. [60] have used both anaesthesia techniques. GA, general anaesthesia. doi:10.1371/journal.pone.0156448.gPLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,31 /Anaesthesia Management for Awake Craniotomyintraoperative seizures and their P144MedChemExpress P144 Peptide consequences [10,17?9,31?9,42?4,47,49?5,57?0,62]. The total number of performed AC purchase U0126-EtOH procedures in these studies was 4942 and 351 (7.1 ) intraoperative seizures were reported (Table 4). Only twenty-three (0.5 ) intraoperative seizures led to a failure of AC, but they were resolved without any serious problems and the surgery was continued in GA [33,34,42,43,55,57]. Interestingly, the AAA technique showed a high proportion of eight seizures in fifty AC procedures, but only one led to AC failure due to required intubation [33]. Intraoperative seizures were more common in younger patients and those with a history of seizures [31,42]. A meta-analysis was performed for thirty-four studies, [10,17?6,28,29,32,34?39,43,47,49?5,57?0,62], which used the MAC and SAS technique, excluding the duplicate studies from Tel Aviv [31,42] and Glostrup [27,44]. Meta-analysis showed an estimated proportion of seizures of 8 [95 CI: 6?1] with substantial heterogeneity between studies (I2 = 75 ) (Fig 4). In the meta-regression analysis, the techniques used did not explain the differences in the studies (QM < 0.001, df = 1, p = 0.983). The OR comparing SAS to MAC technique was 1.01 [CI95 : 0.52?.88]. Postoperative neurological dysfunction (new/ late). Description of particular postoperative neurological dysfunctions differed significantly in the included studies. Therefore we have subsumed all kinds of new neurological dysfunctions under these superordinate two outcome variables. Of note, we did not include data of patients with deterioration of a pre-existing neurological dysfunction. Twenty-nine studies [10,18,19,23,24,28,29,31,33?5,37,38,40?43,48,49,51?5,57?9,61,62] reported new postoperative neurological dysfunctions after 565 (14.0 ) of totally 4029 AC procedures. A later follow up result (six months) was provided for 279 of these patients with new neurological dysfunction. It showed a persistent neurological dysfunction in 64 patients. Of note, late neurological outcome after six months was reported in only seventeen studies comprising 2085 AC procedures in total. Considering twenty-six studies [10,18,19,23,24,28,29,34,35,37,38,40,41,43,48,49,51?5,57?9,61,62], which were reasonable included in our meta-analysis, the proportion of new neurological dysfunction was estimated to be 17 [95 CI: 12?3], with a high heterogeneity (I2 = 90 ) (Fig 5). Meta-regression analysis did not reveal a difference depending on the anaesthesia technique (MAC/ SAS) (QM = 1.52, df = 1, p = 0.217), with an OR of 1.66 [95 CI: 1.35?.70]. Furthermore, there is a large proportion of residual heterogeneity (QE = 187.55, df = 24, p < .0001), which cannot be explained by the applied anaesthesia technique. However, it has to be noted that there are only six studies available in the SAS group. Other adverse events/outcomes. The other extracted adverse events and outcome data are shown in Tables 4 and 5. Mortality was very low with 10 patients (0.2 ) of all forty-four studies comprising 5381 patients, which reported the outcome variable mortality (Table 5). Of note, two deaths include probably duplicate patients [42,43] to the study of Grossman et al. [31]. Furthermore, we have only included deaths within 30 days after surgery in this analysis. Interestingly.. [60] have used both anaesthesia techniques. GA, general anaesthesia. doi:10.1371/journal.pone.0156448.gPLOS ONE | DOI:10.1371/journal.pone.0156448 May 26,31 /Anaesthesia Management for Awake Craniotomyintraoperative seizures and their consequences [10,17?9,31?9,42?4,47,49?5,57?0,62]. The total number of performed AC procedures in these studies was 4942 and 351 (7.1 ) intraoperative seizures were reported (Table 4). Only twenty-three (0.5 ) intraoperative seizures led to a failure of AC, but they were resolved without any serious problems and the surgery was continued in GA [33,34,42,43,55,57]. Interestingly, the AAA technique showed a high proportion of eight seizures in fifty AC procedures, but only one led to AC failure due to required intubation [33]. Intraoperative seizures were more common in younger patients and those with a history of seizures [31,42]. A meta-analysis was performed for thirty-four studies, [10,17?6,28,29,32,34?39,43,47,49?5,57?0,62], which used the MAC and SAS technique, excluding the duplicate studies from Tel Aviv [31,42] and Glostrup [27,44]. Meta-analysis showed an estimated proportion of seizures of 8 [95 CI: 6?1] with substantial heterogeneity between studies (I2 = 75 ) (Fig 4). In the meta-regression analysis, the techniques used did not explain the differences in the studies (QM < 0.001, df = 1, p = 0.983). The OR comparing SAS to MAC technique was 1.01 [CI95 : 0.52?.88]. Postoperative neurological dysfunction (new/ late). Description of particular postoperative neurological dysfunctions differed significantly in the included studies. Therefore we have subsumed all kinds of new neurological dysfunctions under these superordinate two outcome variables. Of note, we did not include data of patients with deterioration of a pre-existing neurological dysfunction. Twenty-nine studies [10,18,19,23,24,28,29,31,33?5,37,38,40?43,48,49,51?5,57?9,61,62] reported new postoperative neurological dysfunctions after 565 (14.0 ) of totally 4029 AC procedures. A later follow up result (six months) was provided for 279 of these patients with new neurological dysfunction. It showed a persistent neurological dysfunction in 64 patients. Of note, late neurological outcome after six months was reported in only seventeen studies comprising 2085 AC procedures in total. Considering twenty-six studies [10,18,19,23,24,28,29,34,35,37,38,40,41,43,48,49,51?5,57?9,61,62], which were reasonable included in our meta-analysis, the proportion of new neurological dysfunction was estimated to be 17 [95 CI: 12?3], with a high heterogeneity (I2 = 90 ) (Fig 5). Meta-regression analysis did not reveal a difference depending on the anaesthesia technique (MAC/ SAS) (QM = 1.52, df = 1, p = 0.217), with an OR of 1.66 [95 CI: 1.35?.70]. Furthermore, there is a large proportion of residual heterogeneity (QE = 187.55, df = 24, p < .0001), which cannot be explained by the applied anaesthesia technique. However, it has to be noted that there are only six studies available in the SAS group. Other adverse events/outcomes. The other extracted adverse events and outcome data are shown in Tables 4 and 5. Mortality was very low with 10 patients (0.2 ) of all forty-four studies comprising 5381 patients, which reported the outcome variable mortality (Table 5). Of note, two deaths include probably duplicate patients [42,43] to the study of Grossman et al. [31]. Furthermore, we have only included deaths within 30 days after surgery in this analysis. Interestingly.

