Abstract Plasmodium falciparum is known to cause severe malaria, current treatment consists in artemisinin-based combination therapy, but resistance can lead to treatment failure. Knowledge concerning P. falciparum essential proteins can be used for searching new antimalarials, among these a potential candidate is shikimate dehydrogenase (SDH), an enzyme part of the shikimate pathway which is responsible for producing endogenous aromatic amino acids. SDH from P. falciparum (PfSDH) is unexplored by the scientific community, therefore, this study aims to establish the first protocol for active PfSDH expression. Putative PfSDH nucleotide sequence was used to construct an optimized expression vector pET28a+PfSDH inserted in E. coli BL21(DE3). As a result, optimal expression conditions were acquired by varying IPTG and temperature through time. Western Blot analysis was applied to verify appropriate PfSDH expression, solubilization and purification started with lysis followed by two-steps IMAC purification. Enzyme activity was measured spectrophotometrically by NADPH oxidation, optimal PfSDH expression occur at 0.1 mM IPTG for 48 hours growing at 37 °C and shaking at 200 rpm, recombinant PfSDH obtained after purification was soluble, pure and its physiological catalysis was confirmed. Thus, this study describes the first protocol for heterologous expression of PfSDH in soluble and active form. malaria artemisininbased artemisinin based therapy failure P antimalarials SDH, , (SDH) acids (PfSDH community therefore pET28aPfSDH pETaPfSDH pET28a pET E BL21DE3. BL21DE3 BLDE BL21 DE3 . BL DE BL21(DE3) result time twosteps two steps oxidation 01 0 1 0. 4 3 C 20 rpm confirmed Thus form (SDH aPfSDH pETa BL21DE BL2 BL21(DE3 2 BL21(DE

