Long-Term Treatment with Citicoline Prevents Cognitive Decline and Predicts a Better Quality of Life after a First Ischemic Stroke

Stroke, as the leading cause of physical disability and cognitive impairment, has a very significant impact on patients' quality of life (QoL). The objective of this study is to know the effect of citicoline treatment in Qol and cognitive performance in the long-term in patients with a first ischemic stroke. This is an open-label, randomized, parallel study of citicoline vs. Usual treatment. All subjects were selected 6 weeks after suffering a first ischemic stroke and randomized into parallel arms. Neuropsychological evaluation was performed at 1 month, 6 months, 1 year and 2 years after stroke, and QoL was measured using the EuroQoL-5D questionnaire at 2 years. 163 patients were followed during 2 years. The mean age was 67.5 years-old, and 50.9% were women. Age and absence of citicoline treatment were independent predictors of both utility and poor quality of life. Patients with cognitive impairment had a poorer QoL at 2 years (0.55 vs. 0.66 in utility, p = 0.015). Citicoline treatment improved significantly cognitive status during follow-up (p = 0.005). In conclusion, treatment with long-term citicoline is associated with a better QoL and improves cognitive status 2 years after a first ischemic stroke

Stroke-associated pneumonia according to mCDC criteria: impact on prognosis and antibiotic therapy

Antibiotics; Infections; Stroke-associated pneumoniaAntibióticos; Infecciones; Neumonía asociada a ictusAntibiòtics; Infeccions; Pneumònia associada a ictusObjective: The modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients. Methods: We conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis. Results: Of the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022–23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation. Interpretation: The mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome.The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Study supported by Fundació La Marató de TV3 (201706-30-31), Instituto de Salud Carlos III (PI17/02130 and PI21/00949), co-financed by the Fondo Europeo de Desarrollo Regional. Some centres take part in Spanish Stroke Research Network RICORS-ICTUS (RD21/0006/0024, RD21/0006/0007 and RD21/0006/0015)

Perampanel: A therapeutic alternative in refractory status epilepticus associated with MELAS syndrome

MELAS; Perampanel; Status epilepticusMELAS; Perampanel; Estatus epilèpticMELAS; Perampanel; Status epilépticoTo our knowledge, there are no reports of status epilepticus (SE) associated with mitochondrial diseases and treated with perampanel (PER). We present three cases of patients with refractory SE associated with MELAS syndrome who responded favorably to PER. All cases were diagnosed as non-convulsive SE (focal without impairment of level of consciousness). After an initial treatment with other anti-seizure drugs, PER was added in all cases (8, 16 and 12 mg) and cessation of SE was observed within the next 4-8 hours. All the cases involved a stroke-like lesion present on brain MRI. In our patients, PER was an effective option in SE associated with MELAS syndrome

Complicaciones neurológicas de la endocarditis infecciosa al inicio del nuevo siglo: importancia del neurólogo en su atención integral