St and philosopher Herbert Spencer in developing a system of hierarchy of psychological functions, each of these functions having a different “coefficient of reality.” In Janet’s view, an individual could potentially have a large amount of mental energy but be unable to use this within the higher mental functions. With high “psychological tension,” however, he could concentrate and unify psychological phenomena,8. See also: TNA, FD2/20, Report of the Medical Research Council for the year 1933?4, London: HMSO (1935), p. 105. 9. TNA, FD6/3, Medical Research Council Minute Book, January 26, 1927 to June 19, 1936, October 26, 1934, it. 163.JOURNAL OF THE HISTORY OF THE BEHAVIORAL SCIENCES DOI 10.1002/jhbsORGAN EXTRACTS AND THE DEVELOPMENT OF PSYCHIATRYthus, engaging in the highest function that of reality (Janet Raymond, 1903; Ellenberger, 1970, pp. 61?37; Valsiner Veer, 2000). Hoskins and Sleeper used this theory to explain the mental changes which followed from thyroid treatment arguing that vital drives and mental energy were altered through endocrine interventions which enabled patients to maintain a stable mental state (Hoskins Sleeper, 1929a). In 1938, Brazier published two articles in the Journal of Mental Science in conjunction with Russel Fraser, a Maudsley physician with a strong interest in endocrinology, and William Sargant, a Maudsley doctor and researcher who had trained with Edward Mapother and was a Quisinostat supplement staunch advocate of physical treatments in psychiatry. These articles referenced Hoskins and Sleeper’s thyroid treatments but critiqued their reliance on psychological theory as a justification for their effectiveness. They claimed that “numerous workers have experimented with thyroid treatment in mental disorder” but these treatments had not been measured effectively (Sargant, Fraser, Brazier, 1938). Instead of relying upon psychological theory, they proposed recording electrical activity in the patient’s body as a measure of the efficacy of thyroid in treating mental illnesses. They claimed that thyroid could be useful in a range of illnesses such as: cases of recurrent katatonic excitement or stupor, cases of acute schizophrenia which exhibit a marked additional depressive component, and cases of depression which form part of a manic-depressive psychosis, or exhibit some depersonalisation, mild confusional features or retardation. Their interest in the depressive aspects of schizophrenia and the psychotic aspects of depression help to explain why they considered it possible to treat schizophrenia and psychosis with thyroid extract. In 1939, Golla took up a new position as director of the newly established Burden Neurological Institute (BNI) in Frenchay, ZM241385MedChemExpress ZM241385 Bristol. The institute was a private charity and Golla had considerable freedom to pursue his own research agenda. He recruited a team of young researchers (including Grey Walter who had worked at the Central Pathological Laboratory) specializing in electrophysiology and endocrinology (Hayward, 2004). By the outbreak of the Second World War, endocrine treatments had become significantly less popular among Maudsley psychiatrists. In their textbook, An Introduction to Physical Methods of Treatment in Psychiatry, Sargant and Eliot Slater, who had served as a medical officer at the Maudsley Hospital from 1931 and worked at Sutton Emergency Hospital during the war, took a critical line (Sargant Slater, 1944, pp. 128?34). They argued that hormones should not be used to trea.St and philosopher Herbert Spencer in developing a system of hierarchy of psychological functions, each of these functions having a different “coefficient of reality.” In Janet’s view, an individual could potentially have a large amount of mental energy but be unable to use this within the higher mental functions. With high “psychological tension,” however, he could concentrate and unify psychological phenomena,8. See also: TNA, FD2/20, Report of the Medical Research Council for the year 1933?4, London: HMSO (1935), p. 105. 9. TNA, FD6/3, Medical Research Council Minute Book, January 26, 1927 to June 19, 1936, October 26, 1934, it. 163.JOURNAL OF THE HISTORY OF THE BEHAVIORAL SCIENCES DOI 10.1002/jhbsORGAN EXTRACTS AND THE DEVELOPMENT OF PSYCHIATRYthus, engaging in the highest function that of reality (Janet Raymond, 1903; Ellenberger, 1970, pp. 61?37; Valsiner Veer, 2000). Hoskins and Sleeper used this theory to explain the mental changes which followed from thyroid treatment arguing that vital drives and mental energy were altered through endocrine interventions which enabled patients to maintain a stable mental state (Hoskins Sleeper, 1929a). In 1938, Brazier published two articles in the Journal of Mental Science in conjunction with Russel Fraser, a Maudsley physician with a strong interest in endocrinology, and William Sargant, a Maudsley doctor and researcher who had trained with Edward Mapother and was a staunch advocate of physical treatments in psychiatry. These articles referenced Hoskins and Sleeper’s thyroid treatments but critiqued their reliance on psychological theory as a justification for their effectiveness. They claimed that “numerous workers have experimented with thyroid treatment in mental disorder” but these treatments had not been measured effectively (Sargant, Fraser, Brazier, 1938). Instead of relying upon psychological theory, they proposed recording electrical activity in the patient’s body as a measure of the efficacy of thyroid in treating mental illnesses. They claimed that thyroid could be useful in a range of illnesses such as: cases of recurrent katatonic excitement or stupor, cases of acute schizophrenia which exhibit a marked additional depressive component, and cases of depression which form part of a manic-depressive psychosis, or exhibit some depersonalisation, mild confusional features or retardation. Their interest in the depressive aspects of schizophrenia and the psychotic aspects of depression help to explain why they considered it possible to treat schizophrenia and psychosis with thyroid extract. In 1939, Golla took up a new position as director of the newly established Burden Neurological Institute (BNI) in Frenchay, Bristol. The institute was a private charity and Golla had considerable freedom to pursue his own research agenda. He recruited a team of young researchers (including Grey Walter who had worked at the Central Pathological Laboratory) specializing in electrophysiology and endocrinology (Hayward, 2004). By the outbreak of the Second World War, endocrine treatments had become significantly less popular among Maudsley psychiatrists. In their textbook, An Introduction to Physical Methods of Treatment in Psychiatry, Sargant and Eliot Slater, who had served as a medical officer at the Maudsley Hospital from 1931 and worked at Sutton Emergency Hospital during the war, took a critical line (Sargant Slater, 1944, pp. 128?34). They argued that hormones should not be used to trea.

