ABSTRACT Dolutegravir (DTG) is amongst the most prescribed antiretrovirals worldwide and is recommended as first line regimen in most HIV treatment guidelines. Its use, although infrequently, had been associated to an increased chance of neural tube defects (NTD) in Botswana, Africa. Herein we describe two cases of NTD in women who conceived while taking DTG as part of their antiretroviral treatment in the city of Porto Alegre, Brazil.

Abstract COVID-19 pandemic has been a problem worldwide. It is important to identify people at risk of progressing to severe complications and to investigate if some existing antivirals could have any action against SARS-CoV-2. In this context, HIV-infected individuals and antiretroviral drugs might be included, respectively. Herein we present the case of a 63-year-old HIV-infected woman with undetectable viral load, on dolutegravir, tenofovir and lamivudine, who was hospitalized due to COVID-19 pneumonia. In spite of having some clinical markers of severity on admission, the patient improved and was discharged after a week. To our knowledge, this is the first report of severe SARS-CoV-2 infection in an HIV-infected individual in Brazil.

Abstract HIV-infected individuals on chronic use of highly active antiretroviral therapy (HAART) are more likely to develop adipose tissue and metabolic disorders, such as lipodystrophy (LD) and metabolic syndrome (MetS). The development of these phenotypes is known to be multifactorial. Thus, variants in genes implicated in adipogenesis and lipid metabolism may increase susceptibility to LD and MetS. Sirtuin 1 (SIRT1) may influence the outcome of these disturbances due to its role in the regulation of transcription factors involved in energy regulation. Therefore, we genotyped four polymorphisms located in SIRT1 (rs2273773 T>C, rs12413112 G>A, rs7895833 A>G, rs12049646 T>C) in 832 HIV-infected patients receiving HAART by real-time polymerase chain reaction. The prevalence of LD was 55.8% and MetS was 35.3%. Lipoatrophy was the most prevalent subtype in all samples (38.0%) and showed significant difference between white and non-white individuals (P = 0.002). None of the genetic variants investigated in SIRT1 was associated with LD and MetS. White individuals and those in longer time of HAART use were more likely to develop LD. We concluded that these SIRT1 polymorphisms are not predictive factors to the development of lipodystrophy and metabolic syndrome in HIV-infected individuals from Brazil.

ABSTRACT In the antibiotic era, aortic aneurysm is a rare complication of syphilis, what makes the diagnostic assumption even more difficult. Nonetheless, this condition should be suspected in patients with aortic aneurysm. Reports of aortic dissection complicating syphilitic aortitis have been distinctly rare in the literature, and their cause-effect relationship has not been definitely established. In this case report, we present a 62-year-old woman with aortic aneurysm and dissection associated with an unexpected diagnosis of syphilitic aortitis.

Abstract Background Development of drug-resistance mutations is the main cause of failure in antiretroviral therapy. In Brazil, there is scarce information on resistance pattern for patients failing antiretroviral therapy. Objectives To define the HIV mutational profile associated with drug resistance in Brazilian patients from 5 large cities, after first, second or further failures to antiretroviral therapy. Methods We reviewed genotyping results of 1520 patients failing therapy in five Brazilian cities. Frequency of mutations, mean number of active drugs, viral susceptibility to each antiretrovirals drug, and regional differences were assessed. Results Mean time of antiretrovirals use was 22.7 ± 41.1 months. Mean pre-genotyping viral load was 4.2 ± 0.8 log (2.1 ± 2.0 after switching antiretrovirals). Mean number of remaining active drugs was 9.4, 9.0, and 7.9 after 1st, 2nd, and 3rd failure, respectively. We detected regional variations in drug susceptibility: while BA and RS showed the highest (∼40%) resistance level to ATV/r, FPV/r and LPV/r, in the remaining cities it was around half of this rate. We detected 90% efavirenz/nevirapine resistance in SP, only 45% in RS, and levels between 25% and 30% in the other cities. Regarding NRTI, we found a similar pattern, with RJ presenting the highest, and CE the lowest susceptibility rates for all NRTI. Zidovudine resistance was detected in only 3% of patients in RJ, against 45–65% in the other cities. RJ and RS showed 3% resistance to tenofovir, while in CE it reached 55%. DRV/r (89–97%) and etravirine (61–85%) were the most active drugs, but again, with a wide variation across cities. Conclusions The resistance mutational profile of Brazilian patients failing antiretroviral therapy is quite variable, depending on the city where patients were tested. This variation likely reflects distinctive choice of antiretrovirals drugs to initiate therapy, adherence to specific drugs, or circulating HIV-1 strains. Overall, etravirine and DRV/r remain as the most active drugs.

