Primary constrained and hinged total knee arthroplasty: 2- and 5-year revision risk compared with unconstrained total knee arthroplasty: a report on 401 cases from the Norwegian Arthroplasty Register 1994-2017

Background and purpose — The number of primary, highly constrained knee arthroplasty implants has increased with a theoretically increased risk of early failure. Therefore we analyzed the risk of all revision following total knee arthroplasty (TKA) in patients receiving a hinged or condylar constrained knee (CCK) compared with a conventional unconstrained TKA. Patients and methods — The analyses included 401 primary highly constrained or hinged implants from 1994 to 2017. Kaplan–Meier survival curves were used to evaluate time to first revision with a maximum follow-up of 20 years. Cox regression was used to calculate hazard ratio (HR) comparing condylar constrained knee (CCK), hinged, and unconstrained TKA. Results — Kaplan–Meier estimated prosthesis survival after 2 years was 94.8% (95% CI 91.4–98.2) and 93.5% after 5 years for the primary CCK and 91.0% (CI 86.6–95.4) after 2 years and 85.5% after 5 years for the primary hinged TKA. Adjusted for sex, age groups, diagnosis, time period, previous surgery, and surgery time HR was 1.4 (CI 0.8–2.3) for the CCK and 2.4 (CI 1.6–3.7) for the hinged implants. The most common cause of revision in hinged implants was infection: 14 of 22 revisions. When excluding infection as revision cause, there were no differences in survival between the implant types. Estimated survival excluding infection revisions at 5 years was 96% for unconstrained, CCK, and hinged primary TKA implants. Interpretation — Primary rotating hinge total knee arthroplasty had a higher risk of revision compared with conventional TKA after 2 and 5 years’ follow-up. Infection was the most common cause of revision. When excluding infection revisions from the survival analysis, hinged and CCK implants had similar performance to unconstrained TKA.publishedVersio

Genetic and Molecular Functional Characterization of Variants within TNFSF13B, a Positional Candidate Preeclampsia Susceptibility Gene on 13q

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Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections

Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα–remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections

Antibiotic-loaded bone cement in prevention of periprosthetic joint infections in primary total knee arthroplasty: A register-based multicentre randomised controlled non-inferiority trial (ALBA trial)

Introduction The current evidence on the efficacy of antibiotic-loaded bone cement (ALBC) in reducing the risk of periprosthetic joint infections (PJI) after primary joint reconstruction is insufficient. In several European countries, the use of ALBC is routine practice unlike in the USA where ALBC use is not approved in low-risk patients. Therefore, we designed a double-blinded pragmatic multicentre register-based randomised controlled non-inferiority trial to investigate the effects of ALBC compared with plain bone cement in primary total knee arthroplasty (TKA). Methods and analysis A minimum of 9,172 patients undergoing full-cemented primary TKA will be recruited and equally randomised into the ALBC group and the plain bone cement group. This trial will be conducted in Norwegian hospitals that routinely perform cemented primary TKA. The primary outcome will be risk of revision surgery due to PJI at 1-year of follow-up. Secondary outcomes will be: risk of revision due to any reason including aseptic loosening at 1, 6, 10 and 20 years of follow-up; patient-related outcome measures like function, pain, satisfaction and health-related quality of life at 1, 6 and 10 years of follow-up; risk of changes in the microbial pattern and resistance profiles of organisms cultured in subsequent revisions at 1, 6, 10 and 20 years of follow-up; cost-effectiveness of routine ALBC versus plain bone cement use in primary TKA. We will use 1:1 randomisation with random permuted blocks and stratify by participating hospitals to randomise patients to receive ALBC or plain bone cement. Inclusion, randomisation and follow-up will be through the Norwegian Arthroplasty Register. Ethics and dissemination The trial was approved by the Western Norway Regional Committees on Medical and Health Research Ethics (reference number: 2019/751/REK vest) on 21 June 2019. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations. Trial registration number NCT04135170.publishedVersio