Her subjects make selfish or pro-social moral choices. Together, these results reveal not only differential neural mechanisms for real and hypothetical moral decisions but also that the nature of real moral decisions can be predicted by dissociable networks within the PFC.Keywords: real moral decision-making; fMRI; amygdala; TPJ; ACCINTRODUCTION Psychology has a long tradition demonstrating a fundamental difference between how people believe they will act and how they actually act in the real world (Milgram, 1963; Higgins, 1987). Recent research (Ajzen et al., 2004; Kang et al., 2011; Teper et al., 2011) has confirmed this intention ehavior discrepancy, revealing that people inaccurately predict their future actions because hypothetical decision-making requires mental simulations that are abbreviated, unrepresentative and decontextualized (Gilbert and Wilson, 2007). This `hypothetical bias’ effect (Kang et al., 2011) has routinely demonstrated that the influence of socio-emotional factors and tangible risk (Wilson et al., 2000) is relatively diluted in hypothetical decisions: not only do hypothetical moral probes lack the tension engendered by competing, real-world emotional choices but also they fail to elicit expectations of consequencesboth of which are endemic to real moral reasoning (Krebs et al., 1997). In fact, research has shown that when real contextual pressures and their associated consequences come into play, people can behave in characteristically immoral ways (Baumgartner et al., 2009; Greene and Paxton, 2009). Although there is also important work examining the neural basis of the opposite behavioral findingaltruistic decision-making (Moll et al., 2006)the neural networks underlying the conflicting motivation of maximizing self-gain at the expense of another are still poorly understood. Studying the neural architecture of this form of moral tension is particularly compelling because monetary incentives to behave immorally are pervasive throughout societypeople frequently cheat on their loved ones, steal from their employers or harm others for monetary gain. Moreover, we AUY922MedChemExpress VER-52296 reasoned that any behavioral and neural disparities between real and hypothetical moral reasoning will likely have the sharpest focus when two fundamental proscriptionsdo not harm others and do not over-benefit the self at the expense of others (Haidt, 2007)are directly pitted against one another. In other words, we speculated that this prototypical moral conflict would provide an ideal test-bed to examine the behavioral and neural differences between intentions and actions.Received 18 April 2012; Accepted 8 June 2012 Advance Access publication 18 June 2012 Correspondence should be addressed to Oriel FeldmanHall, MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 7EF, UK. E-mail: [email protected], we used a `your pain, my gain’ (PvG) laboratory task (Feldmanhall et al., 2012) to operationalize this core choice between personal advantage and another’s welfare: subjects were probed about their willingness to receive money (up to ?00) by Luminespib web physically harming (via electric stimulations) another subject (Figure 1A). The juxtaposition of these two conflicting motivations requires balancing selfish needs against the notion of `doing the right thing’ (Blair, 2007). We carried out a functional magnetic resonance imaging (fMRI) experiment using the PvG task to first explore if real moral behavior mirrors hypothetical in.Her subjects make selfish or pro-social moral choices. Together, these results reveal not only differential neural mechanisms for real and hypothetical moral decisions but also that the nature of real moral decisions can be predicted by dissociable networks within the PFC.Keywords: real moral decision-making; fMRI; amygdala; TPJ; ACCINTRODUCTION Psychology has a long tradition demonstrating a fundamental difference between how people believe they will act and how they actually act in the real world (Milgram, 1963; Higgins, 1987). Recent research (Ajzen et al., 2004; Kang et al., 2011; Teper et al., 2011) has confirmed this intention ehavior discrepancy, revealing that people inaccurately predict their future actions because hypothetical decision-making requires mental simulations that are abbreviated, unrepresentative and decontextualized (Gilbert and Wilson, 2007). This `hypothetical bias’ effect (Kang et al., 2011) has routinely demonstrated that the influence of socio-emotional factors and tangible risk (Wilson et al., 2000) is relatively diluted in hypothetical decisions: not only do hypothetical moral probes lack the tension engendered by competing, real-world emotional choices but also they fail to elicit expectations of consequencesboth of which are endemic to real moral reasoning (Krebs et al., 1997). In fact, research has shown that when real contextual pressures and their associated consequences come into play, people can behave in characteristically immoral ways (Baumgartner et al., 2009; Greene and Paxton, 2009). Although there is also important work examining the neural basis of the opposite behavioral findingaltruistic decision-making (Moll et al., 2006)the neural networks underlying the conflicting motivation of maximizing self-gain at the expense of another are still poorly understood. Studying the neural architecture of this form of moral tension is particularly compelling because monetary incentives to behave immorally are pervasive throughout societypeople frequently cheat on their loved ones, steal from their employers or harm others for monetary gain. Moreover, we reasoned that any behavioral and neural disparities between real and hypothetical moral reasoning will likely have the sharpest focus when two fundamental proscriptionsdo not harm others and do not over-benefit the self at the expense of others (Haidt, 2007)are directly pitted against one another. In other words, we speculated that this prototypical moral conflict would provide an ideal test-bed to examine the behavioral and neural differences between intentions and actions.Received 18 April 2012; Accepted 8 June 2012 Advance Access publication 18 June 2012 Correspondence should be addressed to Oriel FeldmanHall, MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 7EF, UK. E-mail: [email protected], we used a `your pain, my gain’ (PvG) laboratory task (Feldmanhall et al., 2012) to operationalize this core choice between personal advantage and another’s welfare: subjects were probed about their willingness to receive money (up to ?00) by physically harming (via electric stimulations) another subject (Figure 1A). The juxtaposition of these two conflicting motivations requires balancing selfish needs against the notion of `doing the right thing’ (Blair, 2007). We carried out a functional magnetic resonance imaging (fMRI) experiment using the PvG task to first explore if real moral behavior mirrors hypothetical in.

