A circuit-based approach to modulate hypersexuality in Parkinson's disease.

AIM: Impulse-control disorder is a common neuropsychiatric complication in Parkinson's disease (PD) under dopamine replacement therapy. Prior studies tested the balance between enhanced desire towards reward and cognitive control deficits, hypothesized to be biased towards the former in impulse control disorders. We provide evidence for this hypothesis by measuring behavioral and neural patterns behind the influence of sexual desire over response inhibition and tools towards functional restoration using repetitive transcranial stimulation in patients with hypersexuality as predominant impulsive disorder. METHODS: The effect of sexual cues on inhibition was measured with a novel erotic stop-signal task under on and off dopaminergic medication. Task-related functional and anatomical connectivity models were estimated in 16 hypersexual and 17 nonhypersexual patients with PD as well as in 17 healthy controls. Additionally, excitatory neuromodulation using intermittent theta-burst stimulation (sham-controlled) was applied over the pre-supplementary motor area in 20 additional hypersexual patients with PD aiming to improve response inhibition. RESULTS: Compared with their nonhypersexual peers, patients with hypersexuality recruited caudate, pre-supplementary motor area, ventral tegmental area, and anterior cingulate cortex while on medication. Reduced connectivity was found between pre-supplementary motor area and caudate nucleus in hypersexual compared with nonhypersexual patients (while medicated), a result paralleled by compensatory enhanced anatomical connectivity. Furthermore, stimulation over the pre-supplementary motor area improved response inhibition in hypersexual patients with PD when exposed to sexual cues. CONCLUSION: This study, therefore, has identified a specific fronto-striatal and mesolimbic circuitry underlying uncontrolled sexual responses in medicated patients with PD where cortical neuromodulation halts its expression.

Critical analysis of Chagas disease treatment in different countries.

As a result of globalization and constant migratory flows, Chagas disease is now present in almost all continents. The management and treatment of the disease is often influenced by the economic and social context of the societies that host patients. In this manuscript, we aim to provide a comparative review of approaches to patients with Chagas disease in the Americas and Europe.

Imported Arbovirus Infections in Spain, 2009-2018.

To determine the epidemiologic and clinical characteristics of patients in Spain with imported arbovirus infections, we analyzed 22,655 records from a collaborative network for January 2009-December 2018. Among 861 arbovirus infections, 845 were monoinfections (456 [53%] dengue, 280 [32.5%] chikungunya, 109 [12.7%] Zika) and 16 (1.8%) were co-infections. Most patients were travelers (56.3%) or immigrants returning to Spain after visiting friends or relatives (31.3%). Median patient age was 37 years; most (62.3%) were women and some (28.6%) had received pretravel advice. Only 12 patients were immunosuppressed. Six cases (all dengue monoinfections, none in immunosuppressed patients) were severe. Since 2014, nondengue arbovirus infections increased; until 2016, chikungunya and Zika were most common. Imported arbovirus infections (mostly dengue) were frequently diagnosed, although increased chikungunya and Zika virus infections coincided with their introduction and spread in the Americas. A large proportion of cases occurred in women of childbearing age, some despite receipt of pretravel advice.

Remote Monitoring of Treatment Response in Parkinson's Disease: The Habit of Typing on a Computer.

OBJECTIVE: The recent advances in technology are opening a new opportunity to remotely evaluate motor features in people with Parkinson's disease (PD). We hypothesized that typing on an electronic device, a habitual behavior facilitated by the nigrostriatal dopaminergic pathway, could allow for objectively and nonobtrusively monitoring parkinsonian features and response to medication in an at-home setting. METHODS: We enrolled 31 participants recently diagnosed with PD who were due to start dopaminergic treatment and 30 age-matched controls. We remotely monitored their typing pattern during a 6-month (24 weeks) follow-up period before and while dopaminergic medications were being titrated. The typing data were used to develop a novel algorithm based on recursive neural networks and detect participants' responses to medication. The latter were defined by the Unified Parkinson's Disease Rating Scale-III (UPDRS-III) minimal clinically important difference. Furthermore, we tested the accuracy of the algorithm to predict the final response to medication as early as 21 weeks prior to the final 6-month clinical outcome. RESULTS: The score on the novel algorithm based on recursive neural networks had an overall moderate kappa agreement and fair area under the receiver operating characteristic (ROC) curve with the time-coincident UPDRS-III minimal clinically important difference. The participants classified as responders at the final visit (based on the UPDRS-III minimal clinically important difference) had higher scores on the novel algorithm based on recursive neural networks when compared with the participants with stable UPDRS-III, from the third week of the study onward. CONCLUSIONS: This preliminary study suggests that remotely gathered unsupervised typing data allows for the accurate detection and prediction of drug response in PD. © 2019 International Parkinson and Movement Disorder Society.