Genetic Susceptibility to Preeclampsia : Studies on the Nord-Trøndelag Health Study (HUNT) Cohort, an Australian/New Zealand Family Cohort and Decidua Basalis Tissue

Genetisk disposisjon for utvikling av svangerskapsforgiftning : Studier fra Helseundersøkelsen i Nord-Trøndelag, en familiekohort fra Australia/New Zealand og decidua basalis vev Svangerskapsforgiftning er en alvorlig komplikasjon ved graviditet, og på verdensbasis bidrar tilstanden til økt sykelighet og dødelighet for både mor og foster. Både arvelige og miljø-/livsstilsfaktorer kan påvirke risikoen for utvikling av svangerskapsforgiftning. Selv om det fortsatt er uklart hva som forårsaker sykdommen, har forståelsen økt de siste årene, og genetisk forskning har vært en viktig bidragsyter i dette. Når morkaken fester seg til livmorveggen, bryter morkakens celler ned muskellaget i livmorens forsynende blodårer, slik at morkaken etter hvert får god blodgjennomstrømning med tilgang på surstoff og næring til fosteret. Et uheldig samspill mellom fosteret og mors immunsystem ser ut til å være sentralt i sykdomsutviklingen ved svangerskapsforgiftning. Det kliniske bildet er preget av en overdrevet betennelsesreaksjon og sirkulatoriske forandringer. Dette sees også ved hjerte-kar lidelser, og svangerskapsforgiftning deler mange risikofaktorer med disse sykdommene. Kvinner som har hatt svangerskapsforgiftning har dessuten økt risiko for hjerte-kar lidelser senere i livet. Svangerskapsforgiftning viser en klar opphopning i familier, og ulike modeller for det genetiske bakteppet er blitt foreslått. Etter at man kartla hele den menneskelige arvestoffsekvensen (2003) kunne man begynne å analysere markører som er spredt i hele arvestoffet for å finne områder som påvirker risikoen for komplekse sykdommer som kreft, hjerte-kar sykdom og svangerskapsforgiftning. Da man begynte dette arbeidet trodde man at man i fremtiden ville kunne forutse sykdom hos enkeltpersoner ved å lese arvestoffsekvensen deres. Nå, syv år senere, har den teknologiske utviklingen snart gjort det mulig å lese hele arvestoffsekvensen til en person relativt raskt og til en overkommelig pris. Den genetiske forskningen som er gjort i løpet av disse årene har imidlertid endret vårt syn både på hvor stabilt og upåvirkelig arvestoffet er, og på hvor allmenn variasjonen som kan gi sykdom er. Med utgangspunkt i den andre Helseundersøkelsen i Nord-Trøndelag (HUNT2) og Norsk Fødselsregister, har vi identifisert en relativt stor populasjonskohort av kvinner som har hatt svangerskapsforgiftning og kvinner som har hatt normale svangerskap. Kohorten er godt kartlagt med epidemiologiske data og vi har tilgang til blodprøver med mulighet for analyse av biokjemiske markører og isolering av arvestoff. Dette har gjort det mulig for oss å evaluere genetiske funn gjort i andre populasjoner. Vi har også undersøkt det globale genuttrykket i en samling av prøver tatt fra decidua basalis, møtepunktet for morkake og livmorvegg/mors blodårer, hos kvinner med kompliserte og normale svangerskap. De funnene som presenteres i artiklene inkludert i denne tesen må sees i sammenheng med annen forskning for å kunne bidra til en økt forståelse av det genetiske og biologiske grunnlaget for svangerskapsforgiftning. Resultatene støtter teorien om at en forstyrret immunbalanse har betydning. Vi har knyttet TNFSF13B, et gen som er med på å regulere immuncellers aktiveringsgrad og funksjon, til svangerskapsforgiftning i den australske familiekohorten. Tidligere har dette genet vært vist å disponere for spontanabort. Vi viser også at en av de biologiske prosessene som ser ut til å være mest forstyrret ved svangerskapsforgiftning, er tryptofan metabolismen, som har betydning for normal utvikling av immunceller. Både STOX1 og notch signalveier er involvert i nydannelse av blodårer og har vært knyttet til både svangerskapsforgiftning og nevrodegenerative sykdommer. Det er derfor fremsatt en teori om at disse tilstandene kan ha et felles genetisk grunnlag, og våre observasjoner støtter betydningen av disse prosessene for utvikling av svangerskapsforgiftning. Variasjon i COMT  genet har vært vist å ha betydning både for utvikling av hjerte-kar sykdom og svangerskapsforgiftning, via regulering av cellens respons på lav oksygentilførsel. Vi bekrefter at dette genet kan bidra til risiko for svangerskapsforgiftning. Flere av forandringen som vi finner i genuttrykks studien bekrefter også den tette forbindelsen mellom oksygenering-reoksygenerings skader og svangerskapsforgiftning. Oppsummert har vi i løpet av de årene dette prosjektet har pågått opplevd en revolusjon i hvordan vi ser på genetisk variasjon som grunnlag for sykdomsutvikling. Vi har også opplevd en økende forståelse for de biologiske mekanismene som ligger bak utvikling av svangerskapsforgiftning. De funnene som presenteres her bidrar til noe av denne økte forståelsen og åpner for flere nye spørsmål. Videre forskning på dette feltet er nødvendig.

