Rehabilitation of memory following brain injury (ReMemBrIn): study protocol for a randomised controlled trial

Background Impairments of memory are commonly reported by people with traumatic brain injuries (TBI). Such deficits are persistent, debilitating, and can severely impact quality of life. Currently, many do not routinely receive follow-up appointments for residual memory problems following discharge. Methods/Design This is a multi-centre, randomised controlled trial investigating the clinical and cost-effectiveness of a group-based memory rehabilitation programme. Three hundred and twelve people with a traumatic brain injury will be randomised from four centres. Participants will be eligible if they had a traumatic brain injury more than 3 months prior to recruitment, have memory problems, are 18 to 69 years of age, are able to travel to one of our centres and attend group sessions, and are able to give informed consent. Participants will be randomised in clusters of 4 to 6 to the group rehabilitation intervention or to usual care. Intervention groups will receive 10 weekly sessions of a manualised memory rehabilitation programme, which has been developed in previous pilot studies. The intervention will include restitution strategies to retrain impaired memory functions and compensation strategies to enable participants to cope with their memory problems. All participants will receive a follow-up postal questionnaire and an assessment by a research assistant at 6 and 12 months post-randomisation. The primary outcome is the Everyday Memory Questionnaire at 6 months. Secondary outcomes include the Rivermead Behavioural Memory Test-3, General Health Questionnaire-30, health related quality of life, cost-effectiveness analysis determined by the EQ-5D and a service use questionnaire, individual goal attainment, European Brain Injury Questionnaire (patient and relative versions), and the Everyday Memory Questionnaire-relative version. The primary analysis will be based on intention to treat. A mixed-model regression analysis of the Everyday Memory Questionnaire at 6 months will be used to estimate the effect of the group memory rehabilitation programme. Discussion The study will hopefully provide robust evidence regarding the clinical and cost-effectiveness of a group-based memory rehabilitation intervention for civilians and military personnel following TBI. We discuss our decision-making regarding choice of outcome measures and control group, and the unique challenges to recruiting people with memory problems to trials

Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics

age: Observational data from the ICON audit

