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BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA). METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]). INTERPRETATION: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow. FUNDING: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Femenino , Humanos , Masculino , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/tratamiento farmacológico , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/cirugía , Angiografía por Tomografía Computarizada , Países Bajos , Hemorragias Intracraneales/etiología , Accidente Cerebrovascular Isquémico/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND: The effectiveness of endovascular therapy in patients with stroke caused by basilar-artery occlusion has not been well studied. METHODS: We randomly assigned patients within 6 hours after the estimated time of onset of a stroke due to basilar-artery occlusion, in a 1:1 ratio, to receive endovascular therapy or standard medical care. The primary outcome was a favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 to 6, with 0 indicating no disability, 3 indicating moderate disability, and 6 indicating death) at 90 days. The primary safety outcomes were symptomatic intracranial hemorrhage within 3 days after the initiation of treatment and mortality at 90 days. RESULTS: A total of 300 patients were enrolled (154 in the endovascular therapy group and 146 in the medical care group). Intravenous thrombolysis was used in 78.6% of the patients in the endovascular group and in 79.5% of those in the medical group. Endovascular treatment was initiated at a median of 4.4 hours after stroke onset. A favorable functional outcome occurred in 68 of 154 patients (44.2%) in the endovascular group and 55 of 146 patients (37.7%) in the medical care group (risk ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.50). Symptomatic intracranial hemorrhage occurred in 4.5% of the patients after endovascular therapy and in 0.7% of those after medical therapy (risk ratio, 6.9; 95% CI, 0.9 to 53.0); mortality at 90 days was 38.3% and 43.2%, respectively (risk ratio, 0.87; 95% CI, 0.68 to 1.12). CONCLUSIONS: Among patients with stroke from basilar-artery occlusion, endovascular therapy and medical therapy did not differ significantly with respect to a favorable functional outcome, but, as reflected by the wide confidence interval for the primary outcome, the results of this trial may not exclude a substantial benefit of endovascular therapy. Larger trials are needed to determine the efficacy and safety of endovascular therapy for basilar-artery occlusion. (Funded by the Dutch Heart Foundation and others; BASICS ClinicalTrials.gov number, NCT01717755; Netherlands Trial Register number, NL2500.).
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Procedimientos Endovasculares , Fibrinolíticos/uso terapéutico , Accidente Cerebrovascular/cirugía , Trombectomía/métodos , Insuficiencia Vertebrobasilar/complicaciones , Anciano , Arteriopatías Oclusivas/complicaciones , Arteria Basilar/diagnóstico por imagen , Intervalos de Confianza , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Método Simple Ciego , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Terapia Trombolítica , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
BACKGROUND: The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations. METHODS: We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points. RESULTS: The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81). CONCLUSIONS: In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.).
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Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Trombectomía , Anciano , Anciano de 80 o más Años , Terapia Combinada , Procedimientos Endovasculares , Europa (Continente) , Femenino , Fibrinolíticos/uso terapéutico , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Activador de Tejido Plasminógeno/uso terapéutico , Resultado del TratamientoRESUMEN
INTRODUCTION: We investigated the impact of the Corona Virus Disease 2019 (COVID-19) pandemic and the resulting lockdown on reperfusion treatments and door-to-treatment times during the first surge in Dutch comprehensive stroke centers. Furthermore, we studied the association between COVID-19-status and treatment times. METHODS: We included all patients receiving reperfusion treatment in 17 Dutch stroke centers from May 11th, 2017, until May 11th, 2020. We collected baseline characteristics, National Institutes of Health Stroke Scale (NIHSS) at admission, onset-to-door time (ODT), door-to-needle time (DNT), door-to-groin time (DGT) and COVID-19-status at admission. Parameters during the lockdown (March 15th, 2020 until May 11th, 2020) were compared with those in the same period in 2019, and between groups stratified by COVID-19-status. We used nationwide data and extrapolated our findings to the increasing trend of EVT numbers since May 2017. RESULTS: A decline of 14% was seen in reperfusion treatments during lockdown, with a decline in both IVT and EVT delivery. DGT increased by 12 min (50 to 62 min, p-value of < 0.001). Furthermore, median NIHSS-scores were higher in COVID-19 - suspected or positive patients (7 to 11, p-value of 0.004), door-to-treatment times did not differ significantly when stratified for COVID-19-status. CONCLUSIONS: During the first surge of the COVID-19 pandemic, a decline in acute reperfusion treatments and a delay in DGT was seen, which indicates a target for attention. It also appeared that COVID-19-positive or -suspected patients had more severe neurologic symptoms, whereas their EVT-workflow was not affected.