E home and place him or her with a family member ?has become a highly utilized resource. As with many relatively new constructs and policies, research regarding the efficacy of kinship Pan-RAS-IN-1 web foster care in promoting well-being in youth placed in out-of-home care lacks definitive evidence. Many reasons exist for child welfare services to opt to place children with other family members when removed from the home. It is presumed that this process is less disruptive, as the child is being placed with someone he or she already knows. Furthermore, placement with relatives may facilitate communication and contact with the child’s parents (Berrick, Barth, Needell, 1994; Schwartz, 2008). Children in kinship foster care are often able to remain housed with siblings, which has been cited as both a protective and a stabilizing factor (Barth et al., 2007b). Generally kinship foster care placements are more stable, with more children in these settings experiencing as few as one placement, as opposed to nonkinship foster care in which it is not uncommon for children to have four or more placements (Aarons et al., 2010; Fowler, Toro, Miles, 2009; James, Landsverk,J Soc Serv Res. Author manuscript; buy NSC 697286 available in PMC 2016 February 25.Rufa and FowlerPageSlyman, 2004; Perry, Daly, Kotler, 2012). These factors have been the driving rationale for why children may fare better when placed with kin rather than non-kin. Although research supports the potential of kinship settings to increase stability in placements, findings on the impact of this placement on mental health outcomes are mixed. Some studies imply that kinship foster care has positive effects on youth placed out of the home. In one study, kinship foster caregivers were less likely to report internalizing and externalizing problems in the youth in their care than nonkinship foster caregivers (Hegar Rosenthal, 2009), and another corroborated that those in kinship care exhibited fewer behavioral problems than those in nonkinship care, specifically related to fewer placements (Vanschoonlandt, Vanderfaeillie, Van Holen, De Maeyer, Andries, 2012). Other research supports better mental health functioning in general for youth placed in kinship foster care. Youth in kinship care exhibited a better change in social, emotional, and behavioral outcomes compared to those in non-relative foster care in all cases, even when living with depressed caregivers (Garcia et al., 2015). Keller et al. (2001) found that children placed in kinship foster care were no more likely to exceed clinical cut-offs on competence or problem behavior scales on the Child Behavior Checklist than children in the general population; however, children placed in nonkinship foster care were significantly more likely to score in the clinical range on this measure. While this suggests positive effects of kinship foster care on mental health, other studies find null or negative effects. In contrast to studies showing better outcomes when youth are placed in kinship settings, there is evidence to suggest that kinship youth have greater emotional and behavioral problems compared to both the general population (Dubowitz, Zuravin, Starr, Feigelman, Harrington, 1993) as well as youth in nonkinship foster homes (Cuddeback, 2004). In one study, teachers reported higher behavioral problems in kinship foster youth compared to nonkinship foster youth (Hegar Rosenthal, 2009). Another suggested that 26 of children in kinship foster care reported cl.E home and place him or her with a family member ?has become a highly utilized resource. As with many relatively new constructs and policies, research regarding the efficacy of kinship foster care in promoting well-being in youth placed in out-of-home care lacks definitive evidence. Many reasons exist for child welfare services to opt to place children with other family members when removed from the home. It is presumed that this process is less disruptive, as the child is being placed with someone he or she already knows. Furthermore, placement with relatives may facilitate communication and contact with the child’s parents (Berrick, Barth, Needell, 1994; Schwartz, 2008). Children in kinship foster care are often able to remain housed with siblings, which has been cited as both a protective and a stabilizing factor (Barth et al., 2007b). Generally kinship foster care placements are more stable, with more children in these settings experiencing as few as one placement, as opposed to nonkinship foster care in which it is not uncommon for children to have four or more placements (Aarons et al., 2010; Fowler, Toro, Miles, 2009; James, Landsverk,J Soc Serv Res. Author manuscript; available in PMC 2016 February 25.Rufa and FowlerPageSlyman, 2004; Perry, Daly, Kotler, 2012). These factors have been the driving rationale for why children may fare better when placed with kin rather than non-kin. Although research supports the potential of kinship settings to increase stability in placements, findings on the impact of this placement on mental health outcomes are mixed. Some studies imply that kinship foster care has positive effects on youth placed out of the home. In one study, kinship foster caregivers were less likely to report internalizing and externalizing problems in the youth in their care than nonkinship foster caregivers (Hegar Rosenthal, 2009), and another corroborated that those in kinship care exhibited fewer behavioral problems than those in nonkinship care, specifically related to fewer placements (Vanschoonlandt, Vanderfaeillie, Van Holen, De Maeyer, Andries, 2012). Other research supports better mental health functioning in general for youth placed in kinship foster care. Youth in kinship care exhibited a better change in social, emotional, and behavioral outcomes compared to those in non-relative foster care in all cases, even when living with depressed caregivers (Garcia et al., 2015). Keller et al. (2001) found that children placed in kinship foster care were no more likely to exceed clinical cut-offs on competence or problem behavior scales on the Child Behavior Checklist than children in the general population; however, children placed in nonkinship foster care were significantly more likely to score in the clinical range on this measure. While this suggests positive effects of kinship foster care on mental health, other studies find null or negative effects. In contrast to studies showing better outcomes when youth are placed in kinship settings, there is evidence to suggest that kinship youth have greater emotional and behavioral problems compared to both the general population (Dubowitz, Zuravin, Starr, Feigelman, Harrington, 1993) as well as youth in nonkinship foster homes (Cuddeback, 2004). In one study, teachers reported higher behavioral problems in kinship foster youth compared to nonkinship foster youth (Hegar Rosenthal, 2009). Another suggested that 26 of children in kinship foster care reported cl.