INTRODUÇÃO: A terapia antirretroviral combinada (TARV) foi introduzida no Brasil em 1996, como parte da política nacional de acesso gratuito aos serviços de saúde e medicamentos. Infelizmente, o seu uso contínuo tem sido associado com mudanças na distribuição da gordura corporal e com alterações metabólicas que podem aumentar a morbidade e mortalidade nesta população. O treinamento físico tem sido estudado como uma estratégia eficaz de intervenção não farmacológica para melhorar os parâmetros de aptidão física relacionados à saúde e para minimizar os efeitos indesejáveis da infecção pelo HIV e/ou o uso prolongado da TARV, no entanto, há poucos estudos sobre o treinamento físico, síndrome lipodistrófica e cardiologia.OBJETIVO: Avaliar o risco de doença isquêmica cardíaca em sujeitos HIV/AIDS em uso de TARV praticantes de treinamento concorrente com séries simples.MÉTODOS: Quatorze sujeitos foram avaliados através da circunferência abdominal, pressão arterial sistólica (PAS) e diastólica (PAD), colesterol total (CT), HDL, LDL, triglicerídeos (TG) e glicemia. Para a estimativa do risco coronariano em 10 anos utilizou-se o Escore de Framingham.RESULTADOS: A maioria dos sujeitos situou-se dentro dos valores de referência para as variáveis analisadas, exceto para os valores de LDL e TG. Treze sujeitos (92,7%) ficaram abaixo dos 10% de risco coronariano em 10 anos, e apenas um (7,3%) estava em risco moderado. Houve correlação significativa entre o tempo de treinamento e a PAS.CONCLUSÃO: Sugere-se a realização de ensaios clínicos randomizados para avaliar os mesmos desfechos deste estudo.

INTRODUCTION: Highly active antiretroviral therapy (HAART) was introduced to Brazil in 1996, as part of the national policy of free access to health services and drugs. Unfortunately, its continued use has been associated with changes in the redistribution of body fat, and metabolic changes which can increase morbidity and mortality in this population. Physical training has been studied as an effective strategy of non-pharmacological intervention to improve physical fitness parameters related to health and to minimize the undesirable effects of HIV infection and/or prolonged use of HAART. However, there are few studies on physical training, lipodystrophy syndrome and cardiology.OBJECTIVE: To assess the risk of ischemic heart disease in HIV/AIDS subjects on HAART and in concurrent training with single sets.METHODS: Fourteen subjects were assessed by waist circumference, systolic (SBP) and diastolic (DBP) blood pressure, lipid profile, total cholesterol (TC), HDL, LDL, triglycerides (TG) and glucose. The Framingham score was used to estimate the 10-year risk for coronary heart disease.RESULTS: Except for LDL and TG values, most subjects were within the reference limits for the analyzed variables. Thirteen subjects (92.7%) were below the range of 10% for the 10-year risk for coronary heart disease, while only one subject (7.3%) showed a moderate risk. There was a significant correlation between training time and the SBP variable.CONCLUSION: We suggest conducting randomized trials to assess the same outcomes of this study.