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COVID-19 , Procedimientos Endovasculares , Accidente Cerebrovascular , Control de Enfermedades Transmisibles , Humanos , Países Bajos/epidemiología , Pandemias , SARS-CoV-2 , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/terapia , Trombectomía , Terapia Trombolítica , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
Background and Purpose- Patients with acute ischemic stroke treated with endovascular thrombectomy may be treated with repeat endovascular thrombectomy (rEVT) in case of recurrent large vessel occlusion. Data on safety and efficacy of these interventions is scarce. Our aim is to report on frequency, timing, and outcome of rEVT in a large nation-wide multicenter registry. Methods- In the Netherlands, all patients with endovascular thrombectomy have been registered since 2002 (MR CLEAN Pretrial registry, MR CLEAN Trial [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], and MR CLEAN Registry). We retrospectively reviewed these databases for anterior circulation rEVT cases. Patient characteristics, procedural data, and functional outcome (modified Rankin Scale at 90 days) were analyzed. Results- Of 3928 patients treated between 2002 and 2017, 27 (0.7%) underwent rEVT. Median time between first and second procedure was 78 (1-1122) days; 11/27 patients were re-treated within 30 days. Cardioembolism was the most common etiology (18 patients [67%]). In 19 patients (70%), recurrent occlusion occurred ipsilateral to previous occlusion. At 90 days after rEVT procedure, 44% of the patients had achieved functional independence (modified Rankin Scale score of 0-2), and 33% had died. Adverse events were 2/27 (7.4%) intracranial hemorrhage, 1/27 (3.7%) stroke progression, and 1/27 (3.7%) pneumonia. Conclusions- In this large nationwide cohort of patients with acute ischemic stroke treated with endovascular thrombectomy, rEVT was rare. Stroke cause was mainly cardio-embolic, and most recurrent large vessel occlusions in which rEVT was performed occurred ipsilateral. Although there probably is a selection bias on repeated treatment in case of recurrent large vessel occlusion, rEVT appears safe, with similar outcome as in single-treated cases.
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Isquemia Encefálica/tratamiento farmacológico , Isquemia/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica , Adulto , Anciano , Anciano de 80 o más Años , Procedimientos Endovasculares/métodos , Femenino , Humanos , Hemorragias Intracraneales/etiología , Isquemia/complicaciones , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Factores de TiempoRESUMEN
OBJECTIVE: A substantial part of non-traumatic intracerebral haemorrhages (ICH) arises from a macrovascular cause, but there is little guidance on selection of patients for additional diagnostic work-up. We aimed to develop and externally validate a model for predicting the probability of a macrovascular cause in patients with non-traumatic ICH. METHODS: The DIagnostic AngioGRAphy to find vascular Malformations (DIAGRAM) study (n=298; 69 macrovascular cause; 23%) is a prospective, multicentre study assessing yield and accuracy of CT angiography (CTA), MRI/ magnetic resonance angiography (MRA) and intra-arterial catheter angiography in diagnosing macrovascular causes in patients with non-traumatic ICH. We considered prespecified patient and ICH characteristics in multivariable logistic regression analyses as predictors for a macrovascular cause. We combined independent predictors in a model, which we validated in an external cohort of 173 patients with ICH (78 macrovascular cause, 45%). RESULTS: Independent predictors were younger age, lobar or posterior fossa (vs deep) location of ICH, and absence of small vessel disease (SVD). A model that combined these predictors showed good performance in the development data (c-statistic 0.83; 95% CI 0.78 to 0.88) and moderate performance in external validation (c-statistic 0.66; 95% CI 0.58 to 0.74). When CTA results were added, the c-statistic was excellent (0.91; 95% CI 0.88 to 0.94) and good after external validation (0.88; 95% CI 0.83 to 0.94). Predicted probabilities varied from 1% in patients aged 51-70 years with deep ICH and SVD, to more than 50% in patients aged 18-50 years with lobar or posterior fossa ICH without SVD. CONCLUSION: The DIAGRAM scores help to predict the probability of a macrovascular cause in patients with non-traumatic ICH based on age, ICH location, SVD and CTA.