Purpose: To investigate age-related differences in outcomes of critically ill patients with sepsis around the world.Methods: We performed a secondary analysis of data from the prospective ICON audit, in which all adult ( >16 years ) patients admitted to participating ICUs between May 8 and 18, 2012, were included, except admissions for routine postoperative observation. For this sub-analysis, the 10,012 patients with completed age data were included. They were divided into five age groups - 80 years. Sepsis was defined as infection plus at least one organ failure.Results: A total of 2963 patients had sepsis, with similar proportions across the age groups (80 = 30.9%). Hospital mortality increased with age and in patients >80 years was almost twice that of patients 70 years was independently associated with increased risk of dying.Conclusions: The odds for death in ICU patients with sepsis increased with age with the maximal rate of increase occurring between the ages of 71 and 77 years. (C) 2019 Elsevier Inc. 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Nabil] Ain Shams Fac Med, Cairo, Egypt.[Hosny, H.] Zaitoun Specialized Hosp, Cairo, Egypt.[Ashraf, A.] Gums, Tehran, Iran.[Mokhtari, M.] Sbums, Imam Hossein Hosp, Tehran, Iran.[Nowruzinia, S.] Imamreza Hosp, Mashhad, Razavi Khorasan, Iran.[Lotfi, A.] Laleh Hosp, Tehran, Iran.[Zand, F.] Shiraz Anesthesiol & Crit Care Res Ctr, Shiraz, Iran.[Nikandish, R.] Shiraz Univ Med Sci, Shiraz, Iran.[Moghaddam, O. Moradi] Tehran Med Sci Univ, Tehran, Iran.[Cohen, J.] Rabin Med Ctr, Petah Tiqwa, Israel.[Sold, O.] Sourasky Tel Aviv Med Ctr, Tel Aviv, Israel.[Sfeir, T.] Ctr Hosp Nord, Ettelbruck, Luxembourg.[Hasan, A.] Sohar Hosp, Sohar, Oman.[Abugaber, D.] Specialized Arab Hosp, Nablus, Palestine.[Ahmad, H.] Almana Gen Hosp, Khobar, Saudi Arabia.[Tantawy, T.] KFSHRC, Riyadh, Saudi Arabia.[Baharoom, S.] King Abdulaziz Med City Riyadh, Riyadh, Saudi Arabia.[Algethamy, H.] King Abdulaziz Univ, Jeddah, Saudi Arabia.[Amr, A.] King Saud Med City, Riyadh, Saudi Arabia.[Almekhlafi, G.] Riyadh Mil Hosp, Riyadh, Saudi Arabia.[Coskun, R.] Erciyes Univ, Med Fac, Kayseri, Turkey.[Sungur, M.] Erciyes Univ, Med Sch, Kayseri, Turkey.[Cosar, A.] Gulhane Mil Med Acad, Ankara, Turkey.[Gucyetmez, B.] Int Hosp, Istanbul, Turkey.[Demirkiran, O.] Istanbul Univ, Cerrahpasa Med Sch Hosp, Istanbul, Turkey.[Senturk, E.] Istanbul Univ, Istanbul Med Fac, Istanbul, Turkey.[Ulusoy, H.] Karadeniz Tech Univ, Med Fac, Trabzon, Turkey.[Atalan, H.] Mem Atasehir Hosp, Istanbul, Turkey.[Serin, S.] Pamukkale Univ, Denizli, Turkey.[Kati, I] Yuzuncu Yil Univ, Med Fac, Van, Turkey.[Alnassrawi, Z.] Dubai Hosp, Dubai, U Arab Emirates.[Almemari, A.] Mafraq Hosp, Abu Dhabi, U Arab Emirates.[Krishnareddy, K.] Sheikh Khalifa Med City, Abu Dhabi, U Arab Emirates.[Kashef, S.] Tawam Hosp, Al Ain, U Arab Emirates.[Alsabbah, A.] City Hosp, Dubai, U Arab Emirates.[Poirier, G.] Hop Charles Lemoyne, Longueuil, PQ, Canada.[Marshall, J.] St Michaels Hosp, Toronto, ON, Canada.[Herridge, M.] Toronto Gen Hosp, Toronto, ON, Canada.[Herridge, M.] Toronto Western Hosp, Toronto, ON, Canada.[Fernandez-Medero, R.] San Juan Hosp, San Juan, PR USA.[Fulda, G.] Christiana Care Hlth Syst, Newark, DE USA.[Banschbach, S.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA.[Quintero, J.] El Camino Hosp, Mountain View, CA USA.[Schroeder, E.] George Washington Hosp, Washington, DC USA.[Sicoutris, C.] Hosp Univ Penn, Philadelphia, PA 19104 USA.[Gueret, R.] John H Stroger Hosp Cook Cty, Chicago, IL USA.[Kashyap, R.] Mayo Clin, CCM, Rochester, MN USA.[Bauer, P.] Mayo Clin, PCC, Rochester, MN USA.[Nanchal, R.] Med Coll Wisconsin, Milwaukee, WI 53226 USA.[Wunderink, R.] Northwestern Mem Hosp, Chicago, IL 60611 USA.[Jimenez, E.] Orlando Reg Med Ctr Inc, Orlando, FL USA.[Ryan, A.] Washington Hosp Ctr, Washington, DC 20010 USA.[Ryan, A.] Washington Hosp Ctr, 2H, Washington, DC USA.[Ryan, A.] Washington Hosp Ctr, 2G, Washington, DC USA.[Ryan, A.] Washington Hosp Ctr, 3H, Washington, DC USA.[Ryan, A.] Washington Hosp Ctr, 3G, Washington, DC USA.[Ryan, A.] Washington Hosp Ctr, 4H, Washington, DC USA.[Ryan, A.] Washington Hosp Ctr, CVRR, Washington, DC USA.[Prince, D.] Armadale Hlth Serv, Mount Nasura, WA, Australia.[Edington, J.] Bendigo Hosp, Bendigo, Vic, Australia.[Van Haren, F.] Canberra Hosp, Canberra, ACT, Australia.[Bersten, A.] Flinders Med Ctr, Bedford Pk, SA, Australia.[Hawkins, D. J.] Joondalup Hlth Campus, Joondalup, WA, Australia.[Kilminster, M.] Lismore Base Hosp, Lismore, NSW, Australia.[Sturgess, D.] Mater Adult Hosp, South Brisbane, Qld, Australia.[Ziegenfuss, M.] Prince Charles Hosp, Brisbane, Qld, Australia.[O'Connor, S.] Royal Adelaide Hosp, Adelaide, SA, Australia.[Lipman, J.] Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia.[Campbell, L.] Royal Darwin Hosp, Tiwi, NT, Australia.[Mcallister, R.] Royal Hobart Hosp, Hobart, Tas, Australia.[Roberts, B.] Sir Charles Gairdner Hosp, Nedlands, WA, Australia.[Williams, P.] Queen Elizabeth Hosp, Woodville, SA, Australia.[Parke, R.] Auckland Dist Hlth Board, Auckland, New Zealand.[Seigne, P.] Christchurch Hosp, Christchurch, New Zealand.[Freebairn, R.] Hawkes Bay Hosp, Hastings, New Zealand.[Nistor, D.] Palmerston North Hosp, Midcent Hlth, Palmerston North, New Zealand.[Oxley, C.] Middlemore Hosp, Auckland, New Zealand.[Young, P.] Wellington Hosp, Wellington, New Zealand.[Valentini, R.] Cemic, Buenos Aires, DF, Argentina.[Wainsztein, N.] Fleni, Buenos Aires, DF, Argentina.[Comignani, P.] Hosp Aleman, Buenos Aires, DF, Argentina.[Casaretto, M.] Hosp Cent San Isidro, Buenos Aires, DF, Argentina.[Sutton, G.] Hosp Fernandez, Buenos Aires, DF, Argentina.[Villegas, P.] Hosp Francisco Lopez Lima Area Programa Gen Roca, Gen Roca, Argentina.[Galletti, C.] Sanatorio Allende, Cordoba, Argentina.[Neira, J.] Sanatorio Trinidad Palermo, Buenos Aires, DF, Argentina.[Rovira, D.] Sanatorio Julio Corzo Rosario, Rosario, Santa Fe, Argentina.[Hidalgo, J.] Karl Heusner Mem Hosp, Belize City, Belize.[Hidalgo, J.] Belize Healthcare Partner, Belize City, Belize.[Sandi, F.] Hosp Obrero 1, La Paz, Bolivia.[Caser, E.] Cias Unimed Vitoria, Vitoria, ES, Brazil.[Thompson, M.] Evangelical Hosp Cachoeiro De Itapemirim, Cachoeiro De Itapemirim, Brazil.