Abstract Background A cost of illness (COI) study aims to evaluate the socioeconomic burden that an illness imposes on society as a whole. This study aimed to describe the resources used, patterns of care, direct cost, and loss of productivity due to systemic lupus erythematosus (SLE) in Brazil. Methods This 12-month, cross-sectional, COI study of patients with SLE (ACR 1997 Classification Criteria) collected data using patient interviews (questionnaires) and medical records, covering: SLE profile, resources used, morbidities, quality of life (12-Item Short Form Survey, SF-12), and loss of productivity. Patients were excluded if they were retired or on sick leave for another illness. Direct resources included health-related (consultations, tests, medications, hospitalization) or non-health-related (transportation, home adaptation, expenditure on caregivers) hospital resources. Costs were calculated using the unit value of each resource and the quantity consumed. A gamma regression model explored cost predictors for patients with SLE. Results Overall, 300 patients with SLE were included (92.3% female, mean [standard deviation (SD)] disease duration 11.8 [7.9] years), of which 100 patients (33.3%) were on SLE-related sick leave and 46 patients (15.3%) had stopped schooling. Mean (SD) travel time from home to a care facility was 4.4 (12.6) hours. Antimalarials were the most commonly used drugs (222 [74.0%]). A negative correlation was observed between SF-12 physical component and SLE Disease Activity Index (- 0.117, p = 0.042), Systemic Lupus International CollaboratingClinics/AmericanCollegeofRheumatology Damage Index (- 0.115, p = 0.046), medications/day for multiple co-morbidities (- 0.272, p < 0.001), SLE-specific drugs/day (- 0.113, p = 0.051), and lost productivity (- 0.570, p < 0.001). For the mental component, a negative correlation was observed with medications/day for multiple co-morbidities (- 0.272, p < 0.001), SLE-specific medications/day (- 0.113, p = 0.051), and missed appointments (- 0.232, p < 0.001). Mean total SLE cost was US$3,123.53/patient/year (median [interquartile range (IQR)] US$1,618.51 [$678.66, $4,601.29]). Main expenditure was medication, with a median (IQR) cost of US$910.62 ($460, $4,033.51). Mycophenolate increased costs by 3.664 times (p < 0.001), and inflammatory monitoring (erythrocyte sedimentation rate or C-reactive protein) reduced expenditure by 0.381 times (p < 0.001). Conclusion These results allowed access to care patterns, the median cost for patients with SLE in Brazil, and the differences across regions driven by biological, social, and behavioral factors. The cost of SLE provides an updated setting to support the decision-making process across the country. (COI whole (SLE Brazil 12month, 12month month 12 month, 12-month crosssectional, crosssectional cross sectional, sectional cross-sectional ACR 199 Criteria questionnaires (questionnaires records covering profile morbidities 12Item Item Survey SF12, SF12 SF , SF-12) healthrelated health related consultations, consultations (consultations tests medications hospitalization nonhealthrelated non transportation, transportation (transportation adaptation caregivers consumed Overall 30 92.3% 923 92 3 (92.3 female standard SD 118 11 8 11. 7.9 79 7 9 [7.9 years, years years) 10 33.3% 333 33 (33.3% SLErelated 4 15.3% 153 15 (15.3% schooling (SD 44 4. 12.6 126 6 (12.6 hours 222 (22 74.0%. 740 74.0% . 74 0 [74.0%]) SF-1 ( 0117 117 0.117 0.042, 0042 0.042 042 0.042) CollaboratingClinicsAmericanCollegeofRheumatology CollaboratingClinics AmericanCollegeofRheumatology 0115 115 0.115 0.046, 0046 0.046 046 0.046) medicationsday day comorbidities co 0272 272 0.272 0.001, 0001 0.001 001 0.001) SLEspecific specific drugsday 0113 113 0.113 0.051, 0051 0.051 051 0.051) 0570 570 0.570 0.001. 0232 232 0.232 US312353patientyear USpatientyear US 123 53 year interquartile IQR US161851 1 618 51 US$1,618.5 $678.66, 67866 678 66 [$678.66 $4,601.29. 460129 $4,601.29 601 29 $4,601.29]) medication (IQR US91062 910 62 US$910.6 $460, 460 ($460 $4,033.51. 403351 $4,033.51 033 $4,033.51) 3664 664 3.66 erythrocyte Creactive C reactive protein 0381 381 0.38 biological social factors decisionmaking decision making country 19 SF1 92.3 (92. 7. [7. 33.3 (33.3 15.3 (15.3 12. (12. 22 (2 74.0 [74.0%] SF- 011 0.11 004 0.04 04 027 27 0.27 000 0.00 00 005 0.05 05 057 57 0.57 023 23 0.23 patientyear 5 US16185 61 US$1,618. $678.66 6786 67 [$678.6 46012 $4,601.2 60 2 $4,601.29] US9106 91 US$910. $460 ($46 40335 $4,033.5 03 366 3.6 038 38 0.3 92. (92 [7 33. (33. 15. (15. (12 74. [74.0% 01 0.1 0.0 02 0.2 0.5 US1618 US$1,618 $678.6 [$678. 4601 $4,601. US910 US$910 $46 ($4 4033 $4,033. 36 3. 0. (9 [ (33 (15 (1 [74.0 US161 US$1,61 $678. [$678 $4,601 US91 US$91 $4 ($ 403 $4,033 (3 [74. US16 US$1,6 $678 [$67 $4,60 US9 US$9 $ 40 $4,03 [74 US1 US$1, $67 [$6 $4,6 US$ $4,0 US$1 $6 [$ $4,

Abstract Background This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. Methods The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. Results Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/ hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. Conclusions This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus. standardofcare (SLE attainment flares accrual steroidsparing, steroidsparing steroid sparing, sparing APLC (APLC characteristics use models 170 12689 12 689 12,68 219 2 19 2.1 years 133 78.03% 7803 78 03 (78.03% LLDAS , (LLDAS) 97 57.18% 5718 57 18 (57.18% antimalarial anti malarial 69.86% 6986 69 86 (69.86% 76.37%. 7637 76.37% . 76 37 (76.37%) Prednisolone domains countries frequently Japan leflunomide chloroquine mofetilmycophenolic mycophenolic 75 7 5 7. mgday mg day compared effect Odds 95% 95 [95 Interval 1358 13 58 13.5 2.2382.78, 2238278 2.23 82.78 23 82 [2.23-82.78] 0.005 0005 0 005 OR 067 67 0.6 0.530.86, 053086 0.53 0.86 53 [0.53-0.86] 0.001 0001 001 068 68 0.470.98, 047098 0.47 0.98 47 98 [0.47-0.98] 0.038 0038 038 079 79 0.7 0.640.97, 064097 0.64 0.97 64 [0.64-0.97] 0.025. 0025 0.025 025 0.025) treatment 17 1268 1 12,6 21 2. 78.03 780 (78.03 (LLDAS 9 57.18 571 (57.18 69.86 698 6 8 (69.86 763 76.37 3 (76.37% [9 135 13. 2382 2.2382.78 223827 223 2.2 8278 82.7 [2.23-82.78 0.00 000 00 06 0. 530 0.530.86 05308 053 0.5 086 0.8 [0.53-0.86 470 0.470.98 04709 047 0.4 098 0.9 4 [0.47-0.98 0.03 003 07 640 0.640.97 06409 064 097 [0.64-0.97 002 0.02 02 126 12, 78.0 (78.0 57.1 (57.1 69.8 (69.8 76.3 (76.37 [ 238 2.2382.7 22382 22 827 82. [2.23-82.7 0.0 0.530.8 0530 05 08 [0.53-0.8 0.470.9 0470 04 09 [0.47-0.9 0.640.9 0640 [0.64-0.9 78. (78. 57. (57. 69. (69. 76. (76.3 2.2382. 2238 [2.23-82. 0.530. [0.53-0. 0.470. [0.47-0. 0.640. [0.64-0. (78 (57 (69 (76. 2.2382 [2.23-82 0.530 [0.53-0 0.470 [0.47-0 0.640 [0.64-0 (7 (5 (6 (76 2.238 [2.23-8 [0.53- [0.47- [0.64- ( [2.23- [0.53 [0.47 [0.64 [2.23 [0.5 [0.4 [0.6 [2.2 [0. [2. [0 [2