Lymphoproliferation Impairment and Oxidative Stress in Blood Cells from Early Parkinson's Disease Patients.

In Parkinson's Disease (PD), the peripheral changes in the functional capacity and redox state of immune cells has been scarcely investigated, especially in the early PD stages. Aging is a risk factor for PD, and the age-related impairment of the immune system, based on a chronic-oxidative stress situation, is involved in the rate of aging. We analyzed several functions in isolated peripheral blood neutrophils and mononuclear cells from PD stage 2 patients, and compared the results to those in healthy elderly and adult controls. Several oxidative stress and damage parameters were studied in whole blood cells. The results showed an impairment of the lymphoproliferative response in stimulated conditions in the PD patients compared with age-matched controls, who also showed typical immunosenescence in comparison with adult individuals. Higher oxidative stress and damage were observed in whole blood cells from PD patients (lower glutathione peroxidase activity, and higher oxidized glutathione and malondialdehyde contents). Our results suggest an accelerated immunosenescence in PD stage 2, and that several of the parameters studied could be appropriate peripheral biomarkers in the early stages of PD.

Neurocognitive safety after 96 weeks on dual therapy with atazanavir/ritonavir plus lamivudine: results of the neurocognitive substudy of the SALT randomized clinical trial.

Background: Concerns have been voiced over the capacity of deintensification strategies to preserve neurocognitive function and prevent neurocognitive impairment. Methods: We present the 96 week results of a neurocognitive substudy nested within the SALT clinical trial: a randomized, open-label, non-inferiority trial that compares whether atazanavir/ritonavir + lamivudine is non-inferior to atazanavir/ritonavir + two NRTIs in HIV-suppressed patients on stable triple therapy. A global deficit score (GDS) for five neurocognitive tasks was used to assess neurocognitive function. Changes in neurocognitive function (GDS value) were determined at weeks 48 and 96. The effect of atazanavir/ritonavir + lamivudine, adjusted for significant confounders, on the change in neurocognitive function was determined using analysis of covariance (ANCOVA) at week 96. Results: The per-protocol analysis included 92 participants (47 atazanavir/ritonavir + lamivudine and 45 atazanavir/ritonavir + two NRTIs). All baseline characteristics were comparable in both groups. At weeks 48 and 96, changes in GDS [week 48, atazanavir/ritonavir + lamivudine -0.3 (95% CI -0.5 to -0.1) versus atazanavir/ritonavir + two NRTIs -0.2 (95% CI -0.4 to 0.0), P = 0.39; week 96, atazanavir/ritonavir + lamivudine -0.3 (95% CI -0.5 to -0.1) versus atazanavir/ritonavir + two NRTIs -0.2 (95% CI -0.4 to -0.1); P = 0.471] were similar. This absence of differences was also observed in all cognitive tasks. Atazanavir/ritonavir + lamivudine did not impact the change in neurocognitive function at week 96; the adjusted effect of atazanavir/ritonavir + lamivudine on GDS change, considering atazanavir/ritonavir + two NRTIs as a reference, was 0.01 (95% CI -0.18 to 0.21) (P = 0.90). Conclusions: Neurocognitive function remained stable after 96 weeks, both in the atazanavir/ritonavir + lamivudine and in the atazanavir/ritonavir + two NRTIs arms, provided HIV remained suppressed.

Imported malaria in Spain (2009-2016): results from the +REDIVI Collaborative Network.