[D'agostino Dias, M.] Hosp 9 Julho, Sao Paulo, Brazil.[Fontes, L.] Hosp Alcides Carneiro, Petropolis, Brazil.[Lunardi, M.] Hosp Clin Luzia De Pinho Melo, Mogi Das Cruzes, Brazil.[Youssef, N.] Hosp Nacoes Curitiba, Curitiba, Parana, Brazil.[Lobo, S.] Hosp Base Famerp, Sao Jose Do Rio Preto, Brazil.[Silva, R.] Hosp Clin Niteroi, Niteroi, RJ, Brazil.[Sales Jr, J.] Hosp Clin Padre Miguel, Rio De Janeiro, Brazil.[Madeira Campos Melo, L.] Hosp Terapia Intens, Sao Paulo, Brazil.[Oliveira, M.] Hosp Trabalhador, Curitiba, Parana, Brazil.[Fonte, M.] Hosp Esperanza, Olinda, PE, Brazil.[Grion, C.] Hosp Evangel Londrina, Londrina, Brazil.[Feijo, C.] Hosp Geral Fortaleza, Fortaleza, Ceara, Brazil.[Rezende, V] Hosp Geral Roraima, Boa Vista, Brazil.[Assuncao, M.] Hosp Israelita Albert Einstein, Sao Paulo, Brazil.[Neves, A.] Hosp Mater Dei, Belo Horizonte, MG, Brazil.[Gusman, P.; Dalcomune, D.] Hosp Meridional, Cariacica, ES, Brazil.[Teixeira, C.] Hosp Moinhos Vento, Porto Alegre, RS, Brazil.[Kaefer, K.] Hosp Municipal Ruth Cardoso, Balneario, Brazil.[Maia, I] Hosp Nereu Ramos, Florianopolis, SC, Brazil.[Souza Dantas, V] Hosp Pasteur, Rio De Janeiro, Brazil.[Costa Filho, R.] Hosp Pro Cardiaco, Rio De Janeiro, Brazil.[Amorim, F.] Hosp Reg Samambaia, Brasilia, DF, Brazil.[Assef, M.] Hosp Reg Hans Dieter Schmidt, Joinville, Brazil.[Schiavetto, P.] Hosp Santa Casa Campo Mourao, Campo Mourao, PR, Brazil.[Houly, J.] Hosp Santa Paula, Sao Paulo, SP, Brazil.[Houly, J.] Hosp Santapaula, Sao Paulo, Brazil.[Bianchi, F.] Hosp Sao Jose Avai, Itaperuna, RJ, Brazil.[Dias, F.] Hosp Sao Lucas Pucrs, Porto Alegre, RS, Brazil.[Avila, C.] Hosp Sao Vicente Paula, Rio De Janeiro, RJ, Brazil.[Gomez, J.] Hosp Sao Vicente Paulo, Rio De Janeiro, Brazil.[Rego, L.] Hosp Saude Mulher, Belem, Para, Brazil.[Castro, P.] Hosp Tacchini, Bento Goncalves, RS, Brazil.[Passos, J.] Hosp Unimed Costa Do Sol Macae Rj, Macae, RJ, Brazil.[Mendes, C.] Hosp Univ Ufpb Joao Pessoa, Joao Pessoa, Paraiba, Brazil.[Grion, C.] Hosp Univ Londrina, Londrina, Brazil.[Colozza Mecatti, G.] Hosp Univ Sao Francisco, Braganca Paulista, SP, Brazil.[Ferrreira, M.] Santa Casa Caridade Diamantina, Diamantina, MG, Brazil.[Irineu, V] Santa Casa Misericordia Tatui, Tatui, Brazil.[Guerreiro, M.] Sao Francisco de Paula Hosp, Sao Francisco De Paula, RS, Brazil.[Ugarte, S.] Clin Indisa, Providencia, Chile.[Tomicic, V] Clin Las Lilas, Providencia, Chile.[Godoy, C.] Hosp Carlos Van Buren, Valparaiso, Chile.[Samaniego, W.] Hosp Trabajador Santiago, Santiago, Chile.[Escamilla, I] Hosp El Pino, San Bernardo, Chile.[Escamilla, I] Hosp Mutual De Seguridad, Santiago, Chile.[Castro Castro, L.] Ctr Med Imbanaco, Valle Del Cauca, Colombia.[Libreros Duque, G.] Clin Colombia Cali, Cali, Colombia.[Diaz-Guio, D.] Clin Del Cafe, Armenia, Colombia.[Benitez, F.] Clin La Estancia SA, Popayan, Colombia.[Guerra Urrego, A.] Clin Medellin, Medellin, Colombia.[Buitrago, R.] Fdn Clin Shaio, Bogota, Colombia.[Ortiz, G.] Hosp Santa Clara, Bogota, Colomb