Abstract Malaria is a wide-spread disease in tropical areas. The severe form is characterized by organic involve ment and/or hyperparasitaemia. Criteria for early monitoring in intensive care rooms are defined; with out a timely and early treatment, severe malaria has a 100% mortality. Although the literature in these cases is not extensive, extracorporeal therapy used sequentially for hepatic and renal detoxification is a useful and safe tool that can be used in intensive care. We describe the case of a 36-year-old man with a diag nosis of severe malaria according to WHO criteria. He began treatment with intravenous artesunate and due to a torpid evolution, a sudden increase in bilirubine mia with encephalopathy, parameters of acute kidney injury and acute pulmonary edema, undergoes extra corporeal sequential treatment, coupled with plasma filtration adsorption, high-exchange plasmapheresis, and continuous hemodiafiltration with favorable evo lution. This case shows that extracorporeal support in trained hands and in a timely manner is effective when organ failure evolves rapidly to achieve stability and provide necessary time for definitive treatment, in this case rapid action antimalarials until parasitemia becomes negative.

Resumen La malaria es una enfermedad con amplia distribu ción en áreas tropicales. En su forma grave se caracteriza por afección orgánica y/o hiperparasitemia. Se definen los criterios para el monitoreo temprano en las salas de terapia intensiva, debido a que sin tratamiento oportu no y precoz la malaria grave tiene una mortalidad de 100%. Si bien no es amplia la literatura en este aspecto la terapia extracorpórea en forma secuencial para de toxificación hepática y renal es una herramienta útil y segura que puede ser utilizada en terapia intensiva. Se describe un caso de un varón de 36 años con diagnóstico de malaria grave según criterio de la Organización Mun dial de la Salud (OMS) que comenzó con tratamiento con artesunato endovenoso y por evolución tórpida, ascenso brusco de bilirrubinemia con encefalopatía, parámetros de lesión renal aguda y edema agudo de pulmón, realiza tratamiento extracorpóreo secuencial, plasma filtración acoplada a adsorción, plasmaféresis de alto intercambio y hemodiafiltración continua con evolución favorable. En conclusión, el caso presentado nos demuestra que el rol del sostén extracorpóreo en manos entrenadas y en forma oportuna es crucial cuando el fallo de órganos evoluciona rápidamente para lograr dar estabilidad y otorgar el tiempo necesario para la acción del tratamien to definitivo en este caso, los antimaláricos de acción rápida hasta negativización de la parasitemia.

Abstract We critically analyzed clinical trials performed with chloroquine (CQ) and hydroxychloroquine (HCQ) with or without macrolides during the first wave of COVID-19 and discussed the design and limitations of peer-reviewed studies from January to July 2020. Seventeen studies were eligible for the discussion. CQ and HCQ did not demonstrate clinical advantages that justified their inclusion in therapeutic regimens of free prescription for treatment or prophylactic purposes, as suggested by health authorities, including in Brazil, during the first wave. Around August 2020, robust data had already indicated that pharmacological effects of CQ, HCQ and macrolides as anti-SARS-CoV-2 molecules were limited to in vitro conditions and largely based on retrospective trials with low quality and weak internal validity, which made evidence superficial for decision-making. Up to that point, most randomized and nonrandomized clinical trials did not reveal beneficial effects of CQ or HCQ with or without macrolides to reduce lethality, rate of intubation, days of hospitalization, respiratory support/mechanical ventilation requirements, duration, type and number of symptoms, and death and were unsuccessful in increasing virus elimination and/or days alive in hospitalized or ambulatory patients with COVID-19. In addition, many studies have demonstrated that side effects are more common in CQ-or HCQ-treated patients. (CQ (HCQ COVID19 COVID 19 COVID-1 peerreviewed peer reviewed 2020 discussion purposes authorities Brazil antiSARSCoV2 antiSARSCoV anti SARS CoV 2 anti-SARS-CoV- validity decisionmaking. decisionmaking decision making. making decision-making point lethality intubation hospitalization supportmechanical support mechanical requirements duration symptoms andor COVID19. 19. addition CQor HCQtreated treated COVID1 1 COVID- 202 anti-SARS-CoV 20