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Malformaciones Vasculares del Sistema Nervioso Central/complicaciones , Malformaciones Vasculares del Sistema Nervioso Central/diagnóstico por imagen , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/etiología , Adolescente , Adulto , Anciano , Angiografía Cerebral , Angiografía por Tomografía Computarizada , Femenino , Humanos , Modelos Logísticos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Países Bajos , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: Our aim was to compare Axtair One, an alternating pressure air mattress (APAM), with a viscoelastic foam mattress (VFM) in elderly patients at moderate to high risk of developing pressure ulcers (PUs). METHOD: A randomised, controlled, superiority, parallel-group, open-label, multicentre study, was conducted, between February 2012 and March 2015, in nine French, medium- and long-term stay facilities. Eligible patients were aged 70 and over, had no PUs on enrolment, were bedridden for at least 15 hours per day, had reduced mobility, an absent or minimal positioning capability, a Braden score <14, a nutritional status score >12 and a Karnofsky score <40%. The primary endpoint was the appearance of PUs over a 30-day monitoring period. The primary objective was to demonstrate a 50% reduction in instantaneous risk of PUs in the APAM versus the VFM group. Secondary objectives were to determine if preventive care was less frequent in the APAM group, the instantaneous relative risk of PUs (hazard ratio) was constant over time and the comfort experienced was higher in the APAM group and to verify the uniformity of the preventive benefit of an APAM, regardless of the level of exposure to major risk factors for PUs. RESULTS: We randomised 76 patients (39 in the APAM group and 37 in the VFM group). The groups were comparable on enrolment and throughout the study. The cumulative risk of PUs was estimated at 6.46% [95% confidence interval (CI): 1.64; 23.66] in the APAM group and at 38.91% [95% CI: 24.66; 57.59] in the VFM group, p=0.001 (log-rank test). The adjusted hazard ratio according to the Cox model with four prognostic factors for the appearance of PUs was 7.57 [95% CI: 1.67; 34.38, p=0.009]. Preventive care proved to be equivalent in both groups. The only risk factor significantly associated with an increased risk of PUs was the type of mattress (VFM). The comfort and tolerance perceived by the patients were both high and similar in the two groups. The constancy over time of the preventive benefit of an APAM could not be verified because of the lack of a sufficient number of events (appearance of PUs) in the APAM group. CONCLUSION: The APAM was superior to a VFM for preventing PUs in elderly patients, bedridden for more than 15 hours per day, severely dependent, at moderate-to high-risk of PUs, with an instantaneous risk for the appearance of PUs 7.57 times greater in the VFM group than in the APAM group. This study provides descriptive information and evidence for practice.
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Presión del Aire , Lechos , Úlcera por Presión/prevención & control , Sustancias Viscoelásticas , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: In adults with acute stroke, infections occur commonly and are associated with an unfavourable functional outcome. In the Preventive Antibiotics in Stroke Study (PASS) we aimed to establish whether or not preventive antimicrobial therapy with a third-generation cephalosporin, ceftriaxone, improves functional outcome in patients with acute stroke. METHODS: In this multicentre, randomised, open-label trial with masked endpoint assessment, patients with acute stroke were randomly assigned to intravenous ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to stroke unit care, or standard stroke unit care without preventive antimicrobial therapy; assignments were made within 24 h after symptom onset. The primary endpoint was functional outcome at 3 months, defined according to the modified Rankin Scale and analysed by intention to treat. The primary analysis was by ordinal regression of the primary outcome. Secondary outcomes included death, infection rates, antimicrobial use, and length of hospital stay. Participants and caregivers were aware of treatment allocation but assessors of outcome were masked to group assignment. This trial is registered with controlled-trials.com, number ISRCTN66140176. FINDINGS: Between July 6, 2010, and March 23, 2014, a total of 2550 patients from 30 sites in the Netherlands, including academic and non-academic medical centres, were randomly assigned to the two treatment groups: 1275 patients to ceftriaxone and 1275 patients to standard treatment (control group). 12 patients (seven in the ceftriaxone group and five in the control group) withdrew consent immediately after randomisation, leaving 2538 patients available for the intention-to-treat-analysis (1268 in the ceftriaxone group and 1270 in the control group). 2514 (99%) of 2538 patients (1257 in each group) completed 3-month follow-up. Preventive ceftriaxone did not affect the distribution of functional outcome scores on the modified Rankin Scale at 3 months (adjusted common odds ratio 0·95 [95% CI 0·82-1·09], p=0·46). Preventive ceftriaxone did not result in an increased occurrence of adverse events. Overgrowth infection with Clostridium difficile occurred in two patients (<1%) in the ceftriaxone group and none in the control group. INTERPRETATION: Preventive ceftriaxone does not improve functional outcome at 3 months in adults with acute stroke. The results of our trial do not support the use of preventive antibiotics in adults with acute stroke. FUNDING: Netherlands Organization for Health Research and Development, Netherlands Heart Foundation, and the European Research Council.