Las complicaciones neurológicas de la endocarditis infecciosa (EI) constituyen un problema clínico mayor puesto que producen una elevada morbimortalidad. Sin embargo, aún no se conoce en profundidad cómo se pueden prevenir o detectar precozmente y cómo se han de tratar para mejorar el pronóstico de estos pacientes. En la presente tesis se planteó si la presencia activa de un neurólogo en el equipo multidisciplinar de la EI pudiera repercutir positivamente en la atención integral de los pacientes con EI y complicaciones neurológicas al favorecer la detección y diagnóstico precoz de las complicaciones neurológicas y optimizar su tratamiento y el momento para la cirugía cardiaca si se precisara. Los objetivos fueron analizar las complicaciones neurológicas en un centro de referencia de la EI en la actualidad: epidemiología, tipo de complicaciones, morbimortalidad e impacto en el pronóstico, prestando especial atención a las complicaciones cerebrovasculares, que son las más frecuentes y que más morbimortalidad generan. Así mismo, se compararon las características clínicas y el pronóstico en los pacientes con EI y complicaciones neurológicas antes y después de la incorporación reglada de Neurología en el equipo multidisciplinar y se evaluó el impacto de dicha colaboración en el diagnóstico y tratamiento de las complicaciones neurológicas y la influencia en la toma de decisiones de planificación de cirugía cardiaca cuando se precisó. Se analizaron las complicaciones neurológicas desde que existe el registro prospectivo del comité de Endocarditis Infecciosa del Hospital Universitari Vall d’Hebron, enero del año 2000, hasta el final de 2015 y se valoró la repercusión de la presencia de Neurología en el comité, que dio comienzo en el año 2013. Del total de 793 pacientes con EI, 161(20,3%) tuvieron complicaciones neurológicas y éstas se dieron más en los pacientes con EI sobre válvulas nativas izquierdas, con comorbilidad elevada y/o cuyo agente etiológico es S.aureus. Ocurrieron en los primeros días de la enfermedad o fueron el debut de la misma, casi la mitad de los pacientes precisaron cirugía cardiaca y originaron una elevada mortalidad. Las más frecuentes fueron las vasculares, sobre todo las isquémicas. A partir de 2013, los pacientes presentaron más comorbilidad y las complicaciones neurológicas ocurrieron más frecuentemente sobre válvulas protésicas biológicas. Desde la incorporación de Neurología al equipo multidisciplinar, hubo un mayor uso de resonancia magnética, una mayor detección de complicaciones no vasculares y un mayor número de pacientes con varias complicaciones neurológicas. Se implementó el uso de escalas neurológicas de gravedad y funcionalidad y de nuevos tratamientos en fase aguda del ictus. La mortalidad en el periodo 2013-2015 fue menor de forma estadísticamente significativa tras ajustar por los factores asociados a la misma, lo que apoya la relevancia de la presencia de Neurología en el equipo de EI. Como limitaciones más relevantes del estudio, destacaron que se trata de un análisis realizado en un centro de referencia para cirugía cardiaca y EI, con lo que los resultados pueden no ser extrapolables a la población general con EI, que existieron datos que no es posible contrastar con el periodo anterior a la entrada del neurólogo porque no se registraban previamente, y que el menor tamaño muestral desde la incorporación de Neurología, pudo conllevar una pérdida de la capacidad para detectar diferencias significativas en los subanálisis. En resumen, la integración de un especialista en Neurología en el equipo multidisciplinar de EI favoreció una mejor calidad de asistencia a los pacientes con EI y complicaciones neurológicas que revirtió en un mejor pronóstico.Neurological complications in Infective Endocarditis (IE) are a major clinical problem as they cause high morbidity and mortality rates. However, it is still unknown how they can be prevented or early detected or how they should be managed to improve patients’ prognosis. In this thesis we wondered whether the active presence of a neurologist in the IE multidisciplinary team could result in better comprehensive care of patients with IE and neurological complications, as early detection and diagnosis of these neurological complications and their treatment, including appropriate time to cardiac surgery, if needed, is improved. The aim was to analyze neurological complications in a referral IE center at present, taking into account epidemiology, type of neurological complication, morbidity, mortality and prognosis impact, and paying especial attention to neurovascular complications, as they are the most frequent and have worse morbidity and mortality rates. Furthermore, clinical characteristics and prognosis of patients with IE and neurological complications before and after the active participation of the neurologist in the IE team were compared. Impact of this participation in diagnosis and treatment of neurological complications and influence in decision making for cardiac surgery when it was necessary were also evaluated. Data were collected from the prospective register of the Hospital Universitari Vall d’Hebron IE team that was begun in 2000, until December 2015. Impact of neurologist’s participation from January 2013 was evaluated. Of the 793 patients with IE, 161 (20.3%) had neurological complications. Native left side IE, high comorbidity and IE caused by S.aureus were risk factors for having these complications and they occurred in the first days of the disease or even were the first symptom. Nearly half of the patients underwent cardiac surgery and mortality among patients was high. The most frequent neurologic complications were strokes, most of them ischemic. From 2013 until 2015, patients had higher comorbidity and there were more patients with biological prosthetic valve IE. Since the neurologist’s involvement in the IE team, more Magnetic Resonance scans were performed, and more non vascular neurological complications detected. They were also more diagnoses of patients with several neurological complications. Neurologic stroke severity and functional scales and new treatments for acute stroke were introduced. Mortality in 2013-2105 period was significantly lower after adjusting for other mortality associated factors, what supports the relevance of the neurologist in the IE multidisciplinary team. The most important limitations of the study were that the series was from a referral center of cardiac surgery and IE, so results perhaps are not representative for IE general population; there were some variables that were not possible to contrast as they were not collected in the previous period without neurologist, and also, small sample size in the period whit neurologist could result in less power to detect differences in subanalysis. To summarize, neurologist’s participation in the IE multidisciplinary team helped to have better quality of comprehensive care for patients with IE and neurological complications that resulted in better prognosis