INTRODUCCIÓN: La terapia antirretroviral de gran actividad (HAART) se introdujo en Brasil en 1996, como parte de la política nacional de acceso gratuito a los servicios de salud y medicamentos. Desafortunadamente, su uso continuado se ha asociado con cambios en la distribución de la grasa corporal y los cambios metabólicos que pueden aumentar la morbilidad y la mortalidad en esta población. El entrenamiento físico se ha estudiado como una estrategia de intervención no farmacológica eficaz para mejorar los parámetros de la condición física relacionados con la salud y reducir al mínimo los efectos adversos de la infección por VIH y/o el uso prolongado de la terapia HAART, sin embargo, existen pocos estudios sobre entrenamiento físico, el síndrome de lipodistrofia y cardiología.OBJETIVO: Evaluar el riesgo de cardiopatía isquémica en pacientes con VIH/SIDA que reciben HAART que practican entrenamiento concurrente con series simples.MÉTODOS: Catorce sujetos se evaluaron utilizando la circunferencia de cintura, presión arterial sistólica (PAS) y diastólica (PAD), colesterol total (CT), HDL, LDL, triglicéridos (TG) y la glucosa. Para estimar el riesgo coronario en 10 años se utilizó el score de Framingham.RESULTADOS: La mayoría de los sujetos estaban dentro de los límites de referencia de las variables analizadas, a excepción de LDL y TG. Trece sujetos (92,7%) estaban por debajo del riesgo coronario del 10% en 10 años, y sólo uno (7,3%) tenía riesgo moderado. Hubo una correlación significativa entre la duración del entrenamiento y la PAS.CONCLUSIÓN: Se sugiere llevar a cabo ensayos clínicos aleatorios para evaluar los mismos resultados de este estudio

O objetivo do estudo foi avaliar a eficácia de uma oficina educativa sobre HIV/aids em um grupo de idosos. A população incluiu 471 indivíduos entre 60 e 91 anos composta principalmente por mulheres (83,1%). Procedeu-se a aplicação e reaplicação de um questionário organizado em cinco domínios, antes e após as oficinas. O teste de McNemar foi utilizado para comparar as respostas pré e pós-oficina (p<0,05) no programa estatístico STATA 12. Dentre os domínios, a maior variação (202,72%) ocorreu no domínio "conceito" sobre a fase assintomática da infecção. No domínio "transmissão", a variação foi de 168,53% para a transmissão do HIV por picada de mosquito. No domínio "prevenção", na questão sobre existência do preservativo feminino, a variação foi de 44%. O domínio "vulnerabilidade" indicou 34,93% na questão da aids relacionada a grupos específicos. No domínio "tratamento", a abordagem da cura para a aids obteve 50,85% de variação. A realização das oficinas demonstrou ser uma intervenção eficaz nos domínios "conceito", "transmissão", "prevenção", "vulnerabilidade" e "tratamento" nos idosos participantes da pesquisa.

This study aimed to evaluate the effectiveness of educational workshops instructing about HIV/Aids in a group of elderly. The population included 471 individuals between 60 and 91 years old, mostly women (83.1%). A questionnaire comprising five domains was answered by participants before and after taking the educational workshops. McNemar test was used to assess differences between pre-and post-workshop, through thr software STATA 12 (p<0.05). The greatest variation (202.72%) was observed in the "concept" domain related to the asymptomatic infection phase. Regarding "HIV transmission", the variation was 168.53%. The domain "prevention" had variation of 44% concerning the existence of female condom. The "vulnerability" domain inquired about Aids association in specific groups, and a difference of 34.93% was observed. In the "treatment" domain, when inquiring about Aids cure, 50.85% variation was observed. The educational workshops were effective for the domains "concept", "transmission", "prevention", "vulnerability" and "treatment" in a group of elderly.

OBJECTIVE: To evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). Design: Cross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. METHODS: Patients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm³, and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. RESULTS AND DISCUSSION: Overall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p = 0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r = 0.32 and r = 0.33 respectively; p < 0.05 in both cases). no statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. CONCLUSION: in summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p = 0.068).