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Antibacterianos/uso terapéutico , Ceftriaxona/uso terapéutico , Neumonía/prevención & control , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Infecciones Urinarias/prevención & control , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Análisis de Intención de Tratar , Tiempo de Internación , Masculino , Persona de Mediana Edad , Países Bajos , Neumonía/diagnóstico , Neumonía/epidemiología , Estudios Prospectivos , Años de Vida Ajustados por Calidad de Vida , Recuperación de la Función , Resultado del Tratamiento , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/epidemiologíaRESUMEN
BACKGROUND: This study aims at investigating left atrial (LA) deformation by left atrial reservoir (LARS) and pump strain (LAPS) and its implications for long-term survival in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). METHODS: Speckle tracking echocardiography was performed in 198 patients with severe AS undergoing TAVI. Association of strain parameters with cardiovascular mortality was determined. RESULTS: Over a follow-up time of 5 years, 49 patients (24.7%) died. LAPS was more impaired in non-survivors than survivors (P = 0.010), whereas no difference was found for LARS (P = 0.114), LA ejection fraction (P = 0.241), and LA volume index (P = 0.292). Kaplan-Meier analyses yielded a reduced survival probability according to the optimal threshold for LAPS (P = 0.002). A more impaired LAPS was associated with increased mortality risk (HR 1.12 [95% CI 1.02-1.22]; P = 0.014) independent of LVEF, LAVI, age, and sex. Addition of LAPS improved multivariable echocardiographic (LVEF, LAVI) and clinical (age, sex) models with potential incremental value for mortality prediction (P = 0.013 and P = 0.031, respectively). In contrast, LARS and LAVI were not associated with mortality. CONCLUSIONS: In patients undergoing aortic valve replacement for severe AS, LAPS was impaired in patients dying during long-term follow-up after TAVI, differentiated survivors from non-survivors, was independently associated with long-term mortality, and yielded potential incremental value for survival prediction after TAVI. LAPS seems useful for risk stratification in severe AS and timely valve replacement.
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Estenosis de la Válvula Aórtica , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Resultado del Tratamiento , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/cirugía , Atrios Cardíacos , Ecocardiografía , Válvula Aórtica/cirugía , Función Ventricular Izquierda , Volumen SistólicoRESUMEN
BACKGROUND: Intravenous thrombolysis is contraindicated in patients with ischaemic stroke with blood pressure higher than 185/110 mm Hg. Prevailing guidelines recommend to actively lower blood pressure with intravenous antihypertensive agents to allow for thrombolysis; however, there is no robust evidence for this strategy. Because rapid declines in blood pressure can also adversely affect clinical outcomes, several Dutch stroke centres use a conservative strategy that does not involve the reduction of blood pressure. We aimed to compare the clinical outcomes of both strategies. METHODS: Thrombolysis and Uncontrolled Hypertension (TRUTH) was a prospective, observational, cluster-based, parallel-group study conducted across 37 stroke centres in the Netherlands. Participating centres had to strictly adhere to an active blood-pressure-lowering strategy or to a non-lowering strategy. Eligible participants were adults (≥18 years) with ischaemic stroke who had blood pressure higher than 185/110 mm Hg but were otherwise eligible for intravenous thrombolysis. The primary outcome was functional status at 90 days, measured using the modified Rankin Scale and assessed through telephone interviews by trained research nurses. Secondary outcomes were symptomatic intracranial haemorrhage, the proportion of patients treated with intravenous thrombolysis, and door-to-needle time. All ordinal logistic regression analyses were adjusted for age, sex, stroke severity, endovascular thrombectomy, and baseline imbalances as fixed-effect variables and centre as a random-effect variable to account for the clustered design. Analyses were done according to the intention-to-treat principle, whereby all patients were analysed according to the treatment strategy of the participating centre at which they were treated. FINDINGS: Recruitment began on Jan 1, 2015, and was prematurely halted because of a declining inclusion rate and insufficient funding on Jan 5, 2022. Between these dates, we recruited 853 patients from 27 centres that followed an active blood-pressure-lowering strategy and 199 patients from ten centres that followed a non-lowering strategy. Baseline characteristics of participants from the two groups were similar. The 90-day mRS score was missing for 15 patients. The adjusted odds ratio (aOR) for a shift towards a worse 90-day functional outcome was 1·27 (95% CI 0·96-1·68) for active blood-pressure reduction compared with no active blood-pressure reduction. 