The role of the human hippocampus in decision-making under uncertainty

The role of the hippocampus in decision-making is beginning to be more understood. Because of its prospective and inferential functions, we hypothesized that it might be required specifically when decisions involve the evaluation of uncertain values. A group of individuals with autoimmune limbic encephalitis—a condition known to focally affect the hippocampus—were tested on how they evaluate reward against uncertainty compared to reward against another key attribute: physical effort. Across four experiments requiring participants to make trade-offs between reward, uncertainty and effort, patients with acute limbic encephalitis demonstrated blunted sensitivity to reward and effort whenever uncertainty was considered, despite demonstrating intact uncertainty sensitivity. By contrast, the valuation of these two attributes (reward and effort) was intact on uncertainty-free tasks. Reduced sensitivity to changes in reward under uncertainty correlated with the severity of hippocampal damage. Together, these findings provide evidence for a context-sensitive role of the hippocampus in value-based decision-making, apparent specifically under conditions of uncertainty

Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT

Background Management of bone and joint infection commonly includes 4–6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes. Objective To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection. Design Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%. Setting Twenty-six NHS hospitals. Participants Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively). Interventions Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm. Main outcome measure The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data. Results Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was –1.38% (90% confidence interval –4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial. Limitations The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded. Conclusions PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy. Future work Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics. Trial registration Current Controlled Trials ISRCTN91566927. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 38. See the NIHR Journals Library website for further project information

Oral versus intravenous antibiotics for bone and joint infection

BACKGROUND The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of −1.4 percentage points (90% confidence interval [CI], −4.9 to 2.2; 95% CI, −5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927. opens in new tab.

Oral versus intravenous antibiotics for bone and joint infection

Background The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. Methods We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. Results Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of −1.4 percentage points (90% confidence interval [CI], −4.9 to 2.2; 95% CI, −5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). Conclusions Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. </p

Oral versus intravenous antibiotic treatment for bone and joint infections (OVIVA): Study protocol for a randomised controlled trial

Background: Bone and joint infection in adults arises most commonly as a complication of joint replacement surgery, fracture fixation and diabetic foot infection. The associated morbidity can be devastating to patients and costs the National Health Service an estimated £20,000 to £40,000 per patient. Methods: The OVIVA trial is a parallel group, randomised (1:1), un-blinded, non-inferiority trial conducted in thirty hospitals across the UK. Eligible participants are adults (&gt;18 years) with a clinical syndrome consistent with a bone, joint or metalware-associated infection who have received ≤7 days of intravenous antibiotic therapy from the date of definitive surgery (or the start of planned curative therapy in patients treated without surgical intervention). Participants are randomised to receive either oral or intravenous antibiotics, selected by a specialist infection physician, for the first 6 weeks of therapy. The primary outcome measure is definite treatment failure within one year of randomisation, as assessed by a blinded endpoint committee, according to pre-defined microbiological, histological and clinical criteria. Enrolling 1,050 subjects will provide 90 % power to demonstrate non-inferiority, defined as less than 7.5 % absolute increase in treatment failure rate in patients randomised to oral therapy as compared to intravenous therapy (one-sided alpha of 0.05). Discussion: If our results demonstrate non-inferiority of orally administered antibiotic therapy, this trial is likely to facilitate a dramatically improved patient experience and alleviate a substantial financial burden on healthcare services. Trial registration: ISRCTN91566927 - 14/02/201

Oral versus intravenous antibiotics for the treatment of bone and joint infection (OVIVA): a multicentre randomised controlled trial

Aim: Current standard of care in the management of bone and joint infection commonly includes a 4–6 week course of intravenous (IV) antibiotics but there is little evidence to suggest that oral antibiotic therapy results in worse outcomes. The primary objective was to determine whether oral antibiotics are non-inferior to IV antibiotics in this setting. Method: This was a parallel group, randomised (1:1), open label, non-inferiority trial across twenty-six NHS hospitals in the United Kingdom. Eligible patients were adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least six weeks of antibiotics and who had received ≤7 days of IV therapy from the date of definitive surgery (or the start of planned curative treatment in patients managed non-operatively). Participants were randomised to receive either oral or IV antibiotics for the first 6 weeks of therapy. Follow-on oral therapy was permitted in either arm. The primary outcome was the proportion of participants experiencing definitive treatment failure within one year of randomisation. The non-inferiority margin was set at 7.5%. Results: Of 1054 participants randomised (527 to each arm) endpoint data were available for 1015 (96.30%). Definitive treatment failure was identified in 141/1015 (13.89%) participants, 74/506 (14.62%) of those randomised to IV therapy and 67/509 (13.16%) of those randomised to oral therapy. In the intention to treat analysis, the imputed risk difference (PO-IV) for definitive treatment failure was −1.38% (90% CI: −4.94, 2.19), thus meeting the non-inferiority criterion (i.e. the upper limit of 95%CI being &lt;7.5%). A complete cases analysis, a per-protocol analysis and sensitivity analyses for missing data confirmed this result. With the exception of intravenous catheter complications, there was no significant difference between the two arms in the incidence of serious adverse events (SAEs). Health economic analysis suggests that the non-surgical treatment costs over one year for patients randomised to oral therapy were approximately £2,700 less than those of IV therapy. Conclusions: Oral antibiotic therapy is non-inferior to IV therapy when used during the first six weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within one year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy

Oral versus intravenous antibiotics for the treatment of bone and joint infection (OVIVA): a multicentre randomised controlled trial

Aim: Current standard of care in the management of bone and joint infection commonly includes a 4–6 week course of intravenous (IV) antibiotics but there is little evidence to suggest that oral antibiotic therapy results in worse outcomes. The primary objective was to determine whether oral antibiotics are non-inferior to IV antibiotics in this setting. Method: This was a parallel group, randomised (1:1), open label, non-inferiority trial across twenty-six NHS hospitals in the United Kingdom. Eligible patients were adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least six weeks of antibiotics and who had received ≤7 days of IV therapy from the date of definitive surgery (or the start of planned curative treatment in patients managed non-operatively). Participants were randomised to receive either oral or IV antibiotics for the first 6 weeks of therapy. Follow-on oral therapy was permitted in either arm. The primary outcome was the proportion of participants experiencing definitive treatment failure within one year of randomisation. The non-inferiority margin was set at 7.5%. Results: Of 1054 participants randomised (527 to each arm) endpoint data were available for 1015 (96.30%). Definitive treatment failure was identified in 141/1015 (13.89%) participants, 74/506 (14.62%) of those randomised to IV therapy and 67/509 (13.16%) of those randomised to oral therapy. In the intention to treat analysis, the imputed risk difference (PO-IV) for definitive treatment failure was −1.38% (90% CI: −4.94, 2.19), thus meeting the non-inferiority criterion (i.e. the upper limit of 95%CI being &lt;7.5%). A complete cases analysis, a per-protocol analysis and sensitivity analyses for missing data confirmed this result. With the exception of intravenous catheter complications, there was no significant difference between the two arms in the incidence of serious adverse events (SAEs). Health economic analysis suggests that the non-surgical treatment costs over one year for patients randomised to oral therapy were approximately £2,700 less than those of IV therapy. Conclusions: Oral antibiotic therapy is non-inferior to IV therapy when used during the first six weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within one year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy