| 1. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 3. |
- Babich, T, et al.
(författare)
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Ceftazidime, Carbapenems, or Piperacillin-tazobactam as Single Definitive Therapy for Pseudomonas aeruginosa Bloodstream Infection: A Multisite Retrospective Study
- 2020
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Ingår i: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 70:11, s. 2270-2280
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe optimal antibiotic regimen for Pseudomonas aeruginosa bacteremia is controversial. Although β-lactam monotherapy is common, data to guide the choice between antibiotics are scarce. We aimed to compare ceftazidime, carbapenems, and piperacillin-tazobactam as definitive monotherapy.MethodsA multinational retrospective study (9 countries, 25 centers) including 767 hospitalized patients with P. aeruginosa bacteremia treated with β-lactam monotherapy during 2009–2015. The primary outcome was 30-day all-cause mortality. Univariate and multivariate, including propensity-adjusted, analyses were conducted introducing monotherapy type as an independent variable.ResultsThirty-day mortality was 37/213 (17.4%), 42/210 (20%), and 55/344 (16%) in the ceftazidime, carbapenem, and piperacillin-tazobactam groups, respectively. Type of monotherapy was not significantly associated with mortality in either univariate, multivariate, or propensity-adjusted analyses (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.52–2.46, for ceftazidime; OR, 1.3; 95% CI, 0.67–2.51, for piperacillin-tazobactam, with carbapenems as reference in propensity adjusted multivariate analysis; 542 patients). No significant difference between antibiotics was demonstrated for clinical failure, microbiological failure, or adverse events. Isolation of P. aeruginosa with new resistance to antipseudomonal drugs was significantly more frequent with carbapenems (36/206 [17.5%]) versus ceftazidime (25/201 [12.4%]) and piperacillin-tazobactam (28/332 [8.4%] (P = .007).ConclusionsNo significant difference in mortality, clinical, and microbiological outcomes or adverse events was demonstrated between ceftazidime, carbapenems, and piperacillin-tazobactam as definitive treatment of P. aeruginosa bacteremia. Higher rates of resistant P. aeruginosa after patients were treated with carbapenems, along with the general preference for carbapenem-sparing regimens, suggests using ceftazidime or piperacillin-tazobactam for treating susceptible infection.
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| 6. |
- Blom, A. W., et al.
(författare)
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Clinical and cost effectiveness of single stage compared with two stage revision for hip prosthetic joint infection (INFORM): pragmatic, parallel group, open label, randomised controlled trial
- 2022
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Ingår i: Bmj-British Medical Journal. - : BMJ. - 0959-535X. ; 379
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVESTo determine whether patient reported outcomes improve after single stage versus two stage revision surgery for prosthetic joint infection of the hip, and to determine the cost effectiveness of these procedures.DESIGNPragmatic, parallel group, open label, randomised controlled trial.SETTINGHigh volume tertiary referral centres or orthopaedic units in the UK (n=12) and in Sweden (n=3), recruiting from 1 March 2015 to 19 December 2018.PARTICIPANTS 140 adults (aged a18 years) with a prosthetic joint infection of the hip who required revision (65 randomly assigned to single stage and 75 to two stage revision).INTERVENTIONS A computer generated 1:1 randomisation list stratified by hospital was used to allocate participants with prosthetic joint infection of the hip to a single stage or a two stage revision procedure.MAIN OUTCOME MEASURES The primary intention-to-treat outcome was pain, stiffness, and functional limitations 18 months after randomisation, measured by the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) score. Secondary outcomes included surgical complications and joint infection. The economic evaluation (only assessed in UK participants) compared quality adjusted life years and costs between the randomised groups.RESULTS The mean age of participants was 71 years (standard deviation 9) and 51 (36%) were women. WOMAC scores did not differ between groups at 18 months (mean difference 0.13 (95% confidence interval-8.20 to 8.46), P=0.98); however, the single stage procedure was better at three months (11.53 (3.89 to 19.17), P=0.003), but not from six months onwards. Intraoperative events occurred in five (8%) participants in the single stage group and 20 (27%) in the two stage group (P=0.01). At 18 months, nine (14%) participants in the single stage group and eight (11%) in the two stage group had at least one marker of possible ongoing infection (P=0.62). From the perspective of healthcare providers and personal social services, single stage revision was cost effective with an incremental net monetary benefit of (sic)11 167 (95% confidence interval (sic)638 to (sic)21 696) at a (sic)20 000 per quality adjusted life years threshold ((sic)1.0; $1.1; (sic) 1.4).CONCLUSIONS At 18 months, single stage revision compared with two stage revision for prosthetic joint infection of the hip showed no superiority by patient reported outcome. Single stage revision had a better outcome at three months, fewer intraoperative complications, and was cost effective. Patients prefer early restoration of function, therefore, when deciding treatment, surgeons should consider patient preferences and the cost effectiveness of single stage surgery.