798 (94%) of 853 patients in the active blood-pressure-lowering group were treated with intravenous thrombolysis, with a median door-to-needle time of 35 min (IQR 25-52), compared with 104 (52%) of 199 patients treated in the non-lowering group with a median time of 47 min (29-78). 42 (5%) of 852 patients in the active blood-pressure-lowering group had a symptomatic intracranial haemorrhage compared with six (3%) of 199 of those in the non-lowering group (aOR 1·28 [95% CI 0·62-2·62]). INTERPRETATION: Insufficient evidence was available to establish a difference between an active blood-pressure-lowering strategy-in which antihypertensive agents were administered to reduce blood pressure below 185/110 mm Hg-and a non-lowering strategy for the functional outcomes of patients with ischaemic stroke, despite higher intravenous thrombolysis rates and shorter door-to-needle times among those in the active blood-pressure-lowering group. Randomised controlled trials are needed to inform the use of an active blood-pressure-lowering strategy. FUNDING: Fonds NutsOhra.
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Antihipertensivos , Accidente Cerebrovascular Isquémico , Terapia Trombolítica , Humanos , Femenino , Masculino , Países Bajos , Anciano , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/terapia , Terapia Trombolítica/métodos , Persona de Mediana Edad , Estudios Prospectivos , Antihipertensivos/uso terapéutico , Antihipertensivos/administración & dosificación , Hipertensión/tratamiento farmacológico , Fibrinolíticos/administración & dosificación , Fibrinolíticos/uso terapéutico , Resultado del Tratamiento , Anciano de 80 o más Años , Presión Sanguínea/fisiología , Presión Sanguínea/efectos de los fármacosRESUMEN
INTRODUCTION: Acute mechanical thrombectomy (MT) is the preferred treatment for large vessel occlusion-related stroke. Histopathological research on the obtained occlusive embolic thrombus may provide information regarding the aetiology and pathology of the lesion to predict prognosis and propose possible future acute ischaemic stroke therapy. METHODS: A total of 75 consecutive patients who presented to the Amphia Hospital with acute large vessel occlusion-related stroke and underwent MT were included in the study. The obtained thrombus materials were subjected to standard histopathological examination. Based on histological criteria, they were considered fresh (<1 day old) or old (>1 day old). Patients were followed for 2 years for documentation of all-cause mortality. RESULTS: Thrombi were classified as fresh in 40 patients (53%) and as older in 35 patients (47%). Univariate Cox regression analysis showed that thrombus age, National Institutes of Health Stroke Scale at hospital admission, and patient age were associated with long-term mortality (p < 0.1). Multivariable Cox hazards and Kaplan-Meier analysis demonstrated that after extensive adjustment for clinical and procedural variables, thrombus age persisted in being independently associated with higher long-term mortality (hazard ratio: 3.34; p = 0.038, log-rank p = 0.013). CONCLUSION: In this study, older thromboemboli are responsible for almost half of acute large ischaemic strokes. Moreover, the presence of an old thrombus is an independent predictor of mortality in acute large vessel occlusion-related stroke. More research is warranted regarding future therapies based on thrombus composition.
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Arteriopatías Oclusivas , Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Trombosis , Humanos , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Pronóstico , Isquemia Encefálica/diagnóstico por imagen , Isquemia Encefálica/terapia , Trombectomía/efectos adversos , Resultado del Tratamiento , Procedimientos Endovasculares/efectos adversos , Trombosis/diagnóstico por imagen , Trombosis/terapia , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/etiología , Arteriopatías Oclusivas/complicaciones , Estudios RetrospectivosRESUMEN
Importance: Management of checkpoint inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti-tumor necrosis factor on checkpoint-inhibitor efficacy. Objective: To determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy. Design, Setting, and Participants: This population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months. Main Outcomes and Measures: The PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS. Results: Of 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P = .01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P = .04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P = .006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P = .05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P = .04) compared with those receiving steroids alone. Conclusions and Relevance: In this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also other tumor types.