ABSTRACT Background: Malaria is one of the leading causes of morbidity worldwide, and patient adherence to prescribed antimalarials is essential for effective treatment. Methods: This cross-sectional study, with in-depth telephone interviews, analyzed participants’ perceptions of short message service (SMS) in adherence to treatment. Results: Five thematic categories emerged: decreased forgetfulness, the novelty of the tool, easy-to-understand language, the impact of SMS messages during treatment, and suggestions for improvement and complaints. Conclusions: SMS could assist patients in adhering to prescribed antimalarials. Background worldwide treatment Methods crosssectional cross sectional study indepth depth interviews participants (SMS Results emerged forgetfulness tool easytounderstand easy understand language complaints Conclusions

Abstract In this work, an in silico study and evaluation of the cytotoxicity of 4-(4-chlorophenyl)thiazole compounds against mouse splenocytes and the chloroquine-sensitive Plasmodium falciparum 3D7 strain are reported. The in silico results showed that the compounds have important pharmacokinetic properties for compounds with potential drug candidates. Regarding cytotoxicity assays against splenocytes, the compounds have low cytotoxicity. In addition, they were able to promote activation of these cells by increasing nitric oxide production without promoting cell death. Finally, they were able to promote cell proliferation. Regarding the in vitro anti-P. falciparum activity assays, it was observed that the compounds were able to inhibit the parasite’s growth, presenting IC50 values ranging from 0.79 to greater than 10 µM. These results are promising when compared to chloroquine. Therefore, this study showed that 4-(4-chlorophenyl)thiazole compounds are promising candidates for antimalarials. work 44chlorophenylthiazole chlorophenylthiazole 4 chlorophenyl thiazole chloroquinesensitive chloroquine sensitive D 3D reported addition death Finally proliferation antiP. antiP anti P. P anti-P parasites parasite s growth IC IC5 079 0 79 0.7 1 µM Therefore antimalarials 07 7 0.