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| 7. |
- Blom, A. W., et al.
(författare)
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Infection after total joint replacement of the hip and knee: research programme including the INFORM RCT
- 2022
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Ingår i: Programme Grants for Applied Research. - 2050-4322. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: People with severe osteoarthritis, other joint conditions or injury may have joint replacement to reduce pain and disability. In the UK in 2019, over 200,000 hip and knee replacements were performed. About 1 in 100 replacements becomes infected, and most people with infected replacements require further surgery. Objectives: To investigate why some patients are predisposed to joint infections and how this affects patients and the NHS, and to evaluate treatments. Design: Systematic reviews, joint registry analyses, qualitative interviews, a randomised controlled trial, health economic analyses and a discrete choice questionnaire. Setting: Our studies are relevant to the NHS, to the Swedish health system and internationally. Participants: People with prosthetic joint infection after hip or knee replacement and surgeons. Interventions: Revision of hip prosthetic joint infection with a single-or two-stage procedure. Main outcome measures: Long-term patient-reported outcomes and reinfection. Cost-effectiveness of revision strategies over 18 months from two perspectives: health-care provider and Personal Social Services, and societal. Data sources: National Joint Registry; literature databases; published cohort studies; interviews with 67 patients and 35 surgeons; a patient discrete choice questionnaire; and the INFORM (INFection ORthopaedic Management) randomised trial. Review methods: Systematic reviews of studies reporting risk factors, diagnosis, treatment outcomes and cost comparisons. Individual patient data meta-analysis. Results: In registry analyses, about 0.62% and 0.75% of patients with hip and knee replacement, respectively, had joint infection requiring surgery. Rates were four times greater after aseptic revision. The costs of inpatient and day-case admissions in people with hip prosthetic joint infection were about five times higher than those in people with no infection, an additional cost of > £30,000. People described devastating effects of hip and knee prosthetic joint infection and treatment. In the treatment of hip prosthetic joint infection, a two-stage procedure with or without a cement spacer had a greater negative impact on patient well-being than a single-or two-stage procedure with a custom-made articulating spacer. Surgeons described the significant emotional impact of hip and knee prosthetic joint infection and the importance of a supportive multidisciplinary team. In systematic reviews and registry analyses, the risk factors for hip and knee prosthetic joint infection included male sex, diagnoses other than osteoarthritis, high body mass index, poor physical status, diabetes, dementia and liver disease. Evidence linking health-care setting and surgeon experience with prosthetic joint infection was inconsistent. Uncemented fixation, posterior approach and ceramic bearings were associated with lower infection risk after hip replacement. In our systematic review, synovial fluid alpha-defensin and leucocyte esterase showed high diagnostic accuracy for prosthetic joint infection. Systematic reviews and individual patient data meta-analysis showed similar reinfection outcomes in patients with hip or knee prosthetic joint infection treated with single-and two-stage revision. In registry analysis, there was a higher rate of early rerevision after single-stage revision for hip prosthetic joint infection, but, overall, 40% fewer operations are required as part of a single-stage procedure than as part of a two-stage procedure. The treatment of hip or knee prosthetic joint infection with early debridement and implant retention may be effective in > 60% of cases. In the INFORM randomised controlled trial, 140 patients with hip prosthetic joint infection were randomised to single-or two-stage revision. Eighteen months after randomisation, pain, function and stiffness were similar between the randomised groups (p = 0.98), and there were no differences in reinfection rates. Patient outcomes improved earlier in the single-stage than in the two-stage