OBJETIVO: Conhecer a prevalência de sobrepeso, obesidade e risco cardiovascular em nossos pacientes ambulatoriais com HIV/AIDS de acordo com o sexo, tratamento antirretroviral e outras variáveis. SUJEITOS E MÉTODOS: Os pacientes foram submetidos à avaliação antropométrica. O índice de massa corporal e a medida da circunferência da cintura foram utilizados para classificar o estado nutricional e o risco cardiovascular. RESULTADOS: A maior parte dos 345 pacientes (58,8%) era do sexo masculino. A obesidade foi detectada em 8,3% deles; 34,2% tinham sobrepeso e 5,2%, desnutrição. Quase a metade (51,3%) apresentou algum risco cardiovascular, com risco elevado em 24,6% e muito elevado em 26,7%. CONCLUSÕES: O sobrepeso e a obesidade têm elevada prevalência. As mulheres são mais frequentemente obesas (OR = 3,53; IC 95%, 1,47 < OR < 8,69) e seu risco cardiovascular é frequentemente mais alto (OR = 6,97; IC 95%, 4,16 < OR < 11,76). A prevalência de obesidade e de risco cardiovascular não se alterou conforme o tratamento antirretroviral ou outras variáveis.

OBJECTIVE: The aim of this study was to discover the prevalence of overweight, obesity and cardiovascular risk in our HIV/AIDS outpatients according to sex, antiretroviral therapy and other variables. SUBJECTS AND METHODS: Patients underwent an anthropometric assessment. Body mass index and waist circumference were used to classify their nutritional status and their cardiovascular risk. RESULTS: The majority of the 345 patients (58.8%) were males. Obesity was detected in 8.3% of them; 34.2% were overweight, and 5.2% malnourished. Near half of them (51.3%) had some cardiovascular risk, with increased risk in 24.6% of them, and substantially increased risk in 26.7% of them. CONCLUSIONS: Overweight and obesity were highly prevalent. Women were more frequently obese (OR = 3.53; IC 95%, 1.47 < OR < 8.69), and their cardiovascular risk was often higher (OR = 6.97; IC 95%, 4.16 < OR < 11.76). The prevalence of obesity and cardiovascular risk did not change according to antiretroviral therapy or other variables.

Um método rápido para a determinação de seis inibidores de protease (indinavir, amprenavir, saquinavir, atazanavir, lopinavir e ritonavir) e de dois inibidores não-nucleosídicos da transcriptase reversa (efavirenz e nevirapine), empregando cromatografia líquida de ultra-eficiência com detector de arranjo de diodos foi desenvolvido e validado. Após extração liquido-líquido de 0,5 mL de plasma com metil-tert-butil éter, os analitos foram separados em uma coluna ACQUITY UPLC BEH® C18 (2,1 × 150 mm, d.p. 1,7 μm), eluída com um gradiente de tampão fosfato trietilamônio pH 3.0 e acetonitrila. O tempo total de análise cromatográfica foi de 9,5 min. As curvas de calibração foram lineares entre 0,1 a 10,0 μg mL-1. O limite inferior de quantificação foi 0,1 μg mL-1 para todos os fármacos. A exatidão esteve entre 94,9 e 103,5%. Os coeficientes de variação intra e inter-dias foram inferiores a 7,7% para todos os analitos. Os rendimentos de extração foram superiores a 88,2%.

A fast ultra-performance liquid chromatographic with diode-array detection method has been developed and validated for the determination of six protease inhibitors (indinavir, amprenavir, saquinavir, atazanavir, lopinavir, and ritonavir) and two non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine). After liquid-liquid extraction of 0.5 mL plasma with methyl-tert-butyl ether, the analytes were separated on a ACQUITY UPLC BEH® C18 column (2.1 × 150 mm, p.d. 1.7 μm) column eluted with a gradient of acetonitrile and triethylammonium phosphate buffer 5 mmol L-1 pH 3.0. The total run time was 9.5 min. Calibration curves were linear in the range 0.1 to to 10.0 μg mL-1. The lower limit of quantitation was 0.1 μg mL-1 for all drugs. Accuracy ranged from 94.9 to 103.5%. Both interday and intraday coefficients of variation were less than 7.7% for all analytes. The extraction yields were greater than 88.2%.