Thesis on s GW9662 cost heterogeneity heterogeneity heterogeneity no heterogeneityHypothesis on p heterogeneity heterogeneity and linear trend heterogeneity and quadratic trend heterogeneity and linear trenddev 73218 72967 72967rank 190 194 198AIC 73602 73359 73367def 0 0 0The candidate models vary in the presence/absence of heterogeneity on survival (s) and of temporal trends on survival and proportions (p). For all models breeding and success probabilities were state dependent and constant, and encounter and state assignment probabilities were state and time-dependent. For each model the deviance (dev), rank, AIC and DAIC are given. BMS-214662 chemical information Subscripts h and s refer to heterogeneity and state, respectively, T to a linear temporal trend and T+T2 to a quadratic temporal trend. def indicates rank deficiency. doi:10.1371/journal.pone.0060353.tStudy Site and PopulationWandering albatrosses are large (<10 kg), long-lived seabirds that breed on sub-Antarctic Islands. We chose to study the wandering albatrosses from Possession Island (46uS, 52uE), Crozet, south-western Indian Ocean, for this particular study because of the extensive and high quality dataset from a long-term monitoring program. The number of breeding pairs was relatively stable during the 1960s, but there was a marked decline between the early 1970s and 1986, followed by an increase until 2003 [35]. From 2003 to 2010, the breeding population has declined slightly.(numbers of hooks deployed) in 5 by 5 degree spatial blocks obtained from the Indian Ocean Tuna Commission (IOTC).Model Description and Goodness-of-fitOur approach was based upon multi-event capture-markrecapture models [36]. The observer records events [(i) not seen, (ii) seen as a FB, (iii) seen as a SB, (iv) seen as a B] that carry uncertain information on the state of the individual at the current sampling occasion. The relationship between states and events is probabilistic; hence these models belong to the family of hidden Markov models [36]. To take into account the quasi-biennial breeding behavior of wandering albatrosses, and breeding state uncertainty when estimating demographic parameters, we used the approach developed by [37]. In brief, models are described by considering the vector of probabilities of initial presence in the various states, then linking states at successive sampling occasions by a survivaltransition probability matrix, and linking events to states by an event probability matrix. Transition probabilities between states were modelled with a three-step procedure where survival, breeding and success were considered as three successive steps in the transition matrices. This baseline multi-event model developed by [37] considers four events (0 = not observed, 1 = seen as a FB, 2 = seen as a SB, 3 = seen as a B), and five states (FB = failed breeder, SB = successful breeder, PFB = post-failed breeder, PSB = post-successful breeder, and dead). Post-failed and postsuccessful breeder states account for those individuals that skip breeding and remain unobservable at sea in the year following a breeding attempt. Only birds in the FB or SB states are observable, whereas birds in the PFB and PSB states are unobservable. To accommodate heterogeneity, two categories of individuals were built, each category being associated with a distinct value of the parameter(s) [38,39]. Because our main predictions concern the effect of heterogeneity on the initial proportions and survival of individuals, the two categories of individual.Thesis on s heterogeneity heterogeneity heterogeneity no heterogeneityHypothesis on p heterogeneity heterogeneity and linear trend heterogeneity and quadratic trend heterogeneity and linear trenddev 73218 72967 72967rank 190 194 198AIC 73602 73359 73367def 0 0 0The candidate models vary in the presence/absence of heterogeneity on survival (s) and of temporal trends on survival and proportions (p). For all models breeding and success probabilities were state dependent and constant, and encounter and state assignment probabilities were state and time-dependent. For each model the deviance (dev), rank, AIC and DAIC are given. Subscripts h and s refer to heterogeneity and state, respectively, T to a linear temporal trend and T+T2 to a quadratic temporal trend. def indicates rank deficiency. doi:10.1371/journal.pone.0060353.tStudy Site and PopulationWandering albatrosses are large (<10 kg), long-lived seabirds that breed on sub-Antarctic Islands. We chose to study the wandering albatrosses from Possession Island (46uS, 52uE), Crozet, south-western Indian Ocean, for this particular study because of the extensive and high quality dataset from a long-term monitoring program. The number of breeding pairs was relatively stable during the 1960s, but there was a marked decline between the early 1970s and 1986, followed by an increase until 2003 [35]. From 2003 to 2010, the breeding population has declined slightly.(numbers of hooks deployed) in 5 by 5 degree spatial blocks obtained from the Indian Ocean Tuna Commission (IOTC).Model Description and Goodness-of-fitOur approach was based upon multi-event capture-markrecapture models [36]. The observer records events [(i) not seen, (ii) seen as a FB, (iii) seen as a SB, (iv) seen as a B] that carry uncertain information on the state of the individual at the current sampling occasion. The relationship between states and events is probabilistic; hence these models belong to the family of hidden Markov models [36]. To take into account the quasi-biennial breeding behavior of wandering albatrosses, and breeding state uncertainty when estimating demographic parameters, we used the approach developed by [37]. In brief, models are described by considering the vector of probabilities of initial presence in the various states, then linking states at successive sampling occasions by a survivaltransition probability matrix, and linking events to states by an event probability matrix. Transition probabilities between states were modelled with a three-step procedure where survival, breeding and success were considered as three successive steps in the transition matrices. This baseline multi-event model developed by [37] considers four events (0 = not observed, 1 = seen as a FB, 2 = seen as a SB, 3 = seen as a B), and five states (FB = failed breeder, SB = successful breeder, PFB = post-failed breeder, PSB = post-successful breeder, and dead). Post-failed and postsuccessful breeder states account for those individuals that skip breeding and remain unobservable at sea in the year following a breeding attempt. Only birds in the FB or SB states are observable, whereas birds in the PFB and PSB states are unobservable. To accommodate heterogeneity, two categories of individuals were built, each category being associated with a distinct value of the parameter(s) [38,39]. Because our main predictions concern the effect of heterogeneity on the initial proportions and survival of individuals, the two categories of individual.

Fic health-related topics with professionals from the local academic and health care communities. Handouts were distributed each week on the topics for further reading. Topics included the “10 Keys to Healthy Aging” (Newman et al.2010), AARP?safe driving, medication management, caregiving, healthy cooking, sleep hygiene, emergency preparedness, urinary incontinence, dementia resources, and others. To promote social interaction similar to the Wii groups, participants were divided into stable groups of 3 or 4 members for small group activities for approximately the last 30 minutes of each session. These same groups also competed in a Jeopardy?style tournament in weeks 10 and 20 to encourage retention of the health information and to match the level of friendly competition in the Wii tournaments. Outcome Measures Feasibility–We calculated the proportion of participants completing the intervention. Attendance was examined as the average number of sessions attended and the proportion of those attending 20/24 sessions. At the end of the intervention period, all participants rated, on a 5-point Likert Scale (not at all to very much), their level of satisfaction with the program and how mentally and socially engaging they found it. At the 1- year follow-up assessment, participants indicated their level of interest in future participation and whether or not they would recommend the program to others. Additional measures were examined for the Wii group only, including: satisfaction with the training and use of the gamingInt J Geriatr Psychiatry. Author manuscript; available in PMC 2015 September 01.Hughes et al.Pagetechnology, and the level of enjoyment in, and the mental, social, and physical stimulation of, each of the Wii Sports games.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptClinical Outcomes Assessments were performed in a fixed order within a 2-week window at baseline, postintervention, and 1 year. Each assessment lasted approximately 90 minutes. The primary outcome was cognitive performance. Secondary outcomes included subjective cognitive ability, mood/social functioning, performance-based instrumental activities of daily living, and gait speed. The Computerized Assessment of Mild Cognitive Impairment (CAMCI; Saxton et al., 2009) was used to assess cognitive performance. CAMCI is a self-administered, computer-based set of cognitive tests tapping the domains of attention, executive function, memory, and processing speed. The total CAMCI score is age and education adjusted based on a normative sample, and ranges between 0?1.4 with a score of 34.3 or higher representing “normal” performance. Two tracking tasks requiring participants to (1) track numbers (from 24-1) in reverse order (Tracking A), and (2) months H 4065 site forward (January ?December) and numbers in reverse (Tracking B), were added to the CAMCI battery as measures of psychomotor speed/attention and executive functioning, respectively. We calculated connections per second for each tracking task. The Cognitive Self-Report Questionnaire-25 (Hexanoyl-Tyr-Ile-Ahx-NH2MedChemExpress Dihexa CSRQ-25; Spina et al., 2006) was used to examine intervention-related improvements in cognition and mood/social functioning. We reverse-coded scores for the cognition and social functioning subscales so that higher scores represented better functioning. The Timed Instrumental Activities of Daily Living (TIADL; Owsley et al., 2002) was used to evaluate speed and accuracy of completing everyday tasks with overall