group. Participants randomised to a single-stag procedure had lower costs (mean difference –£10,055, 95% confidence interval –£19,568 to –£542) and higher quality-adjusted life-years (mean difference 0.06, 95% confidence interval –0.07 to 0.18) than those randomised to a two-stage procedure. Single-stage was the more cost-effective option, with an incremental net monetary benefit at a threshold of £20,000 per quality-adjusted life-year of £11,167 (95% confidence interval £638 to £21,696). In a discrete choice questionnaire completed by 57 patients 18 months after surgery to treat hip prosthetic joint infection, the most valued characteristics in decisions about revision were the ability to engage in valued activities and a quick return to normal activity. Limitations: Some research was specific to people with hip prosthetic joint infection. Study populations in meta-analyses and registry analyses may have been selected for joint replacement and specific treatments. The INFORM trial was not powered to study reinfection and was limited to 18 months’ follow-up. The qualitative study subgroups were small. Conclusions: We identified risk factors, diagnostic biomarkers, effective treatments and patient preferences for the treatment of hip and knee prosthetic joint infection. The risk factors include male sex, diagnoses other than osteoarthritis, specific comorbidities and surgical factors. Synovial fluid alpha-defensin and leucocyte esterase showed high diagnostic accuracy. Infection is devastating for patients and surgeons, both of whom describe the need for support during treatment. Debridement and implant retention is effective, particularly if performed early. For infected hip replacements, single-and two-stage revision appear equally efficacious, but single-stage has better early results, is cost-effective at 18-month follow-up and is increasingly used. Patients prefer treatments that allow full functional return within 3–9 months.
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| 8. |
- Kostyanev, T., et al.
(författare)
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The Innovative Medicines Initiative's New Drugs for Bad Bugs programme : European public-private partnerships for the development of new strategies to tackle antibiotic resistance
- 2016
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 71:2, s. 290-295
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Forskningsöversikt (refereegranskat)abstract
- Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than a,not sign660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.
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| 9. |
- Kluytmans, J, et al.
(författare)
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Obituary: Johan Willem Mouton
- 2020
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Ingår i: CLINICAL MICROBIOLOGY AND INFECTION. - : Elsevier BV. - 1198-743X. ; 26:1, s. 125-126
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Mcleod, Elizabeth, et al.
(författare)
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The future of resilience-based management in coral reef ecosystems
- 2019
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Ingår i: Journal of Environmental Management. - : Elsevier BV. - 0301-4797 .- 1095-8630. ; 233, s. 291-301
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Forskningsöversikt (refereegranskat)abstract
- Resilience underpins the sustainability of both ecological and social systems. Extensive loss of reef corals following recent mass bleaching events have challenged the notion that support of system resilience is a viable reef management strategy. While resilience-based management (RBM) cannot prevent the damaging effects of major disturbances, such as mass bleaching events, it can support natural processes that promote resistance and recovery. Here, we review the potential of RBM to help sustain coral reefs in the 21st century. We explore the scope for supporting resilience through existing management approaches and emerging technologies and discuss their opportunities and limitations in a changing climate. We argue that for RBM to be effective in a changing world, reef management strategies need to involve both existing and new interventions that together reduce stress, support the fitness of populations and species, and help people and economies to adapt to a highly altered ecosystem.
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