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Enfermedades del Sistema Inmune , Melanoma , Humanos , Masculino , Persona de Mediana Edad , Femenino , Ipilimumab/efectos adversos , Nivolumab/uso terapéutico , Estudios de Cohortes , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melanoma/patología , Enfermedades del Sistema Inmune/inducido químicamente , Esteroides/uso terapéutico , Inmunosupresores/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. METHODS: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7-90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. FINDINGS: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73-83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21-74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0-3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7-21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2-20·8]; adjusted hazard ratio 1·05 [95% CI 0·48-2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. INTERPRETATION: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. FUNDING: Dutch Heart Foundation (grant 2012T077).
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Fibrilación Atrial , Accidente Cerebrovascular , APACHE , Anciano , Anticoagulantes/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Femenino , Humanos , Masculino , Países Bajos/epidemiología , Estudios Prospectivos , Pirazoles , Piridonas , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/prevención & control , Resultado del TratamientoRESUMEN
Improvement of a patient's essential tremor (ET) after a stroke has rarely been reported. In such patients, cerebral imaging could help to identify structures involved in the maintenance of ET and improves the knowledge of its physiopathology. This article reports the disappearance of ET, after a stroke in 4 patients and reviews similar previously published cases. These cases suggest that the interruption of cerebellar loops during a stroke could be responsible for the disappearance of ET.
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Encéfalo/patología , Infarto Cerebral/patología , Accidente Cerebrovascular/patología , Anciano , Temblor Esencial/patología , Humanos , Persona de Mediana Edad , Remisión EspontáneaRESUMEN
The blue absorbance change occurring in flashed bean (Phaseolus vulgaris L.) leaves when exposed to continuous light (first observed by Strasser; Strasser, R.J. (1973) Arch. Int. Physiol. Biochem. 81, 935--955) is caused by the conversion of the following xanthophylls: violaxanthine leads to antheraxanthine leads to zeaxanthine. This conclusion is derived from the simultaneous occurrence of both reactions: (a) In flashed leaves, blue absorbance change and xanthophyll conversion take place under strong (2 mW . cm-2) but not under weak (0.02 mW . cm-2) white light. (b) In chloroplasts isolated from flashed leaves, the blue absorbance change occurs in the dark under conditions that also induce the xanthophyll conversion. (c) Blue absorbance change and xanthophyll conversion are both inhibited by dithiothreitol. In addition, the light-induced blue absorbance change is reversed in the dark if aerobic conditions are maintained, i.e. under conditions that in normal leaves favor the reversal of the above reaction sequence. The significance of the xanthophyll conversion is discussed in relation to other phenomena occurring in flashed leaves after exposure to continuous illumination.
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Carotenoides/metabolismo , Cloroplastos/metabolismo , Oxígeno/metabolismo , Fotosíntesis , Plantas/metabolismo , Ácido Ascórbico/farmacología , Clorofila/metabolismo , Cloroplastos/efectos de los fármacos , Oscuridad , Ditiotreitol/farmacología , Concentración de Iones de Hidrógeno , Luz , Fotosíntesis/efectos de los fármacos , Plantas/efectos de los fármacos , EspectrofotometríaRESUMEN
OBJECTIVE: To investigate whether staff radiologists working in nonacademic hospitals can adequately rule out subarachnoid hemorrhage (SAH) on head CT <6 hours after headache onset. METHODS: In a multicenter, retrospective study, we studied a consecutive series of patients presenting with acute headache to 11 nonacademic hospitals. Inclusion criteria were (1) normal level of consciousness without focal deficits, (2) head CT <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist, and (3) subsequent CSF spectrophotometry. Two neuroradiologists and one stroke neurologist from 2 academic tertiary care centers independently reviewed admission CTs of patients with CSF results that were considered positive for presence of bilirubin according to local criteria. We investigated the negative predictive value for detection of SAH by staff radiologists in nonacademic hospitals on head CT in patients scanned <6 hours after onset of acute headache. RESULTS: Of 760 included patients, CSF analysis was considered positive for bilirubin in 52 patients (7%). Independent review of these patients' CTs identified one patient (1/52; 2%) with a perimesencephalic nonaneurysmal SAH. Negative predictive value for detection of subarachnoid blood by staff radiologists working in a nonacademic hospital was 99.9% (95% confidence interval 99.3%-100.0%). CONCLUSIONS: Our results support a change of practice wherein a lumbar puncture can be withheld in patients with a head CT scan performed <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist in the described nonacademic setting.