Metabolic complications continue to play a major role in the management of HIV infection. Dyslipidemia associated with HIV infection and with the use of combined antiretroviral therapy includes elevations in triglycerides, reduced high-density cholesterol, and variable increases in low-density and total cholesterol. The association between dyslipidemia and specific antiretroviral agents has been underscored. Multiple pathogenic mechanisms by which HIV and antiretroviral agents lead to dyslipidemia have been hypothesized, but they are still controversial. The potential clinical and pathological consequences of HIV-associated hyperlipidemia are not completely known, but several studies reported an increased risk of coronary artery disease in HIV-positive individuals receiving combined antiretroviral therapy. HIV-infected persons who have hyperlipidemia should be managed similarly to those without HIV infection in accordance with the National Cholesterol Education Program. Life style changes are the primary target. Statins and fibrates and/or modification in antiretroviral therapy are possible approaches to this problem.

O objetivo deste estudo é avaliar o nível de conhecimento sobre HIV/aids nos indivíduos de meia idade, participantes de grupos de convivência do Vale do Sinos (RS). O estudo caracterizou-se como transversal, obtendo-se uma amostra de 168 indivíduos, sendo 9,5% homens e 90,5% mulheres, na faixa etária entre 40 e 59 anos. Utilizou-se como instrumento um questionário composto pelos domínios "conceito", "transmissão", "vulnerabilidade", "prevenção" e "tratamento". O ensino fundamental caracterizou 61,3% da escolaridade dos participantes e a renda mensal situou-se entre um e três salários mínimos para 45,2%. No domínio "conceito", 65,2% desconheciam a fase assintomática da infecção e 34,5% apontaram o mosquito como transmissor da aids, no domínio "transmissão". Nos domínios "prevenção" e "vulnerabilidade", 19,5% desconheciam a existência do preservativo feminino e 29,2% acreditaram que a doença é característica de grupos específicos. Quanto ao "tratamento", 12,5% ignoraram a sua existência. De acordo com os achados, os indivíduos da meia idade participantes de grupos de convivência do Vale do Sinos tinham conceitos errôneos sobre HIV/aids que poderiam aumentar o risco à infecção. Sendo assim, é necessário proporcionar programas de saúde pública direcionados para esta população para prevenir ou diminuir o risco de transmissão do HIV.

The objective of this article is to assess the knowledge about HIV/aids in middle aged acquaintance group participants from the Vale do Sinos, Rio Grande do Sul State, Brazil. A prospective cross-sectional study with 168 individuals (9.5% male and 90.5% female) between 40 and 59 years of age was performed. A questionnaire comprising questions about the concept, transmission, vulnerability, prevention, and treatment domains on HIV issues was constructed. It was observed that 61.3% of the sample had finished elementary education and 45.2% had a monthly income ranging from 1 to 3 minimum wages. In the conceptual domain, 65.2% did not know that HIV infection has an asymptomatic phase and 34.5% believed HIV could be transmitted by a mosquito bite. In prevention and vulnerability domains, 19.5% had no knowledge about female condoms and 29.2% believed that the disease was confined to specific groups. Regarding to antiretroviral treatment, 12.5% had no idea about its existence. According to findings, middle aged participants from acquaintance groups in Vale do Sinos had misconceptions about HIV/aids which might enhance the risk of infection. Therefore it is necessary to provide public health programs directed to this population group in order to prevent or decrease the risk of HIV transmission.

O objetivo deste estudo é avaliar o nível de conhecimento sobre HIV/aids nos indivíduos de meia idade, participantes de grupos de convivência do Vale do Sinos (RS). O estudo caracterizou-se como transversal, obtendo-se uma amostra de 168 indivíduos, sendo 9,5% homens e 90,5% mulheres, na faixa etária entre 40 e 59 anos. Utilizou-se como instrumento um questionário composto pelos domínios "conceito", "transmissão", "vulnerabilidade", "prevenção" e "tratamento". O ensino fundamental caracterizou 61,3% da escolaridade dos participantes e a renda mensal situou-se entre um e três salários mínimos para 45,2%. No domínio "conceito", 65,2% desconheciam a fase assintomática da infecção e 34,5% apontaram o mosquito como transmissor da aids, no domínio "transmissão". Nos domínios "prevenção" e "vulnerabilidade", 19,5% desconheciam a existência do preservativo feminino e 29,2% acreditaram que a doença é característica de grupos específicos. Quanto ao "tratamento", 12,5% ignoraram a sua existência. De acordo com os achados, os indivíduos da meia idade participantes de grupos de convivência do Vale do Sinos tinham conceitos errôneos sobre HIV/aids que poderiam aumentar o risco à infecção. Sendo assim, é necessário proporcionar programas de saúde pública direcionados para esta população para prevenir ou diminuir o risco de transmissão do HIV.