Abstract Background Several studies have compared the clinical features and outcomes of late- and early-onset systemic lupus erythematosus (SLE) patients. However, these previous studies were uncontrolled. The current study aimed to compare late- and early-onset SLE patients while controlling for sex and year at diagnosis (± 1 year). Methods The medical records of SLE patients in a lupus cohort from January 1994 to June 2020 were reviewed. Late-onset patients were identified as those with an age at diagnosis ≥ 50 years. The early-onset patients (age at diagnosis < 50 years) were matched by sex and year at diagnosis with the late-onset patients at a ratio of 2:1. Clinical manifestations, disease activity (mSLEDAI-2K), organ damage scores, treatment, and mortality were compared between the two groups. Results The study comprised 62 and 124 late- and early-onset patients, respectively, with a mean follow-up duration of 5 years. At disease onset, when comparing the early-onset patients with the late-onset patients, the latter group had a higher prevalence rate of serositis (37.0% vs. 14.5%, p < 0.001) and hemolytic anemia (50.0% vs. 33.9%, p = 0.034) but lower prevalence rate of malar rash (14.5% vs. 37.1%, p = 0.001), arthritis (41.9% vs. 62.1%, p = 0.009), leukopenia (32.3% vs. 50.0%, p = 0.022) and lymphopenia (50.0% vs. 66.1%, p = 0.034). The groups had similar SLE disease activity (7.41 vs. 7.50), but the late-onset group had higher organ damage scores (0.37 vs. 0.02, p < 0.001). The rates of treatment with corticosteroids, antimalarial drugs, or immunosuppressive drugs were not different. At their last visit, the late-onset patients still had the same pattern of clinically significant differences except for arthritis; additionally, the late-onset group had a lower rate of nephritis (53.2% vs. 74.2%, p = 0.008). They also had a lower level of disease activity (0.41 vs. 0.57, p = 0.006) and received fewer antimalarials (67.7% vs. 85.5%, p = 0.023) and immunosuppressive drugs (61.3% vs. 78.2%, p = 0.044), but they had higher organ damage scores (1.37 vs. 0.47, p < 0.001) and higher mortality rates/100-person year (3.2 vs. 1.1, p = 0.015). After adjusting for disease duration and baseline clinical variables, the late-onset patients only had lower rate of nephritis (p = 0.002), but still received fewer immunosuppressive drugs (p = 0.005) and had a higher mortality rate (p = 0.037). Conclusions In this sex- and year at diagnosis-matched controlled study, after adjusting for disease duration and baseline clinical variables, the late-onset SLE patients had less renal involvement and received less aggressive treatment, but had a higher mortality rate than the early-onset patients. late earlyonset early onset (SLE However uncontrolled ± ( year. . year) 199 202 reviewed Lateonset Late years lateonset 21. 21 2 1. 2:1 manifestations mSLEDAI2K, mSLEDAI2K mSLEDAIK mSLEDAI 2K , K (mSLEDAI-2K) 6 12 respectively followup follow up 37.0% 370 37 0 (37.0 vs 145 14 14.5% 0.001 0001 001 50.0% 500 (50.0 339 33 9 33.9% 0.034 0034 034 (14.5 371 37.1% 0.001, 41.9% 419 41 (41.9 621 62.1% 0.009, 0009 0.009 009 0.009) 32.3% 323 32 3 (32.3 0.022 0022 022 661 66 66.1% 0.034. 7.41 741 7 (7.4 7.50, 750 7.50 7.50) 0.37 037 (0.3 002 02 0.02 0.001. corticosteroids different visit additionally 53.2% 532 53 (53.2 742 74 74.2% 0.008. 0008 0.008 008 0.008) 0.41 041 (0.4 057 57 0.57 0.006 0006 006 67.7% 677 67 (67.7 855 85 85.5% 0.023 0023 023 61.3% 613 61 (61.3 782 78 78.2% 0.044, 0044 0.044 044 0.044) 1.37 137 (1.3 047 47 0.47 rates/100person rates100person ratesperson rates/100 person 100 3.2 (3. 11 1.1 0.015. 0015 0.015 015 0.015) variables 0.002, 0002 0.002 0.002) 0.005 0005 005 0.037. 0037 0.037 0.037) diagnosismatched 19 20 2: (mSLEDAI-2K 37.0 (37. 14.5 0.00 000 00 50.0 (50. 33.9 0.03 003 03 (14. 37.1 41.9 4 (41. 62.1 32.3 (32. 66.1 7.4 (7. 75 7.5 0.3 (0. 0.0 53.2 (53. 74.2 0.4 04 05 0.5 67.7 (67. 8 85.5 61.3 (61. 78.2 004 0.04 1.3 13 (1. 100person rates100 rates/10 10 3. (3 0.01 01 37. (37 14. 50. (50 33. (14 41. (41 62. 32. (32 66. 7. (7 0. (0 53. (53 74. 67. (67 85. 61. (61 78. (1 rates10 rates/1 (5 (4 (6 rates1 rates/

RESUMEN El daño refleja los cambios irreversibles que se producen en los pacientes con lupus eritematoso sistémico (LES) como consecuencia de la enfermedad, de su tratamiento o por causa de comorbilidades. El patrón de dano aumenta de forma lineal, constante a lo largo del tiempo. Al menos la mitad de todos los pacientes con LES presentará alguna forma de daño orgánico 10 años después de haber sido diagnosticados. Entre los factores asociados con el desarrollo de dano encontramos la edad avanzada, la duración de la enfermedad, el sexo masculino, la etnia no caucásica, la actividad de la enfermedad, el uso de corticoesteroides, la pobreza, la hipertensión y comportamientos anormales de la enfermedad; por otra parte, los antimaláricos protegen contra el dano de la enfermedad. Puesto que la presencia de daño es un predictor de danno adicional y de mortalidad, la prevención de acumulación de dano deberá ser un objetivo terapéutico fundamental en LES. Los tratamientos novedosos para el LES que logren un mejor control de la enfermedad y que tengan propiedades ahorradoras de corticoesteroides, podrían lograr mejores desenlaces en los pacientes, pues reducirían el daño acumulado y mejorarían la sobrevida.

ABSTRACT Damage reflects the irreversible changes that occur in systemic lupus erythematosus (SLE) patients as a consequence of the disease, its treatment or comorbidities. The pattern of damage increases in a steady linear fashion over time. At least half of all patients with SLE will have some form of organ damage 10 years after their diagnosis. Factors associated with the occurrence of damage include older age, disease duration, male gender, non-Caucasian ethnicity, disease activity, corticosteroid use, poverty, hypertension and abnormal illness behaviors. In contrast, antimalarials are protective against damage. Since damage predicts further damage and mortality, prevention of damage accrual should be a major therapeutic goal in SLE. Novel therapies for SLE that achieve better control of the disease and with corticosteroid-sparing properties, may lead to improved outcomes in patients as they will reduce damage accrual and improve survival.

Resumen Con base en la persistencia de los casos de malaria, dados por múltiples razones, entre las cuales se encuentra la resistencia de Plasmodium falciparum a los antimálaricos establecidos para su tratamiento, surge la necesidad de encontrar nuevos compuestos antimaláricos frente a otros blancos terapéuticos. En vista de ello, las Nuevas Rutas de Permeabilidad (NPP) han sido un objetivo promisorio y a partir de su descubrimiento, se han realizado diversos estudios enfocados en comprender su mecanismo y los componentes utilizados para el transporte de solutos y otras moléculas a través de la membrana del eritrocito. El objetivo de esta revisión de tema es presentar una recopilación de los estudios más significativos realizados en torno a las NPP. Para ello, se revisó la literatura para conocer el estado del desarrollo de las investigaciones referentes al tema, consultando bases de datos electrónicas y combinando los descriptores o palabras clave: (NPP AND malaria, AND Plasmodium falciparum AND inhibitors), además, se realizaron búsquedas secundarias en las listas de referencias bibliográficas de los artículos identificados. Luego de revisar los artículos de la literatura publicados entre los años 1980 y 2019, se concluye que muchos estudios han sido dedicados a la búsqueda de inhibidores de esta vía con fines terapéuticos y hay gran cantidad de moléculas candidatas como el híbrido MA-DFO y las diaminidas que han mostrado actividad en modelos de malaria tanto in vitro como in vivo.

Abstract In malaria, the persistent resistance to antimalarial drugs by Plasmodium falciparum constitute a problem to world public health. New Permeability Pathways (NPP) are a promissory therapeutic target, because the parasite uses them to modify the membrane of the erythrocyte and make it permeable to various nutrients needed for its growth. We present a theme review where a compilation of various studies related to NPP, its importance and its inhibitors was made.

ABSTRACT Introduction: The development of recommendations for the treatment of rheumatoid arthritis (RA) in the Cuban context may be one of the ways to achieve better control of this disease. Objective: To reach a consensus and update relevant aspects of conventional and biological RA modifier therapy in Cuba. Methods: 18 specialists from 8 Cuban provinces, experts in RA care, were summoned, according to the years of dedication to the specialty, the conferences on this topic and their publications. The first meeting took place in March 2016 in the provincial hospital of Villa Clara, Cuba, with the participation of all the experts. A review of the literature on conventional and biological therapy previously collected by the participants was developed, and two teams were formed: the first would address everything related to conventional therapy in RA (HRCT) and the other, biological therapy in RA (TBAR). Three questionnaires related to the use of corticosteroids, HRCT and TBAR, were prepared, answered by the participants via email. In a second meeting, held in October 2016 in Havana, the analysis of all the responses provided was carried out. Questions with a response of 90% or more votes were considered as recommendations. Results: The questionnaires were answered by 95% of the participants. 9 recommendations and 1 algorithm were established. The recommendations are as follows: methotrexate is the drug of choice in the treatment of RA after diagnosis; The administration of another conventional drug (DMARDc) (azathioprine, salazosulfapyridine, antimalarials and leflunomide) is recommended in patients with a diagnosis of active RA in whom methotrexate is contraindicated or there is a failure in response - consider the administration of low doses of prednisone or equivalent (<7.5 mg/d) associated with DMARDc in patients with active moderate to severe RA, for the shortest possible time; perform serological control including tests for hepatitis B and C viruses and screening for HIV in all patients diagnosed with RA before starting treatment with DMARDc and biologics; in patients in remission or, at least, with a DAS-28 below 3.2, consideration should be given to withdrawing one of the DMARDs or reducing, to the minimum possible expression, the dose of both disease modifiers; if methotrexate fails, tocilizumab in combination with methotrexate or as monotherapy will be indicated. Conclusions: Aspects related to conventional therapy with methotrexate, azathioprine, salazosulfapyridine, antimalarials and leflunomide were agreed. The value of early diagnosis and immediate initiation of DMARDc therapy and the use of glucocorticoids was analyzed. Treatment with tocilizumab, the only biological available in Cuba against RA, will be administered when there is a failure in the response to conventional therapy and combinations between these drugs. It is recommended to hold educational conferences through the mass media aimed at patients.