BACKGROUND: Imported malaria is a frequent diagnosis in travellers and migrants. The objective of this study was to describe the epidemiological and clinical characteristics of patients diagnosed with imported malaria within a Spanish collaborative network registering imported diseases (+REDIVI). In addition, the possible association between malaria and type of case, gender, age or area of exposure was explored. METHODS: Cases of imported malaria were identified among all cases registered in the +REDIVI database during the period October 2009-October 2016. Demographic, epidemiological and clinical characteristics were analysed. RESULTS: In total, 11,816 cases of imported infectious diseases were registered in +REDIVI's database between October 2009 and October 2016. Immigrants seen for the first time after migration accounted for 60.2% of cases, 21.0% of patients were travellers, and 18.8% were travellers/immigrants visiting friends and relatives (VFRs). There were 850 cases of malaria (850/11,816, 7.2%). Malaria was significantly more frequent in men than in women (56.8% vs 43.2%) and in VFR-immigrants (52.6%) as compared to travellers (21.3%), immigrants (20.7%) and VFR-travellers (5.4%) (p < 0.001). Although this data was not available for most patients with malaria, only a minority (29/217, 13.4%) mentioned correct anti-malarial prophylaxis. Sub-Saharan Africa was found to be the most common region of acquisition of malaria. Most common reason for consultation after travel was a febrile syndrome although an important proportion of immigrants were asymptomatic and presented only for health screening (27.3%). Around 5% of travellers presented with severe malaria. The most prevalent species of Plasmodium diagnosed was Plasmodium falciparum (81.5%). Malaria due to Plasmodium ovale/Plasmodium vivax was frequent among travellers (17%) and nearly 5% of all malaria cases in immigrants were caused by Plasmodium malariae. CONCLUSIONS: Malaria was among the five most frequent diagnoses registered in +REDIVI's database. Some significant differences were found in the distribution of malaria according to gender, type of case, species. Among all malaria cases, the most frequent diagnosis was P. falciparum infection in VFR-immigrant men.

Costs and cost-efficacy analysis of the 2016 GESIDA/Spanish AIDS National Plan recommended guidelines for initial antiretroviral therapy in HIV-infected adults.

INTRODUCTION: GESIDA and the AIDS National Plan panel of experts suggest preferred (PR), alternative (AR), and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for the year 2016. The objective of this study is to evaluate the costs and the efficacy of initiating treatment with these regimens. METHODS: Economic assessment of costs and efficiency (cost/efficacy) based on decision tree analyses. Efficacy was defined as the probability of reporting a viral load <50copies/mL at week 48 in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug resistance studies) during the first 48 weeks. The payer perspective (National Health System) was applied, only taking into account differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting is Spain and the costs correspond to those of 2016. A sensitivity deterministic analysis was conducted, building three scenarios for each regimen: base case, most favourable, and least favourable. RESULTS: In the base case scenario, the cost of initiating treatment ranges from 4663 Euros for 3TC+LPV/r (OR) to 10,894 Euros for TDF/FTC+RAL (PR). The efficacy varies from 0.66 for ABC/3TC+ATV/r (AR) and ABC/3TC+LPV/r (OR), to 0.89 for TDF/FTC+DTG (PR) and TDF/FTC/EVG/COBI (AR). The efficiency, in terms of cost/efficacy, ranges from 5280 to 12,836 Euros per responder at 48 weeks, for 3TC+LPV/r (OR), and RAL+DRV/r (OR), respectively. CONCLUSION: Despite the overall most efficient regimen being 3TC+LPV/r (OR), among the PR and AR, the most efficient regimen was ABC/3TC/DTG (PR). Among the AR regimes, the most efficient was TDF/FTC/RPV.

[Diagnosis and treatment of imported malaria in Spain: Recommendations from the Malaria Working Group of the Spanish Society of Tropical Medicine and International Health (SEMTSI)]. / Diagnóstico y tratamiento de la malaria importada en España: recomendaciones del Grupo de Trabajo de Malaria de la Sociedad Española de Medicina Tropical y Salud Internacional (SEMTSI).

Malaria is a common parasitic disease diagnosed in the returned traveler. Mortality in travelers with imported malaria is around 2-3%, and one of the main factors associated with poor prognosis is the delay in the diagnosis and treatment. Imported malaria cases usually present with fever, headache and myalgia, but other symptoms may appear. The diagnosis should be performed as soon as possible, using thick smear or rapid diagnostic tests, and a blood smear. Treatment should be initiated urgently. In cases of severe malaria, the use of intravenous artemisinins has proved to be superior to intravenous quinine. This document reviews the recommendations of the expert group of the Spanish Society of Tropical Medicine and International Health (SEMTSI) for the diagnosis and treatment of imported malaria in Spain.