The objective of this article is to assess the knowledge about HIV/aids in middle aged acquaintance group participants from the Vale do Sinos, Rio Grande do Sul State, Brazil. A prospective cross-sectional study with 168 individuals (9.5% male and 90.5% female) between 40 and 59 years of age was performed. A questionnaire comprising questions about the concept, transmission, vulnerability, prevention, and treatment domains on HIV issues was constructed. It was observed that 61.3% of the sample had finished elementary education and 45.2% had a monthly income ranging from 1 to 3 minimum wages. In the conceptual domain, 65.2% did not know that HIV infection has an asymptomatic phase and 34.5% believed HIV could be transmitted by a mosquito bite. In prevention and vulnerability domains, 19.5% had no knowledge about female condoms and 29.2% believed that the disease was confined to specific groups. Regarding to antiretroviral treatment, 12.5% had no idea about its existence. According to findings, middle aged participants from acquaintance groups in Vale do Sinos had misconceptions about HIV/aids which might enhance the risk of infection. Therefore it is necessary to provide public health programs directed to this population group in order to prevent or decrease the risk of HIV transmission.

O uso da terapia anti-retroviral combinada (TARV) aumentou a expectativa de vida dos portadores do vírus da imunodeficiência humana (HIV) e, como conseqüência, torna-se constante o estudo do processo fisiopatológico da infecção e das estratégias de intervenção que possam melhorar a qualidade de vida destes indivíduos. O treinamento concorrente, definido como a associação dos componentes aeróbios e força na mesma sessão de exercícios pode ser inserido neste contexto. O objetivo deste artigo é revisar os aspectos centrais da infecção pelo HIV e as evidências existentes sobre o treinamento concorrente com séries múltiplas e simples nos parâmetros imunológico, virológico, cardiorrespiratório e neuromuscular de pessoas infectadas pelo HIV. O método utilizado foi uma revisão sistemática, com artigos publicados entre 2000-2007, nas bases de dados scielo e pubmed e também em dissertações e teses da biblioteca digital da educação física, esporte e saúde. As evidências científicas encontradas nos 8 estudos analisados indicam que o treinamento concorrente, tanto com séries múltiplas quanto séries simples, melhora os parâmetros cardiorrespiratório e neuromuscular; no entanto, os resultados dos parâmetros imunológico e virológico ainda não estão completamente esclarecidos, principalmente sobre os protocolos com séries simples. Considerando o número restrito de trabalhos apresentados, sugere-se o desenvolvimento de estudos com treinamento concorrente em vários desfechos clínicos para pessoas infectadas pelo HIV.

The highly active antiretroviral therapy (HAART) increased life expectancy in individuals infected with the human immunodeficiency virus (HIV). Alternative strategies have been used in order to improve their quality of life and minimize the HAART effect; among these we can name physical exercise. Concurrent training, the combination of aerobic and strength training in the same exercise session, is used to improve aerobic and strength capacities with shorter time of training and stands out within the used methods. It is crucial to understand this syndrome's characteristics for the best application of physical exercise in the HIV infected patients. Therefore, the aim of this study is to review the main HIV infection characteristics and the evidence available on concurrent training with single and multiple sets in immunological, virological, cardiorespiratory and neuromuscular parameters in subjects living with HIV/AIDS. A systematic review of papers published from 2000-2007 in the Scielo and Pubmed database, as well as theses and dissertations on Physical Education, Sports and Health fields from the digital library totalizing 8 studies, was performed. Evidence from these 8 investigated studies showed that concurrent training, both with single and multiple sets, improves cardiorespiratory and neuromuscular parameters. However, the results in the immunological and virological parameters are not completely understood, especially on protocols with single sets.