toroitich S, Auko J, Kiplang’at S, Cosmas L, Audi A, et al. Burden of Invasive Nontyphoidal Salmonella Disease in a Rural and Urban Site in Kenya, 2009–2014. Clin Infect Dis. 2015;61 Suppl 4:S302–9.
26. Chung MH, Drake AL, Richardson BA, Reddy A, Thiga J, Sakr SR, et al. Impact of prior HAART use on clinical outcomes in a large Kenyan HIV treatment program. Curr HIV Res. 2009;7(4):441–6. 19601781
27. Chung MH, Richardson BA, Tapia K, Benki-Nugent S, Kiarie JN, Simoni JM, et al. A randomized controlled trial comparing the effects of counseling and alarm device on HAART adherence and virologic outcomes. PLoS Med. 2011;8(3):e1000422. doi: 10.1371/journal.pmed.1000422 21390262
28. Chung MH, Silverman R, Beck IA, Yatich N, Dross S, McKernan-Mullin J, et al. Increasing HIV-1 pre-treatment drug resistance among antiretroviral-naive adults initiating treatment between 2006 and 2014 in Nairobi, Kenya. AIDS. 2016.
29. Silverman RA, Beck IA, Kiptinness C, Levine M, Milne R, McGrath CJ, et al. Prevalence of Pre-antiretroviral Treatment Drug Resistance by Gender, Age, and Other Factors in HIV-infected Individuals Initiating Therapy in Kenya, 2013–2014. J Infect Dis. 2017.
30. NASCOP. Guidelines for Antiretroviral Drug Therapy in Kenya. Nairobi. 4th Edition. 2011.
31. NASCOP. Guidelines for Antiretroviral Drug Therapy in Kenya. Nairobi. Rapid Advice Booklet. 2014.
32. Beck IA, Deng W, Payant R, Hall R, Bumgarner RE, Mullins JI, et al. Validation of an oligonucleotide ligation assay for quantification of human immunodeficiency virus type 1 drug-resistant mutants by use of massively parallel sequencing. J Clin Microbiol. 2014;52(7):2320–7. doi: 10.1128/JCM.00306-14 24740080
33. Beck IA, Mahalanabis M, Pepper G, Wright A, Hamilton S, Langston E, et al. Rapid and sensitive oligonucleotide ligation assay for detection of mutations in human immunodeficiency virus type 1 associated with high-level resistance to protease inhibitors. J Clin Microbiol. 2002;40(4):1413–9. doi: 10.1128/JCM.40.4.1413-1419.2002 11923366
34. Chung MH, Beck IA, Dross S, Tapia K, Kiarie JN, Richardson BA, et al. Oligonucleotide ligation assay detects HIV drug resistance associated with virologic failure among antiretroviral-naive adults in Kenya. J Acquir Immune Defic Syndr. 2014;67(3):246–53. doi: 10.1097/QAI.0000000000000312 25140907
35. May MT, Vehreschild JJ, Trickey A, Obel N, Reiss P, Bonnet F, et al. Mortality According to CD4 Count at Start of Combination Antiretroviral Therapy Among HIV-infected Patients Followed for up to 15 Years After Start of Treatment: Collaborative Cohort Study. Clin Infect Dis. 2016;62(12):1571–7. doi: 10.1093/cid/ciw183 27025828
36. Zachariah R, Harries K, Moses M, Manzi M, Line A, Mwagomba B, et al. Very early mortality in patients starting antiretroviral treatment at primary health centres in rural Malawi. Trop Med Int Health. 2009;14(7):713–21. doi: 10.1111/j.1365-3156.2009.02291.x 19497082
37. Weigel R, Estill J, Egger M, Harries AD, Makombe S, Tweya H, et al. Mortality and loss to follow-up in the first year of ART: Malawi national ART programme. AIDS. 2012;26(3):365–73. doi: 10.1097/QAD.0b013e32834ed814 22095194
38. Chalamilla G, Hawkins C, Okuma J, Spiegelman D, Aveika A, Christian B, et al. Mortality and treatment failure among HIV-infected adults in Dar Es Salaam, Tanzania. J Int Assoc Physicians AIDS Care (Chic). 2012;11(5):296–304.