Complicaciones neurológicas de la endocarditis infecciosa al inicio del nuevo siglo: importancia del neurólogo en su atención integral

Las complicaciones neurológicas de la endocarditis infecciosa (EI) constituyen un problema clínico mayor puesto que producen una elevada morbimortalidad. Sin embargo, aún no se conoce en profundidad cómo se pueden prevenir o detectar precozmente y cómo se han de tratar para mejorar el pronóstico de estos pacientes. En la presente tesis se planteó si la presencia activa de un neurólogo en el equipo multidisciplinar de la EI pudiera repercutir positivamente en la atención integral de los pacientes con EI y complicaciones neurológicas al favorecer la detección y diagnóstico precoz de las complicaciones neurológicas y optimizar su tratamiento y el momento para la cirugía cardiaca si se precisara. Los objetivos fueron analizar las complicaciones neurológicas en un centro de referencia de la EI en la actualidad: epidemiología, tipo de complicaciones, morbimortalidad e impacto en el pronóstico, prestando especial atención a las complicaciones cerebrovasculares, que son las más frecuentes y que más morbimortalidad generan. Así mismo, se compararon las características clínicas y el pronóstico en los pacientes con EI y complicaciones neurológicas antes y después de la incorporación reglada de Neurología en el equipo multidisciplinar y se evaluó el impacto de dicha colaboración en el diagnóstico y tratamiento de las complicaciones neurológicas y la influencia en la toma de decisiones de planificación de cirugía cardiaca cuando se precisó. Se analizaron las complicaciones neurológicas desde que existe el registro prospectivo del comité de Endocarditis Infecciosa del Hospital Universitari Vall d’Hebron, enero del año 2000, hasta el final de 2015 y se valoró la repercusión de la presencia de Neurología en el comité, que dio comienzo en el año 2013. Del total de 793 pacientes con EI, 161(20,3%) tuvieron complicaciones neurológicas y éstas se dieron más en los pacientes con EI sobre válvulas nativas izquierdas, con comorbilidad elevada y/o cuyo agente etiológico es S.aureus. Ocurrieron en los primeros días de la enfermedad o fueron el debut de la misma, casi la mitad de los pacientes precisaron cirugía cardiaca y originaron una elevada mortalidad. Las más frecuentes fueron las vasculares, sobre todo las isquémicas. A partir de 2013, los pacientes presentaron más comorbilidad y las complicaciones neurológicas ocurrieron más frecuentemente sobre válvulas protésicas biológicas. Desde la incorporación de Neurología al equipo multidisciplinar, hubo un mayor uso de resonancia magnética, una mayor detección de complicaciones no vasculares y un mayor número de pacientes con varias complicaciones neurológicas. Se implementó el uso de escalas neurológicas de gravedad y funcionalidad y de nuevos tratamientos en fase aguda del ictus. La mortalidad en el periodo 2013-2015 fue menor de forma estadísticamente significativa tras ajustar por los factores asociados a la misma, lo que apoya la relevancia de la presencia de Neurología en el equipo de EI. Como limitaciones más relevantes del estudio, destacaron que se trata de un análisis realizado en un centro de referencia para cirugía cardiaca y EI, con lo que los resultados pueden no ser extrapolables a la población general con EI, que existieron datos que no es posible contrastar con el periodo anterior a la entrada del neurólogo porque no se registraban previamente, y que el menor tamaño muestral desde la incorporación de Neurología, pudo conllevar una pérdida de la capacidad para detectar diferencias significativas en los subanálisis. En resumen, la