Higher glutamate to glutamine ratios in occipital regions in women with migraine during the interictal state.

BACKGROUND: Glutamate (Glu) and glutamine (Gln) are strongly compartmentalized (in neurons for Glu and in astrocytes for Gln). The visual cortex is the brain region with a higher neuron/astrocyte ratio (the highest neuronal density and the relatively lowest density of astrocytes). Elevations in extracellular Glu or potassium above certain thresholds are likely candidates to be the final common steps in the multiple distinct processes that can lead to cortical spreading depression. Astrocytes play a key role in this phenomenon, by acting as a sink for extracellular Glu and potassium, as well as generally acting as a buffer for the ionic and neurochemical changes that initiate and propagate cortical spreading depression. OBJECTIVE: The purpose of this study was to quantify Glu and Gln to generate Glu/Gln ratios in women with migraine during the interictal state compared with healthy control women. METHODS: Twenty-seven patients with migraine (8 with aura and 19 without aura) and 19 matched healthy controls were included in the study. We performed proton magnetic resonance spectroscopy in the anterior paracingulate cortex and occipital cortex (OC). Spectral analysis was performed by LCModel, allowing a separation of Glu and Gln using a 3T machine. RESULTS: The main result was a significantly higher Glu/Gln ratio in the OC of migraine patients compared with healthy control subjects (4.87 for migraineurs [standard deviation (SD) = 2.74] and 3.42 for controls [SD = 1.52], P = .042). We also observed higher Glu levels (6.98 for migraineurs [SD = 0.85] and 6.22 for controls [SD = 0.97], P = .007) and Glu/creatine + phosphocreatine ratio (1.18 for migraineurs [SD = 0.18] and 1.00 for controls [SD = 0.16], P = .001) in anterior paracingulate cortex in migraine patients but saw no differences in Glu/Gln ratio (2.79 for migraineurs [SD = 1.11] and 2.63 for controls [SD = 1.61], P = .68). CONCLUSION: These findings are consistent with glutamatergic differences in migraine patients during the interictal period compared with healthy controls. We hypothesize that an increased Glu/Gln ratio could arise from neuronal-glial coupling of glutamatergic metabolism differences or an increased neuron/astrocyte ratio in the OC.

[External evaluation of population-based cancer registries: the REDEPICAN Guide for Latin America]. / Evaluación externa de registros de cáncer de base poblacional: la Guía REDEPICAN para América Latina.

OBJECTIVE: Evaluate the feasibility of the REDEPICAN Guide (Red Iberoamericana de Epidemiología y Sistemas de Información en Cáncer) and its adaptation to the current situation of population-based cancer registries (PBCRs) in Latin America and the Caribbean as a useful tool to improve these registries. METHODS: Experts in cancer registries and health audits designed the guide and developed seven domains to evaluate in PBCRs. Several criteria were selected for each domain, with corresponding standards, scored according to three levels of compliance. Two training courses for external evaluators and three discussion panels for experts were organized. The guide was tested in six PBCRs in Latin America and Spain. RESULTS: The guide contains 68 criteria, 10 of which are considered essential for a PBCR. Based on its score, a registry is regarded as acceptable (41-199), good (200-299), or excellent (300-350). The registry methods domain accounts for 25% of the score, followed by completeness and validity (19%), dissemination of outcomes (19%), structure (13%), confidentiality and ethical aspects (11%), comparability (9%), and the procedures manual (3%). The pilot project enabled (1) enhancement of criteria and standards, (2) expansion of the quality concept to include client needs, and (3) strengthening the dissemination of outcomes section. Two of the Latin American registries that were evaluated improved their quality, meeting the standards of the International Agency for Research on Cancer. CONCLUSIONS: Development of the REDEPICAN Guide has taken into account the context of the registries in Latin America and is a useful and innovative tool for improving the quality of PBCRs. Furthermore, it is ready for use in other countries and registries.

Reluctance to do blood testing limits HIV diagnosis and appropriate health care of sub-Saharan African migrants living in Spain.

This study investigates the reasons why sub-Saharan African migrants (SSAM) living in Spain may be unwilling to have their blood tested. A qualitative study was developed for 3 years (2006-2009) with the participation of 1338 SSAM. Cultural differences along with lack of information about Spanish health care system and health-related rights produced a feeling of mistrust towards medical staff. Reluctance to do blood testing may prevent SSAM from having a prompt HIV diagnosis and an appropriate health care. Linguistically and culturally adapted information is essential to overcome these barriers and achieve an equal access to health care services and HIV testing.

Screening of imported malaria infection in asymptomatic migrants from Sub-Saharan Africa: A retrospective analysis of a 2010-2019 cohort.

BACKGROUND: Up to 40% of cases of imported malaria in Europe are diagnosed in recently arrived migrants, who generally exhibit asymptomatic or mild symptoms and show low parasitaemia (submicroscopic). The study describes the prevalence of malaria infection among asymptomatic Sub-Saharan African migrants (ASSAM) and compares asymptomatic malaria-infected (AMI) vs non-malaria infected patients. METHODS: An observational, comparative, retrospective study was carried out in ASSAM who underwent a medical examination, between 2010 and 2019 at the National Reference Unit for Tropical Diseases (NRU-Trop) in Madrid, Spain. Medical examination and systematic screening protocol for infectious diseases, including screening for malaria infection by Polymerase Chain Reaction (PCR) was performed. RESULTS: During the study period, 632 out of 1061 ASSAM were screened for malaria, median age: 24 years (IQR:1-5); median time from arrival to diagnosis: 2 months (IQR:1-5). P. falciparum was the most frequent species: 61 patients (67.8%). Compared to non-malaria infected, AMI subjects had: higher rate of co-infection with S. stercoralis (41.1%VS 22.9%;p < 0.001) and filariae (8.9% VS 2.4%;p = 0.006), lower erythrocyte corpuscular volume (83.6 VS 84.4;p = 0.008) and lower levels of cholesterol (151.0 VS 167.3;p < 0.001). CONCLUSIONS: We observed a high prevalence of AMI among ASSAM. This highlights the need to consider routing screening of migrants from endemic areas and to study if such screening could avoid the potential morbidities associated with chronic infection, reduce morbi-mortality of acute malaria and the risk of transmission in host communities.

Visceral larva migrans in immigrants from latin america.

To determine whether increased migration is associated with an increase in incidence of toxocariasis (visceral larva migrans), we analyzed clinical data obtained from immigrants from Latin America. Although infection with Toxocara sp. roundworm larvae is distributed worldwide, seroprevalence is highest in tropical and subtropical areas.

[Filariasis in clinical practice]. / Las filariasis en la práctica clínica.

Filariases are infections caused by distinct species of nematodes. These infections are transmitted through insect bites and primarily affect lymph nodes and skin. Filariases are classified as neglected diseases and affect millions, producing severe disability and social stigma. This type of infection is rarely diagnosed in travellers, as prolonged stays in endemic areas are usually required acquire infection. Infections may be asymptomatic, and clinical manifestations depend on the host immune response to the infection and the parasite burden. Diagnosis is based on the demonstration of microfilariae in blood or skin, but there are other methods that support the diagnosis. Individual treatment is effective, but community interventions, mostly mass drug administration, have helped to diminish the incidence of filariases.

Increased YKL-40 but Not C-Reactive Protein Levels in Patients with Alzheimer's Disease.

Neuroinflammation is a common feature in Alzheimer's (AD) and Parkinson's (PD) disease. In the last few decades, a testable hypothesis was proposed that protein-unfolding events might occur due to neuroinflammatory cascades involving alterations in the crosstalk between glial cells and neurons. Here, we tried to clarify the pattern of two of the most promising biomarkers of neuroinflammation in cerebrospinal fluid (CSF) in AD and PD. This study included cognitively unimpaired elderly patients, patients with mild cognitive impairment, patients with AD dementia, and patients with PD. CSF samples were analyzed for YKL-40 and C-reactive protein (CRP). We found that CSF YKL-40 levels were significantly increased only in dementia stages of AD. Additionally, increased YKL-40 levels were found in the cerebral orbitofrontal cortex from AD patients in agreement with augmented astrogliosis. Our study confirms that these biomarkers of neuroinflammation are differently detected in CSF from AD and PD patients.

Aberrant Salient and Corticolimbic Connectivity in Hypersexual Parkinson's Disease.

Introduction: Impulse control disorders (ICDs) represent a side effect of dopaminergic medication in Parkinson's disease (PD). Patients experience an excessive desire toward natural rewards paired with uncontrolled actions. Yet, the precise neural and behavioral mechanisms associated with ICDs and, importantly, each specific subdomain remain unclear. We aim to decipher resting-state and corticolimbic functional connectivity in PD patients with and without hypersexual ICD. Materials and Methods: Seventeen PD patients with hypersexuality (PD+HS) and 15 PD patients without hypersexuality (PD-HS) underwent two sessions (with and without medication) of resting-state functional magnetic resonance imaging and were compared with 17 healthy controls. Dual-regression independent component analyses extracted salience, sensorimotor, default-mode, and central executive networks. Seed-based functional connectivity with three striatal subdivisions (motor, associative, and limbic) was obtained and significant changes were correlated with key impulsivity and inhibitory measures. Results: Enhanced salience network (SN) activity represented by a significant rise in the right inferior frontal gyrus was found in PD+HS compared with PD-HS. Connectivity analyses revealed a functional disconnection between associative and limbic striatum with precuneus and superior parietal lobe in PD+HS, some connections explained by abnormal sexual behavior and inhibition in PD+HS. Conclusions: Hypersexual ICD is associated with enhanced SN signaling and corticolimbic disconnections, including striatal associative and limbic loops that contribute to altered control of sexually driven behavior and overall severity in PD and ICD. Impact statement We enlarge the neurobiological basis to one specific Parkinson's disease (PD) and impulse control disorder (ICD) (PD+ICD) subtype-that is, hypersexuality-and reveal its associated resting-state functional connectivity linked to altered behavior. We report enhanced salience network and right inferior frontal gyrus as part of the underlying resting-state functional networks in PD patients with hypersexuality (PD+HS). Corticolimbic changes were associated with sexual severity in PD+HS to hypoactive connectivity between associative-limbic striatum with precuneus and superior parietal lobe. The connectivity changes seen in PD+HS could explain baseline differences that engender aberrant control over sexual behavior in ICD.

Seroprevalence of vaccine-preventable and non-vaccine-preventable infections in migrants in Spain.

BACKGROUND: Updated seroprevalence studies of infections in migrants may aid the design of tailored vaccination and prevention programmes. The objective of this study was to describe the seroprevalence rates for potentially transmissible viral infections in migrants attended at a referral centre in a major European city. METHODS: Descriptive analysis of seroprevalence of vaccine-preventable and non-vaccine-preventable infections in migrants attended at a centre in Madrid, Spain (2018-19). Recorded variables included age, gender, country of birth/continent of origin, time from arrival to Spain until first clinic visit, rubella, measles, mumps, varicella (VZV), hepatitis B virus (HBV), hepatitis A virus (HAV), hepatitis C virus (HCV) and HIV serology. RESULTS: In total, 468 patients were included, 135 females (28.8%) and 333 males (71.2%), mean age 30.4 years. The majority of patients were from Africa (52.5%, of which 88.2% from sub-Saharan Africa), followed by Latin America (38.5%) and other areas (9%). Seroprevalence for tested migrants for rubella, measles and mumps was < 95% in the group overall (91% rubella, 88% measles, 83% mumps) and lower rates were observed in migrants >20 years (compared with those ≤ 20 years). Over 10% of females were potentially susceptible (negative/indeterminate serology) to rubella (11.4%), measles (12.7%) or mumps (10.3%). Lowest rates of rubella seropositivity were in Latin American migrants (over 12% potentially susceptible); measles and mumps seropositivity was lowest in migrants from areas other than Africa/Latin America (74% and 68%, respectively). Seroprevalence rates were 91% for VZV, 90% overall for HAV, ~6% for HBV chronic infection (~50% of migrants tested susceptible), 2% for HCV and 6% for HIV. CONCLUSIONS: Differences in seroprevalence for vaccine-preventable and transmissible infections according to gender, age range and area of origin were observed. Tailored screening, vaccination and prevention strategies in potentially vulnerable migrant groups should be designed.