39. Pavlinac PB, Naulikha JM, Chaba L, Kimani N, Sangare LR, Yuhas K, et al. Water filter provision and home-based filter reinforcement reduce diarrhea in Kenyan HIV-infected adults and their household members. Am J Trop Med Hyg. 2014;91(2):273–80. doi: 10.4269/ajtmh.13-0552 24842881
40. Walson JL, Sangare LR, Singa BO, Naulikha JM, Piper BK, Yuhas K, et al. Evaluation of impact of long-lasting insecticide-treated bed nets and point-of-use water filters on HIV-1 disease progression in Kenya. AIDS. 2013;27(9):1493–501. doi: 10.1097/QAD.0b013e32835ecba9 23324658
41. Hakim J, Musiime V, Szubert AJ, Mallewa J, Siika A, Agutu C, et al. Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa. N Engl J Med. 2017;377(3):233–45. doi: 10.1056/NEJMoa1615822 28723333
42. Blanco JR, Caro AM, Perez-Cachafeiro S, Gutierrez F, Iribarren JA, Gonzalez-Garcia J, et al. HIV infection and aging. AIDS Rev. 2010;12(4):218–30. 21179186
43. Hassan AS, Mwaringa SM, Ndirangu KK, Sanders EJ, de Wit TF, Berkley JA. Incidence and predictors of attrition from antiretroviral care among adults in a rural HIV clinic in Coastal Kenya: a retrospective cohort study. BMC Public Health. 2015;15:478. doi: 10.1186/s12889-015-1814-2 25957077
44. Marson KG, Tapia K, Kohler P, McGrath CJ, John-Stewart GC, Richardson BA, et al. Male, mobile, and moneyed: loss to follow-up vs. transfer of care in an urban African antiretroviral treatment clinic. PLoS One. 2013;8(10):e78900. doi: 10.1371/journal.pone.0078900 24205345
45. Sharma M, Ying R, Tarr G, Barnabas R. Systematic review and meta-analysis of community and facility-based HIV testing to address linkage to care gaps in sub-Saharan Africa. Nature. 2015;528(7580):S77–85. doi: 10.1038/nature16044 26633769
46. Tesfamariam K, Baraki N, Kedir H. Pre-ART nutritional status and its association with mortality in adult patients enrolled on ART at Fiche Hospital in North Shoa, Oromia region, Ethiopia: a retrospective cohort study. BMC Res Notes. 2016;9(1):512. doi: 10.1186/s13104-016-2313-y 27998310
47. Evans D, Maskew M, Sanne I. Increased risk of mortality and loss to follow-up among HIV-positive patients with oropharyngeal candidiasis and malnutrition before antiretroviral therapy initiation: a retrospective analysis from a large urban cohort in Johannesburg, South Africa. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(3):362–72. doi: 10.1016/j.oooo.2011.09.004 22669142
48. Johannessen A, Naman E, Ngowi BJ, Sandvik L, Matee MI, Aglen HE, et al. Predictors of mortality in HIV-infected patients starting antiretroviral therapy in a rural hospital in Tanzania. BMC Infect Dis. 2008;8:52. doi: 10.1186/1471-2334-8-52 18430196
49. Liu E, Spiegelman D, Semu H, Hawkins C, Chalamilla G, Aveika A, et al. Nutritional status and mortality among HIV-infected patients receiving antiretroviral therapy in Tanzania. J Infect Dis. 2011;204(2):282–90. doi: 10.1093/infdis/jir246 21673040
50. Masiira B, Baisley K, Mayanja BN, Kazooba P, Maher D, Kaleebu P. Mortality and its predictors among antiretroviral therapy naive HIV-infected individuals with CD4 cell count >/ = 350 cells/mm(3) compared to the general population: data from a population-based prospective HIV cohort in Uganda. Glob Health Action. 2014;7:21843. doi: 10.3402/gha.v7.21843 24433941
51. Biadgilign S, Reda AA, Digaffe T. Predictors of mortality among HIV infected patients taking antiretroviral treatment in Ethiopia: a retrospective cohort study. AIDS Res Ther. 2012;9(1):15. doi: 10.1186/1742-6405-9-15 22606951
52. Koethe JR, Lukusa A, Giganti MJ, Chi BH, Nyirenda CK, Limbada MI, et al. Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka, Zambia. J Acquir Immune Defic Syndr. 2010;53(4):507–13. doi: 10.1097/QAI.0b013e3181b32baf 19730111
53. Madec Y, Szumilin E, Genevier C, Ferradini L, Balkan S, Pujades M, et al. Weight gain at 3 months of antiretroviral therapy is strongly associated with survival: evidence from two developing countries. AIDS. 2009;23(7):853–61. doi: 10.1097/QAD.0b013e32832913ee 19287299