integración de un especialista en Neurología en el equipo multidisciplinar de EI favoreció una mejor calidad de asistencia a los pacientes con EI y complicaciones neurológicas que revirtió en un mejor pronóstico.Neurological complications in Infective Endocarditis (IE) are a major clinical problem as they cause high morbidity and mortality rates. However, it is still unknown how they can be prevented or early detected or how they should be managed to improve patients’ prognosis. In this thesis we wondered whether the active presence of a neurologist in the IE multidisciplinary team could result in better comprehensive care of patients with IE and neurological complications, as early detection and diagnosis of these neurological complications and their treatment, including appropriate time to cardiac surgery, if needed, is improved. The aim was to analyze neurological complications in a referral IE center at present, taking into account epidemiology, type of neurological complication, morbidity, mortality and prognosis impact, and paying especial attention to neurovascular complications, as they are the most frequent and have worse morbidity and mortality rates. Furthermore, clinical characteristics and prognosis of patients with IE and neurological complications before and after the active participation of the neurologist in the IE team were compared. Impact of this participation in diagnosis and treatment of neurological complications and influence in decision making for cardiac surgery when it was necessary were also evaluated. Data were collected from the prospective register of the Hospital Universitari Vall d’Hebron IE team that was begun in 2000, until December 2015. Impact of neurologist’s participation from January 2013 was evaluated. Of the 793 patients with IE, 161 (20.3%) had neurological complications. Native left side IE, high comorbidity and IE caused by S.aureus were risk factors for having these complications and they occurred in the first days of the disease or even were the first symptom. Nearly half of the patients underwent cardiac surgery and mortality among patients was high. The most frequent neurologic complications were strokes, most of them ischemic. From 2013 until 2015, patients had higher comorbidity and there were more patients with biological prosthetic valve IE. Since the neurologist’s involvement in the IE team, more Magnetic Resonance scans were performed, and more non vascular neurological complications detected. They were also more diagnoses of patients with several neurological complications. Neurologic stroke severity and functional scales and new treatments for acute stroke were introduced. Mortality in 2013-2105 period was significantly lower after adjusting for other mortality associated factors, what supports the relevance of the neurologist in the IE multidisciplinary team. The most important limitations of the study were that the series was from a referral center of cardiac surgery and IE, so results perhaps are not representative for IE general population; there were some variables that were not possible to contrast as they were not collected in the previous period without neurologist, and also, small sample size in the period whit neurologist could result in less power to detect differences in subanalysis. To summarize, neurologist’s participation in the IE multidisciplinary team helped to have better quality of comprehensive care for patients with IE and neurological complications that resulted in better prognosis

Complicaciones neurológicas de la endocarditis infecciosa al inicio del nuevo siglo : importancia del neurólogo en su atención integral /