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Servicios Médicos de Urgencia/estadística & datos numéricos , Cefalea/diagnóstico , Cefalea/epidemiología , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/epidemiología , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Centros Médicos Académicos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Causalidad , Comorbilidad , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y Especificidad , Factores de Tiempo , Adulto JovenRESUMEN
STUDY QUESTION: What are the diagnostic yield and accuracy of early computed tomography (CT) angiography followed by magnetic resonance imaging/angiography (MRI/MRA) and digital subtraction angiography (DSA) in patients with non-traumatic intracerebral haemorrhage? METHODS: This prospective diagnostic study enrolled 298 adults (18-70 years) treated in 22 hospitals in the Netherlands over six years. CT angiography was performed within seven days of haemorrhage. If the result was negative, MRI/MRA was performed four to eight weeks later. DSA was performed when the CT angiography or MRI/MRA results were inconclusive or negative. The main outcome was a macrovascular cause, including arteriovenous malformation, aneurysm, dural arteriovenous fistula, and cavernoma. Three blinded neuroradiologists independently evaluated the images for macrovascular causes of haemorrhage. The reference standard was the best available evidence from all findings during one year's follow-up. STUDY ANSWER AND LIMITATIONS: A macrovascular cause was identified in 69 patients (23%). 291 patients (98%) underwent CT angiography; 214 with a negative result underwent additional MRI/MRA and 97 with a negative result for both CT angiography and MRI/MRA underwent DSA. Early CT angiography detected 51 macrovascular causes (yield 17%, 95% confidence interval 13% to 22%). CT angiography with MRI/MRA identified two additional macrovascular causes (18%, 14% to 23%) and these modalities combined with DSA another 15 (23%, 18% to 28%). This last extensive strategy failed to detect a cavernoma, which was identified on MRI during follow-up (reference strategy). The positive predictive value of CT angiography was 72% (60% to 82%), of additional MRI/MRA was 35% (14% to 62%), and of additional DSA was 100% (75% to 100%). None of the patients experienced complications with CT angiography or MRI/MRA; 0.6% of patients who underwent DSA experienced permanent sequelae. Not all patients with negative CT angiography and MRI/MRA results underwent DSA. Although the previous probability of finding a macrovascular cause was lower in patients who did not undergo DSA, some small arteriovenous malformations or dural arteriovenous fistulas may have been missed. WHAT THIS STUDY ADDS: CT angiography is an appropriate initial investigation to detect macrovascular causes of non-traumatic intracerebral haemorrhage, but accuracy is modest. Additional MRI/MRA may find cavernomas or alternative diagnoses, but DSA is needed to diagnose macrovascular causes undetected by CT angiography or MRI/MRA. FUNDING, COMPETING INTERESTS, DATA SHARING: Dutch Heart Foundation and The Netherlands Organisation for Health Research and Development, ZonMw. The authors have no competing interests. Direct requests for additional data to the corresponding author.
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Angiografía de Substracción Digital , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/etiología , Malformaciones Arteriovenosas Intracraneales/diagnóstico , Angiografía por Resonancia Magnética , Tomografía Computarizada por Rayos X , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Malformaciones Arteriovenosas Intracraneales/complicaciones , Modelos Logísticos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
We describe a method to transfer cDNA into neuronal primary cultures with a commercialised cationic lipid, Transfast. Cultures were transfected at a rate of about 5% with green fluorescent protein (GFP) cDNA. Comparing Transfast to other transfection reagents, we found this compound to be the most efficient. GFP-transfected mouse cerebellar granule cells displayed normal whole-cell voltage-sensitive and unitary big K+ channel currents. We also used this transfection method with success to transfer GFP cDNA into primary cultures of striatum and colliculus. Transfast was then used to cotransfect cultured cerebellar cells with GFP cDNA, in conjunction with cDNA coding for the metabotropic glutamate receptor type 5 (mGlu5 receptor). Ninety percent of the cells expressing GFP also expressed mGlu5 receptor. Though neurones were best transfected one day after plating, they still expressed both GFP and mGlu5 receptor proteins 2 weeks after plating, i.e. after full differentiation. A functional test of the expressed mGlu5 receptor was thus performed in GFP-transfected neurones. Stimulation of mGlu5 receptor induced single big K+ channel activity, as it was the case for the native mGlu1 receptor. This indicated that the transfected mGlu5 receptor plasmid was functionally expressed and that both mGlu1 and mGlu5 receptors may share common coupling mechanisms to big K+ channels in neurones.