time to com.Fic health-related topics with professionals from the local academic and health care communities. Handouts were distributed each week on the topics for further reading. Topics included the “10 Keys to Healthy Aging” (Newman et al.2010), AARP?safe driving, medication management, caregiving, healthy cooking, sleep hygiene, emergency preparedness, urinary incontinence, dementia resources, and others. To promote social interaction similar to the Wii groups, participants were divided into stable groups of 3 or 4 members for small group activities for approximately the last 30 minutes of each session. These same groups also competed in a Jeopardy?style tournament in weeks 10 and 20 to encourage retention of the health information and to match the level of friendly competition in the Wii tournaments. Outcome Measures Feasibility–We calculated the proportion of participants completing the intervention. Attendance was examined as the average number of sessions attended and the proportion of those attending 20/24 sessions. At the end of the intervention period, all participants rated, on a 5-point Likert Scale (not at all to very much), their level of satisfaction with the program and how mentally and socially engaging they found it. At the 1- year follow-up assessment, participants indicated their level of interest in future participation and whether or not they would recommend the program to others. Additional measures were examined for the Wii group only, including: satisfaction with the training and use of the gamingInt J Geriatr Psychiatry. Author manuscript; available in PMC 2015 September 01.Hughes et al.Pagetechnology, and the level of enjoyment in, and the mental, social, and physical stimulation of, each of the Wii Sports games.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptClinical Outcomes Assessments were performed in a fixed order within a 2-week window at baseline, postintervention, and 1 year. Each assessment lasted approximately 90 minutes. The primary outcome was cognitive performance. Secondary outcomes included subjective cognitive ability, mood/social functioning, performance-based instrumental activities of daily living, and gait speed. The Computerized Assessment of Mild Cognitive Impairment (CAMCI; Saxton et al., 2009) was used to assess cognitive performance. CAMCI is a self-administered, computer-based set of cognitive tests tapping the domains of attention, executive function, memory, and processing speed. The total CAMCI score is age and education adjusted based on a normative sample, and ranges between 0?1.4 with a score of 34.3 or higher representing “normal” performance. Two tracking tasks requiring participants to (1) track numbers (from 24-1) in reverse order (Tracking A), and (2) months forward (January ?December) and numbers in reverse (Tracking B), were added to the CAMCI battery as measures of psychomotor speed/attention and executive functioning, respectively. We calculated connections per second for each tracking task. The Cognitive Self-Report Questionnaire-25 (CSRQ-25; Spina et al., 2006) was used to examine intervention-related improvements in cognition and mood/social functioning. We reverse-coded scores for the cognition and social functioning subscales so that higher scores represented better functioning. The Timed Instrumental Activities of Daily Living (TIADL; Owsley et al., 2002) was used to evaluate speed and accuracy of completing everyday tasks with overall time to com.

1.Latkin et al.PageReception to HIV testing also depends on how different individuals, groups, and organizations interact in immediate and broader settings (social interconnectedness). At the micro level, interactions that can affect HIV testing behavior involve relationships among staff in the testing facility. The competing priorities and responsibilities of staff at an HIV testing site, whether a clinic, emergency department or a bar, may deter interpersonal Thonzonium (bromide) chemical information connections necessary to carry out HIV testing objectives.79 Heavy workloads may make health care providers reluctant to recommend HIV testing. This hinders opportunities for testing among persons at risk, even when individuals have access to health care and other services.88 Other interpersonal connections that can influence individuals’ HIV testing behavior are their interactions within their networks and communities. Individuals’ interactions with their immediate network and the larger community provide resources (e.g. referrals or information) and act as informal sources of social influence (e.g., role models) and control (e.g., social segregation or integration mechanisms).89 Program developers have taken advantage of these spontaneous connections to increase HIV testing uptake. For example, the CDC has funded CBOs to provide incentives for at-risk individuals to persuade members of their immediate networks to request an HIV test.90,91 Other examples of interventions making use of spontaneous social connections are social network and community-based programs.92 Informal social influences also operate within immediate networks (e.g., friendship groups) or broader networks (e.g., neighborhoods) by providing social perceptions about HIV, the behaviors associated with HIV risk (e.g., sex, drug use), and the most affected groups (e.g., MSM, drug users, sex workers). Similarly, informal sources of support and control influence HIV-related settings (e.g., availability of spaces and times to engage in healthy or risky behaviors).93 However, changes in settings can change social control effects (e.g., greater availability of services in the community creates more positive HIV testing norms).16 Broader and more distal informal social influences on HIV testing include the endorsement or disapproval from role models including religious, political, or cultural leaders. Finally, HIV testing behavior can depend on interactions among organizations at the county, state, national, and even multinational levels. These include organizations involved in HIV testing development, provision, and promotion (e.g., technology, research, public health and medical groups), organizations that represent the interests of potential clients and affected individuals (e.g., human rights groups), and organizations that I-CBP112MedChemExpress I-CBP112 develop HIV testing policies (e.g., legislative entities). Interactions among macro level organizations can ultimately influence resource distribution and allocation, scientific and technological development, formal control, and settings. Social interactions at the macro level affect such diverse factors as the types of HIV tests available, the way HIV tests are provided, the decision rules for testing a person for HIV, the allocation of HIV testing resources among different communities, and the medical and legal consequences of testing positive for HIV. Interconnections at this level, therefore, strongly determine other structural influences on HIV testing and ultimately affect both individuals’.1.Latkin et al.PageReception to HIV testing also depends on how different individuals, groups, and organizations interact in immediate and broader settings (social interconnectedness). At the micro level, interactions that can affect HIV testing behavior involve relationships among staff in the testing facility. The competing priorities and responsibilities of staff at an HIV testing site, whether a clinic, emergency department or a bar, may deter interpersonal connections necessary to carry out HIV testing objectives.79 Heavy workloads may make health care providers reluctant to recommend HIV testing. This hinders opportunities for testing among persons at risk, even when individuals have access to health care and other services.88 Other interpersonal connections that can influence individuals’ HIV testing behavior are their interactions within their networks and communities. Individuals’ interactions with their immediate network and the larger community provide resources (e.g. referrals or information) and act as informal sources of social influence (e.g., role models) and control (e.g., social segregation or integration mechanisms).89 Program developers have taken advantage of these spontaneous connections to increase HIV testing uptake. For example, the CDC has funded CBOs to provide incentives for at-risk individuals to persuade members of their immediate networks to request an HIV test.90,91 Other examples of interventions making use of spontaneous social connections are social network and community-based programs.92 Informal social influences also operate within immediate networks (e.g., friendship groups) or broader networks (e.g., neighborhoods) by providing social perceptions about HIV, the behaviors associated with HIV risk (e.g., sex, drug use), and the most affected groups (e.g., MSM, drug users, sex workers). Similarly, informal sources of support and control influence HIV-related settings (e.g., availability of spaces and times to engage in healthy or risky behaviors).93 However, changes in settings can change social control effects (e.g., greater availability of services in the community creates more positive HIV testing norms).16 Broader and more distal informal social influences on HIV testing include the endorsement or disapproval from role models including religious, political, or cultural leaders. Finally, HIV testing behavior can depend on interactions among organizations at the county, state, national, and even multinational levels. These include organizations involved in HIV testing development, provision, and promotion (e.g., technology, research, public health and medical groups), organizations that represent the interests of potential clients and affected individuals (e.g., human rights groups), and organizations that develop HIV testing policies (e.g., legislative entities). Interactions among macro level organizations can ultimately influence resource distribution and allocation, scientific and technological development, formal control, and settings. Social interactions at the macro level affect such diverse factors as the types of HIV tests available, the way HIV tests are provided, the decision rules for testing a person for HIV, the allocation of HIV testing resources among different communities, and the medical and legal consequences of testing positive for HIV. Interconnections at this level, therefore, strongly determine other structural influences on HIV testing and ultimately affect both individuals’.