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RESUMEN Introducción: la púrpura trombocitopénica inmune (PTI) es una manifestación hematológica frecuente en el lupus eritematoso sistémico (LES). Los corticoesteroides son la primera línea de manejo para la trombocitopenia moderada o grave, en conjunto con antimaláricos y otros inmunosupresores. En casos particulares, en donde la respuesta a las intervenciones iniciales no sea la adecuada, se cuenta con terapias de segunda línea. Objetivo: esta revisión narrativa se enfocará en dos medicamentos agonistas del receptor de trombopoyetina (RTPO): eltrombopag y romiplostim y en su papel en la PTI secundaria a LES. Además, se revisará su perfil farmacológico, dosis e indicaciones en el contexto de esta enfermedad. Métodos: se realizó una búsqueda de literatura en diferentes bases de datos, se analizaron artículos científicos y guías de manejo, tanto de LES como de trombocitopenia inmune, con el fin de contestar diferentes preguntas clínicas surgidas en el escenario de la práctica cotidiana. Resultados y conclusiones: el uso de los estimulantes de TPO es una alternativa terapéutica para escenarios particulares de pacientes con LES y trombocitopenia inmune. Sin embargo, son necesarios estudios enfocados en esta población específica para poder hacer recomendaciones acertadas acerca de su manejo. Los datos actuales son extrapolados de la trombocitopenia inmune primaria.

SUMMARY Introduction: Immune thrombocytopenia is a frequent hematologic manifestation in systemic lupus erythematosus (SLE). Corticosteroids are the first line of treatment for moderate to severe thrombocytopenia in this disease, in conjunction with antimalarials or other immunosuppressants. In particular cases where the response to initial interventions is not achieved, second-line therapies with different mechanisms of action are available. Objective: This narrative review will focus on two thrombopoietin receptor agonist drugs (TPO-RA): eltrombopag and romiplostim, and their role in immune thrombocytopenia secondary to SLE. In addition, its pharmacological profile, dose and indications will be reviewed in the context of this disease. Methods: A literature search was conducted in different databases; scientific articles and guidelines were analyzed, both for SLE and immune thrombocytopenia. With the purpose of answering different clinical questions that constantly arise in the scene of daily practice. Results and conclusions: The use of TPO-RA stimulants is a therapeutic alternative for particular scenarios in patients with SLE and immune thrombocytopenia, however studies focused on this particular population are necessary to be able to make strong recommendations about its utility. Current data are extrapolated from primary immune thrombocytopenia.

Herbal medicines made from the bark of the Cinchona tree, and later quinine, have been widely used for centuries to treat medical conditions such as tropical malaria. More recently, chloroquine (CQ) and its synthetic derivatives have been used as antimalarials and to treat systemic lupus erythematosus, rheumatoid arthritis, and in the past 14 months or so, COVID-19 pneumonia. Anecdotal evidence and the erratic covering through social media of its potential efficacy in the treatment of COVID-19 pneumonia have resulted in the widespread off-label use of CQ in South Africa and worldwide. This study aimed to show that access to CQ as a chronic medication for rheumatic and musculoskeletal diseases was limited during the COVID-19 pandemic, and that this resulted in an increased incidence of flares in these patients, affecting their morbidity and potentially leading to mortality.