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Cerebelo/fisiología , ADN/genética , Técnicas de Transferencia de Gen , Neuronas/fisiología , Plásmidos/genética , Receptores de Glutamato Metabotrópico/fisiología , Animales , Canales de Calcio/fisiología , Células Cultivadas , Cerebelo/citología , Ratones , Técnicas de Placa-Clamp , Canales de Potasio/fisiologíaRESUMEN
BACKGROUND: Both the supine position and the existence of a gastric drainage procedure are suspected to promote reflux of duodenal juice into the denervated intrathoracic stomach. Erythromycin has been shown to weaken pyloric resistance to gastric outflow and to enhance antral motility, gastric emptying, and gallbladder contractility. METHODS: The presence of bile in the gastric transplant of 79 patients was monitored over a 24-hour period with use of the Bilitec 2000 optoelectronic device 3 to 195 months after subtotal esophagectomy. Ten patients were reinvestigated after a 3-year period. Five groups were studied: group I: n = 12, no gastric drainage, never given erythromycin, group 2: n = 40, gastric drainage, never given erythromycin, group 3: n = 7, no gastric drainage, given erythromycin, group 4: n = 13, gastric drainage, given erythromycin, and group 5: n = 7, no longer given erythromycin (with or without gastric drainage). The percentage of time gastric bile absorbance was more than 0.25 was calculated for the total, supine, and upright periods of recording in reference to data from 25 healthy volunteers. RESULTS: The Bilitec test was pathologic in 9 of the 12 patients of group 1 whereas it was normal in three. Gastric exposure to bile was longer in group I patients than in controls for the total (p = 0.012) and supine (0.036) periods, but the difference did not reach statistical significance for the upright period (p = 0.080). Bile exposure in group 4 did not significantly differ from controls (total: p = 0.701; supine: p = 0.124; upright: p = 0.712). Bile exposure for the total period did not significantly differ whether patients were taking erythromycin or the drug had been discontinued at the time of the study (p = 0.234); and it tended to decrease with time in patients investigated twice (p = 0.046). CONCLUSIONS: Gastric exposure to bile after truncal vagotomy and transposition of the stomach up to the neck is pathologic in three quarters of patients. It is more marked in the supine than in the upright position and tends to decrease with time. The addition of a gastric drainage procedure in combination with erythromycin therapy tends to normalize gastric exposure to bile. The effects of erythromycin may persist after discontinuation of the drug.
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Reflujo Biliar/diagnóstico , Esofagectomía , Desnervación Muscular , Complicaciones Posoperatorias/diagnóstico , Estómago/trasplante , Adulto , Anciano , Anciano de 80 o más Años , Reflujo Biliar/tratamiento farmacológico , Eritromicina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/tratamiento farmacológico , Estómago/inervación , Vagotomía TroncalRESUMEN
BACKGROUND: Minimally invasive surgery (MIS) for primary hyperparathyroidism includes unilateral neck exploration, access via a totally endoscopic approach, and access via a video-assisted procedure. We report herein our initial experience with the video-assisted neck exploration procedure for primary (PHPT) and secondary hyperparathyroidism (SHPT). METHODS: Between June 1999 and May 2000, 35 patients were selected for PHPT (n = 25) and SHPT (n = 10). In all cases, video-assisted neck exploration was performed under general anesthesia, leading to selective adenoma removal in PHPT or subtotal parathyroid resection in SHPT. Patient selection was based on the preoperative localization studies (ultrasonography and sestamibi scintigraphy). RESULTS: Five of the 25 patients operated on for PHPT (20%) and three of the 10 patients who underwent surgery for SHPT (30 %) were converted to a conventional surgical technique. The mean operative times in PHPT and SHPT were 48.9 +/- 18.7 min and 136.8 +/- 18.7 min, respectively. The recurrent laryngeal nerve was identified in 45% of the patients. The median size and weight of the resected parathyroid glands were 1.8 cm (range, 0.9-2.5) and 1 g (range, 0.5-7), respectively. The length of skin incision was 24 +/- 1.2 mm. All but one patient are currently cured, with a median follow-up of 6 months (range, 2-13). Postoperative complications included hematoma and transient hoarseness in one patient each (2.85%). The median pain intensity, based on the visual analogue scale (VAS) method, as measured at postoperative day 1 was 0.5 (range, 0-3.6). In the PHPT group, the postoperative hospital stay was