Ity was that paramedics self-assurance was typically low in having the ability to know when it was and was not protected to leave a seizure patient in the scene. Participants mentioned scant attention was provided to seizure management, specifically the postseizure state, inside basic paramedic education and postregistration training opportunities. Traditionally, paramedic instruction has focused on the assessment and procedures for treating sufferers with lifethreatening circumstances. There is a drive to now revise its content material, so paramedics are superior ready to carry out the evolved duties anticipated of them. New curriculum guidance has not too long ago been developed for larger education providers.64 It does not specify what clinical presentations needs to be covered, nor to what extent. It does though state paramedics have to be in a position to “understand the dynamic connection in between human anatomy and physiology. This ought to contain all key physique systems with an emphasis on amyloid P-IN-1 custom synthesis cardiovascular, respiratory, nervous, digestive, endocrine, urinary and musculoskeletal systems” ( p. 21). And, that they should be in a position to “evaluate and respond accordingly for the healthcare needs of individuals across the lifespan who present with acute, chronic, minor illness or injury, healthcare or mental health emergencies” ( p. 35). It remains to become observed how this will be translated by institutions and what mastering students will receive on seizures.Open Access We would acknowledge right here that any curriculum would ought to reflect the workload of paramedics and there might be other presentations competing for slots within it. Dickson et al’s1 proof may be valuable right here in prioritising attention. In examining 1 year of calls to a regional UK ambulance service, they located calls relating to suspected seizures had been the seventh most typical, accounting for three.3 of calls. Guidance documents and tools It is actually vital to also think about what is usually carried out to help already qualified paramedics. Our second paper describes their mastering needs and how these could be addressed (FC Sherratt, et al. BMJ Open submitted). One more important concern for them although relates to guidance. Participants said the lack of detailed national guidance around the management of postictal patients compounded challenges. Only 230 with the 1800 words dedicated for the management of convulsions in adults within JRCALC19 relate for the management of such a state. Our findings suggest this section warrants revision. Having stated this, evidence from medicine shows altering and revising recommendations does not necessarily imply practice will transform,65 66 and so the impact of any adjustments to JRCALC ought to be evaluated. Paramedic Pathfinder can be a new tool and minimal proof on its utility is out there.20 Most of our participants stated it was not helpful in promoting care good quality for seizure sufferers. In no way, did it address the issues and challenges they reported. Indeed, 1 criticism was that the alternative care pathways it directed them to did not exist in reality. Last year eight overall health vanguards have been initiated in England. These seek to implement and explore new approaches that distinctive components from the urgent and emergency care sector can function with each other in a additional coordinated way.67 These could possibly present a mechanism by which to bring regarding the improved access to alternative care pathways that paramedics need to have.62 This awaits to be seen. Strengths and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/20363167 limitations This can be the very first study to explore from a national viewpoint paramedics’ views and experiences of managi.

Ity was that paramedics confidence was typically low in having the ability to know when it was and was not protected to leave a seizure patient in the scene. Participants said scant attention was offered to seizure management, particularly the postseizure state, within simple paramedic coaching and postregistration training opportunities. Traditionally, paramedic education has focused around the assessment and ONO-7300243 web procedures for treating individuals with lifethreatening circumstances. There’s a drive to now revise its content, so paramedics are superior prepared to execute the evolved duties expected of them. New curriculum guidance has lately been developed for higher education providers.64 It does not specify what clinical presentations must be covered, nor to what extent. It does though state paramedics must be in a position to “understand the dynamic partnership amongst human anatomy and physiology. This need to involve all major body systems with an emphasis on cardiovascular, respiratory, nervous, digestive, endocrine, urinary and musculoskeletal systems” ( p. 21). And, that they must be in a position to “evaluate and respond accordingly for the healthcare requirements of patients across the lifespan who present with acute, chronic, minor illness or injury, health-related or mental overall health emergencies” ( p. 35). It remains to be noticed how this will likely be translated by institutions and what learning students will acquire on seizures.Open Access We would acknowledge here that any curriculum would must reflect the workload of paramedics and there will likely be other presentations competing for slots within it. Dickson et al’s1 evidence could be useful here in prioritising focus. In examining 1 year of calls to a regional UK ambulance service, they found calls relating to suspected seizures were the seventh most typical, accounting for 3.3 of calls. Guidance documents and tools It’s significant to also think about what is usually carried out to help already qualified paramedics. Our second paper describes their finding out wants and how these might be addressed (FC Sherratt, et al. BMJ Open submitted). One more significant concern for them although relates to guidance. Participants said the lack of detailed national guidance on the management of postictal sufferers compounded complications. Only 230 of the 1800 words devoted to the management of convulsions in adults inside JRCALC19 relate to the management of such a state. Our findings suggest this section warrants revision. Possessing stated this, evidence from medicine shows changing and revising recommendations doesn’t necessarily imply practice will adjust,65 66 and so the effect of any changes to JRCALC need to be evaluated. Paramedic Pathfinder is a new tool and minimal evidence on its utility is offered.20 The majority of our participants mentioned it was not helpful in advertising care high quality for seizure sufferers. In no way, did it address the difficulties and challenges they reported. Certainly, one particular criticism was that the alternative care pathways it directed them to did not exist in reality. Last year eight overall health vanguards have been initiated in England. These seek to implement and discover new approaches that unique parts from the urgent and emergency care sector can function together inside a much more coordinated way.67 These may possibly give a mechanism by which to bring regarding the enhanced access to alternative care pathways that paramedics need to have.62 This awaits to be observed. Strengths and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/20363167 limitations That is the very first study to discover from a national point of view paramedics’ views and experiences of managi.

C Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA; bDivision of Hematology Oncology, Knight Cancer Institute, cDepartment of Public Health and Preventive Medicine, and dCenter for Health Care Ethics, Oregon Health Science University, Portland, Oregon, USADisclosures of potential conflicts of interest may be found at the end of this article.aDebates surrounding the appropriateness of expanded access programs and right-to-try laws center on the question of under what TAPI-2MedChemExpress TAPI-2 circumstances should cancer patients be able to receive drugs or combinations that have not fully completed the stages of drug development (not completed testing in phase I, II, or III).The commonality here is that the agent in question has not been approved for any use in the U.S. A path to the drug thus requires special logistics. However, the fundamental question raised by expanded access is a broader one. Given that many cancer drugs are approved for one indication but, once approved, can be used alone or in combination for many others, the core question of expanded access is: Under what circumstances should providers and patients be able to attempt drugs or combinations for indications for which we still lack formal clinical trials? At the outset, let us stipulate that we consider this question only as it pertains to off-protocol use of these drugs (i.e., use outside of clinical trials) and for patients who have exhausted all proventherapies.Whenclinicaltrialsareanoption,weencourage theirenrollment, and the ethics ofsuch trials has been extensively discussed. But, outside of trials, few articles have tackled the offprotocol use ofdrugsfor unapproved uses, although authors have recognized that this is a key challenge in clinical medicine [1] and such use is common. It must also be remembered that off-label use often pertains to cancer drugs with annual costs in excess of 100,000[2];thus financial implications ofthis usearelarge.As an example, one of us recently faced the question of whether, for a patient with relapsed refractory multiple myeloma, it was permissible to treat with daratumumab, a monoclonal antibody approved as single agent, in combination with pomalidomide–a combination that has demonstrated relative safety in phase I trials but lacks phase II or phase III efficacy results (i.e., no proof that the combination is better than either agent alone). Thesekinds ofquestions arefrequentlyencountered in clinical oncology, although reliable statistics are absent. For patients with relatively good performance status who are interested in pursuing more treatment but who have exhausted recommended options, many oncologists attempt single drugs or combinations that are not yet vetted. We believe that a pragmatic framework can aid in such decisions. While we admit there is no canonical answer forwhat is best, we believe consideration of three factors may frame this topic.These factors are safety, efficacy, and cost, and are TAPI-2 solubility depicted in Figure 1.SAFETYIt should be remembered that novel drugs and their combinations may have unexpected safety signals. For example, vemurafenib, a small molecule inhibitor of BRAF, and ipilimumab, an antibody against an immunologic checkpoint, are individually active in BRAF V600E mutant metastatic melanoma, but the combination demonstrated adverse hepatic toxicity in 66 ?5 of patients when combined in a phase I study, requiring the trial to be halted [3]. Notably, this toxicity could not have been predicted,.C Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA; bDivision of Hematology Oncology, Knight Cancer Institute, cDepartment of Public Health and Preventive Medicine, and dCenter for Health Care Ethics, Oregon Health Science University, Portland, Oregon, USADisclosures of potential conflicts of interest may be found at the end of this article.aDebates surrounding the appropriateness of expanded access programs and right-to-try laws center on the question of under what circumstances should cancer patients be able to receive drugs or combinations that have not fully completed the stages of drug development (not completed testing in phase I, II, or III).The commonality here is that the agent in question has not been approved for any use in the U.S. A path to the drug thus requires special logistics. However, the fundamental question raised by expanded access is a broader one. Given that many cancer drugs are approved for one indication but, once approved, can be used alone or in combination for many others, the core question of expanded access is: Under what circumstances should providers and patients be able to attempt drugs or combinations for indications for which we still lack formal clinical trials? At the outset, let us stipulate that we consider this question only as it pertains to off-protocol use of these drugs (i.e., use outside of clinical trials) and for patients who have exhausted all proventherapies.Whenclinicaltrialsareanoption,weencourage theirenrollment, and the ethics ofsuch trials has been extensively discussed. But, outside of trials, few articles have tackled the offprotocol use ofdrugsfor unapproved uses, although authors have recognized that this is a key challenge in clinical medicine [1] and such use is common. It must also be remembered that off-label use often pertains to cancer drugs with annual costs in excess of 100,000[2];thus financial implications ofthis usearelarge.As an example, one of us recently faced the question of whether, for a patient with relapsed refractory multiple myeloma, it was permissible to treat with daratumumab, a monoclonal antibody approved as single agent, in combination with pomalidomide–a combination that has demonstrated relative safety in phase I trials but lacks phase II or phase III efficacy results (i.e., no proof that the combination is better than either agent alone). Thesekinds ofquestions arefrequentlyencountered in clinical oncology, although reliable statistics are absent. For patients with relatively good performance status who are interested in pursuing more treatment but who have exhausted recommended options, many oncologists attempt single drugs or combinations that are not yet vetted. We believe that a pragmatic framework can aid in such decisions. While we admit there is no canonical answer forwhat is best, we believe consideration of three factors may frame this topic.These factors are safety, efficacy, and cost, and are depicted in Figure 1.SAFETYIt should be remembered that novel drugs and their combinations may have unexpected safety signals. For example, vemurafenib, a small molecule inhibitor of BRAF, and ipilimumab, an antibody against an immunologic checkpoint, are individually active in BRAF V600E mutant metastatic melanoma, but the combination demonstrated adverse hepatic toxicity in 66 ?5 of patients when combined in a phase I study, requiring the trial to be halted [3]. Notably, this toxicity could not have been predicted,.