Las complicaciones neurológicas de la endocarditis infecciosa (EI) constituyen un problema clínico mayor puesto que producen una elevada morbimortalidad. Sin embargo, aún no se conoce en profundidad cómo se pueden prevenir o detectar precozmente y cómo se han de tratar para mejorar el pronóstico de estos pacientes. En la presente tesis se planteó si la presencia activa de un neurólogo en el equipo multidisciplinar de la EI pudiera repercutir positivamente en la atención integral de los pacientes con EI y complicaciones neurológicas al favorecer la detección y diagnóstico precoz de las complicaciones neurológicas y optimizar su tratamiento y el momento para la cirugía cardiaca si se precisara. Los objetivos fueron analizar las complicaciones neurológicas en un centro de referencia de la EI en la actualidad: epidemiología, tipo de complicaciones, morbimortalidad e impacto en el pronóstico, prestando especial atención a las complicaciones cerebrovasculares, que son las más frecuentes y que más morbimortalidad generan. Así mismo, se compararon las características clínicas y el pronóstico en los pacientes con EI y complicaciones neurológicas antes y después de la incorporación reglada de Neurología en el equipo multidisciplinar y se evaluó el impacto de dicha colaboración en el diagnóstico y tratamiento de las complicaciones neurológicas y la influencia en la toma de decisiones de planificación de cirugía cardiaca cuando se precisó. Se analizaron las complicaciones neurológicas desde que existe el registro prospectivo del comité de Endocarditis Infecciosa del Hospital Universitari Vall d'Hebron, enero del año 2000, hasta el final de 2015 y se valoró la repercusión de la presencia de Neurología en el comité, que dio comienzo en el año 2013. Del total de 793 pacientes con EI, 161(20,3%) tuvieron complicaciones neurológicas y éstas se dieron más en los pacientes con EI sobre válvulas nativas izquierdas, con comorbilidad elevada y/o cuyo agente etiológico es S.aureus. Ocurrieron en los primeros días de la enfermedad o fueron el debut de la misma, casi la mitad de los pacientes precisaron cirugía cardiaca y originaron una elevada mortalidad. Las más frecuentes fueron las vasculares, sobre todo las isquémicas. A partir de 2013, los pacientes presentaron más comorbilidad y las complicaciones neurológicas ocurrieron más frecuentemente sobre válvulas protésicas biológicas. Desde la incorporación de Neurología al equipo multidisciplinar, hubo un mayor uso de resonancia magnética, una mayor detección de complicaciones no vasculares y un mayor número de pacientes con varias complicaciones neurológicas. Se implementó el uso de escalas neurológicas de gravedad y funcionalidad y de nuevos tratamientos en fase aguda del ictus. La mortalidad en el periodo 2013-2015 fue menor de forma estadísticamente significativa tras ajustar por los factores asociados a la misma, lo que apoya la relevancia de la presencia de Neurología en el equipo de EI. Como limitaciones más relevantes del estudio, destacaron que se trata de un análisis realizado en un centro de referencia para cirugía cardiaca y EI, con lo que los resultados pueden no ser extrapolables a la población general con EI, que existieron datos que no es posible contrastar con el periodo anterior a la entrada del neurólogo porque no se registraban previamente, y que el menor tamaño muestral desde la incorporación de Neurología, pudo conllevar una pérdida de la capacidad para detectar diferencias significativas en los subanálisis. En resumen, la integración de un especialista en Neurología en el equipo multidisciplinar de EI favoreció una mejor calidad de asistencia a los pacientes con EI y complicaciones neurológicas que revirtió en un mejor pronóstico.Neurological complications in Infective Endocarditis (IE) are a major clinical problem as they cause high morbidity and mortality rates. However, it is still unknown how they can be prevented or early detected or how they should be managed to improve patients' prognosis. In this thesis we wondered whether the active presence of a neurologist in the IE multidisciplinary team could result in better comprehensive care of patients with IE and neurological complications, as early detection and diagnosis of these neurological complications and their treatment, including appropriate time to cardiac surgery, if needed, is improved. The aim was to analyze neurological complications in a referral IE center at present, taking into account epidemiology, type of neurological complication, morbidity, mortality and prognosis impact, and paying especial attention to neurovascular complications, as they are the most frequent and have worse morbidity and mortality rates. Furthermore, clinical characteristics and prognosis of patients with IE and neurological complications before and after the active participation of the neurologist in the IE team were compared. Impact of this participation in diagnosis and treatment of neurological complications and influence in decision making for cardiac surgery when it was necessary were also evaluated. Data were collected from the prospective register of the Hospital Universitari Vall d'Hebron IE team that was begun in 2000, until December 2015. Impact of neurologist's participation from January 2013 was evaluated. Of the 793 patients with IE, 161 (20.3%) had neurological complications. Native left side IE, high comorbidity and IE caused by S.aureus were risk factors for having these complications and they occurred in the first days of the disease or even were the first symptom. Nearly half of the patients underwent cardiac surgery and mortality among patients was high. The most frequent neurologic complications were strokes, most of them ischemic. From 2013 until 2015, patients had higher comorbidity and there were more patients with biological prosthetic valve IE. Since the neurologist's involvement in the IE team, more Magnetic Resonance scans were performed, and more non vascular neurological complications detected. They were also more diagnoses of patients with several neurological complications. Neurologic stroke severity and functional scales and new treatments for acute stroke were introduced. Mortality in 2013-2105 period was significantly lower after adjusting for other mortality associated factors, what supports the relevance of the neurologist in the IE multidisciplinary team. The most important limitations of the study were that the series was from a referral center of cardiac surgery and IE, so results perhaps are not representative for IE general population; there were some variables that were not possible to contrast as they were not collected in the previous period without neurologist, and also, small sample size in the period whit neurologist could result in less power to detect differences in subanalysis. To summarize, neurologist's participation in the IE multidisciplinary team helped to have better quality of comprehensive care for patients with IE and neurological complications that resulted in better prognosis

Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment

Demència; Mal de cap; IctusDemencia; Dolor de cabeza; IctusDementia; Headache; StrokeCADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the EGF-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, being executive function characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further. A genome-wide transcriptome study (four cases paired with three healthy siblings) was carried out, in addition to a qRT-PCR for validation purposes (ten new cases and eight new controls). To study the expression profile by cell type of the significant mRNAs found, we performed an in situ hybridization (ISH) (nine cases and eight controls) and a research in the Single-nuclei Brain RNA-seq expression browser (SNBREB). Pathway analysis enrichment was carried out with Gene Ontology and Reactome. Neuropsychological tests were performed in five of the qRT-PCR cases. The two most significant differentially expressed mRNAs (BANP, p-value = 7.23 × 10–4 and PDCD6IP, p-value = 8.36 × 10–4) were selected for the validation study by qRT-PCR. Additionally, we selected two more mRNAs (CAMK2G, p-value = 4.52 × 10–3 and E2F4, p-value = 4.77 × 10–3) due to their association with ischemic neuronal death. E2F4 showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p = 1.23 × 10–3), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expression was associated with worse executive function (p = 2.04 × 10–2) and attention and information processing speed (IPS) (p = 8.73 × 10–2). In situ hibridization showed E2F4 expression in endothelial and vascular smooth vessel cells. In silico studies indicated that E2F4 is also expressed in brain endothelial cells. Among the most significant pathways analyzed, there was an enrichment of vascular development, cell adhesion and vesicular machinery terms and autophagy process. E2F4 is more highly expressed in the skin biopsy of CADASIL patients compared to controls, and its expression is present in endothelial cells and VSMCs. Further studies are needed to understand whether E2F4 could be useful as a biomarker, to monitor the disease or be used as a therapeutic target.This work was supported by a grant from the Carlos III Health Institute (PI 11/0176), Generación Project, Maestro Project, INVICTUS + network, Epigenesis Project (Marató de TV3), FEDER funds and economic donations from “Asociación CADASIL España”. E. Muiño is supported by a Río Hortega Contract (CM18/00198) from the Carlos III Health Institute. J. Cárcel-Márquez is supported by an AGAUR Contract (agència de gestió d'ajuts universitaris i de recerca; FI_DGR 2019, grant number 2019_FI_B 00853) co-financed with Fons Social Europeu (FSE). M. Lledós is supported by a PFIS Contract (Contratos Predoctorales de Formación en Investigación en Salud) from the Carlos III Health Institute