54. Nagata JM, Cohen CR, Young SL, Wamuyu C, Armes MN, Otieno BO, et al. Descriptive characteristics and health outcomes of the food by prescription nutrition supplementation program for adults living with HIV in Nyanza Province, Kenya. PLoS One. 2014;9(3):e91403. doi: 10.1371/journal.pone.0091403 24646586
55. Olsen MF, Abdissa A, Kaestel P, Tesfaye M, Yilma D, Girma T, et al. Effects of nutritional supplementation for HIV patients starting antiretroviral treatment: randomised controlled trial in Ethiopia. BMJ. 2014;348:g3187. doi: 10.1136/bmj.g3187 25134117
56. Rawat R, Faust E, Maluccio JA, Kadiyala S. The impact of a food assistance program on nutritional status, disease progression, and food security among people living with HIV in Uganda. J Acquir Immune Defic Syndr. 2014;66(1):e15–22. doi: 10.1097/QAI.0000000000000079 24326603
57. Rawat R, Kadiyala S, McNamara PE. The impact of food assistance on weight gain and disease progression among HIV-infected individuals accessing AIDS care and treatment services in Uganda. BMC Public Health. 2010;10:316. doi: 10.1186/1471-2458-10-316 20529283
58. Nustart Study Team, Filteau S, PrayGod G, Kasonka L, Woodd S, Rehman AM, et al. Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial. BMC Med. 2015;13:17. doi: 10.1186/s12916-014-0253-8 25630368
59. Grobler L, Siegfried N, Visser ME, Mahlungulu SS, Volmink J. Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database Syst Rev. 2013(2):CD004536. doi: 10.1002/14651858.CD004536.pub3 23450554
60. Koethe JR, Marseille E, Giganti MJ, Chi BH, Heimburger D, Stringer JS. Estimating the cost-effectiveness of nutrition supplementation for malnourished, HIV-infected adults starting antiretroviral therapy in a resource-constrained setting. Cost Eff Resour Alloc. 2014;12:10. doi: 10.1186/1478-7547-12-10 24839400
61. Kuritzkes DR, Lalama CM, Ribaudo HJ, Marcial M, Meyer WA 3rd, Shikuma C, et al. Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. J Infect Dis. 2008;197(6):867–70. doi: 10.1086/528802 18269317
62. Gupta RK, Jordan MR, Sultan BJ, Hill A, Davis DH, Gregson J, et al. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet. 2012;380(9849):1250–8. doi: 10.1016/S0140-6736(12)61038-1 22828485
63. Gupta RK, Gregson J, Parkin N, Haile-Selassie H, Tanuri A, Andrade Forero L, et al. HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis. Lancet Infect Dis. 2017.
64. Wainberg MA, Han YS. Will drug resistance against dolutegravir in initial therapy ever occur? Front Pharmacol. 2015;6:90. doi: 10.3389/fphar.2015.00090 25972810
65. NASCOP. Guidelines on Use of Antiretroviral Drugs for Treating and Preventing HIV Infections in Kenya. 2016.
66. Girardi E, Arici C, Ferrara M, Ripamonti D, Aloisi MS, Alessandrini A, et al. Estimating duration of HIV infection with CD4 cell count and HIV-1 RNA at presentation. AIDS. 2001;15(16):2201–3. doi: 10.1097/00002030-200111090-00021 11684945
67. Gordon CL, Cheng AC, Cameron PU, Bailey M, Crowe SM, Mills J. Quantitative Assessment of Intra-Patient Variation in CD4+ T Cell Counts in Stable, Virologically-Suppressed, HIV-Infected Subjects. PLoS One. 2015;10(6):e0125248. doi: 10.1371/journal.pone.0125248 26110761
68. Goujard C, Bonarek M, Meyer L, Bonnet F, Chaix ML, Deveau C, et al. CD4 cell count and HIV DNA level are independent predictors of disease progression after primary HIV type 1 infection in untreated patients. Clin Infect Dis. 2006;42(5):709–15. doi: 10.1086/500213 16447119
69. Brown ER, Otieno P, Mbori-Ngacha DA, Farquhar C, Obimbo EM, Nduati R, et al. Comparison of CD4 cell count, viral load, and other markers for the prediction of mortality among HIV-1-infected Kenyan pregnant women. J Infect Dis. 2009;199(9):1292–300. doi: 10.1086/597617 19317628
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