ABSTRACT: Lupus erythematosus is an immune-mediated, inflammatory, chronic, multisystemic disease, with cutaneous involvement in most cases. Cutaneous involvement may precede systemic involvement by decades, or be a marker of activity. Cutaneous involvement of lupus is divided into specific and nonspecific lesions, depending on whether or not they have interface dermatitis on histopathology. Objectives: To describe the clinical, epidemiological and histopathological characteristics of patients with lupus erythematosus with cutaneous manifestations who attend the Department of Dermatology of FCM-UNA from January 2008 to December 2018. 2018, regardless of age, patients with SLE associated lesions confirmed by pathology. Method: Design: Descriptive cross-sectional observational study. Sample: Nonprobabilistic of consecutive cases. Inclusion criteria: patients with lupus erythematosus of both sexes and any age who attended the Outpatient Clinic of the Department of Dermatology of the Hospital de Clínicas-UNA from January 2008 to December 2018, with skin lesions associated with lupus erythematosus. to December 2018, carriers of skin lesions associated with Lupus Erythematosus with anatomopathological confirmation. Sources of information: patients who attended the Chair of Dermatology and clinical histories of patients diagnosed with lupus erythematosus. Results: Patients were predominantly females (79%) of reproductive age (32.7%). Most patients were from urban areas (56%) and housewives (37.7%). Sixty two percent reported sun exposure. Most patients had multiple lesions (71%), and 28% had facial lesions. Lesions were mostly lupus specific (68%), and classified a chronic cutaneous lupus erythematosus (CCLE) (56%). Among the nonspecific lesions vasculitis was the most frequent (38%). All patients received antimalarials and sun protection recommendations. Multidisciplinary management with rheumatology and other departments according to the case was frequent. Conclusion: Adequately identifying these lesions provides fundamental data for the diagnosis and management of lupus patients; on many occasions these cutaneous and/or mucosal manifestations may reveal systemic activity.

RESUMEN: El lupus eritematoso, enfermedad inmunomediada, inflamatoria, crónica, multisistémica, con toque cutáneo en la mayoría de los casos, pudiendo la afectación cutánea preceder incluso en décadas a la sistémica, o ser un marcador de actividad. La afectación cutánea del lupus se divide en lesiones específicas e inespecíficas, según tengan o no dermatitis de interfase a la histopatología. Objetivos: General: Describir las características clínicas, epidemiológicas e histopatológicas de los pacientes con lupus eritematoso con manifestaciones cutáneas que acudieron a la Cátedra de Dermatología de FCM-UNA desde enero de 2008 a diciembre de 2018. Material y método: Diseño: Estudio observacional descriptivo de corte transversal. Mues treo: No probabilístico de casos consecutivos. Criterios de Inclusión: Pacientes portadores de lupus eritematoso de ambos sexos y cualquier edad que acudieron al Consultorio Ex terno de la Cátedra de Dermatología del Hospital de Clínicas-UNA desde enero de 2008 a diciembre de 2018, portadores de lesión cutánea asociada a Lupus Eritematoso con confirmación anátomo-patológica. Fuentes de información: Pacientes que acudieron a la Cátedra de Dermatología e Historias clínicas de pacientes con diagnóstico de lupus eritematoso. Resultados: Obtuvimos preponderancia en mujeres (79%) en edad reproductiva (32,7%), procedentes de área urbana (56%), amas de casa (37,7%), con exposición solar (62%), en su mayoría múltiples lesiones (71%), localizadas en rostro (28%), correspondiendo preferentemente a lesiones específicas del lupus (68%), los cuales fueron representados por el lupus eritematoso cutáneo crónico (LECC) en 56% de las lesiones. Dentro de las lesiones inespecíficas fueron mayoría las vasculitis (38%), todos los pacientes recibieron indicación de antipalúdicos y protección solar, manejo multidisciplinario con reumatología y otros departamentos según el caso. Conclusión: Identificar de manera adecuada éstas lesiones proporciona un dato fundamental para el diagnóstico y el manejo de los pacientes lúpicos, en muchas ocasiones estas manifestaciones cutáneas y/o mucosas pueden revelar actividad sistémica.

RESUMEN La enfermedad por Coronavirus 2019 (COVID-19) es una pandemia inesperada que ha pro vocado un estado de emergencia y que ha generado cambios drásticos en los protocolos de atención clínica. Para su tratamiento se ha descrito el papel de algunos medicamen tos usados habitualmente en artritis reumatoide, lupus eritematoso sistémico y otras enfermedades autoinmunitarias sistémicas. Debido a ello, existe un inminente riesgo de desabastecimiento, por lo cual el objetivo de esta revisión narrativa y opinión de expertos es formular recomendaciones generales clínicas y administrativas sobre el manejo de pacien tes ambulatorios con enfermedad autoinmunitaria o inflamatoria sistémica en el contexto de la pandemia por COVID-19.

ABSTRACT Coronavirus 2019 (COVID-19) is an unexpected pandemic that has caused a state of emergency, as well as generating drastic changes in clinical care protocols. Some drugs commonly used in rheumatoid arthritis, systemic lupus erythematosus, and other systemic autoimmune diseases have been described for its treatment. Therefore, there is an imminent risk of shortages. The aim of this narrative review and expert opinion is to present general recommendations on the clinical and administrative management of outpatients with autoimmune or systemic inflammatory disease, in the context of the COVID-19 pandemic.