Primary constrained and hinged total knee arthroplasty: 2- and 5-year revision risk compared with unconstrained total knee arthroplasty: a report on 401 cases from the Norwegian Arthroplasty Register 1994-2017

Background and purpose — The number of primary, highly constrained knee arthroplasty implants has increased with a theoretically increased risk of early failure. Therefore we analyzed the risk of all revision following total knee arthroplasty (TKA) in patients receiving a hinged or condylar constrained knee (CCK) compared with a conventional unconstrained TKA. Patients and methods — The analyses included 401 primary highly constrained or hinged implants from 1994 to 2017. Kaplan–Meier survival curves were used to evaluate time to first revision with a maximum follow-up of 20 years. Cox regression was used to calculate hazard ratio (HR) comparing condylar constrained knee (CCK), hinged, and unconstrained TKA. Results — Kaplan–Meier estimated prosthesis survival after 2 years was 94.8% (95% CI 91.4–98.2) and 93.5% after 5 years for the primary CCK and 91.0% (CI 86.6–95.4) after 2 years and 85.5% after 5 years for the primary hinged TKA. Adjusted for sex, age groups, diagnosis, time period, previous surgery, and surgery time HR was 1.4 (CI 0.8–2.3) for the CCK and 2.4 (CI 1.6–3.7) for the hinged implants. The most common cause of revision in hinged implants was infection: 14 of 22 revisions. When excluding infection as revision cause, there were no differences in survival between the implant types. Estimated survival excluding infection revisions at 5 years was 96% for unconstrained, CCK, and hinged primary TKA implants. Interpretation — Primary rotating hinge total knee arthroplasty had a higher risk of revision compared with conventional TKA after 2 and 5 years’ follow-up. Infection was the most common cause of revision. When excluding infection revisions from the survival analysis, hinged and CCK implants had similar performance to unconstrained TKA

The risk of revision in total knee arthroplasty is not affected by previous high tibial osteotomy

Background and purpose — Previous studies have found different outcomes after revision of knee arthroplasties performed after high tibial osteotomy (HTO). We evaluated the risk of revision of total knee arthroplasty with or without previous HTO in a large registry material. Patients and methods — 31,077 primary TKAs were compared with 1,399 TKAs after HTO, using Kaplan-Meier 10-year survival percentages and adjusted Cox regression analysis. Results — The adjusted survival analyses showed similar survival in the 2 groups. The Kaplan-Meier 10-year survival was 93.8% in the primary TKA group and 92.6% in the TKA-post-HTO group. Adjusted RR was 0.97 (95% CI: 0.77–1.21; p = 0.8). Interpretation — In this registry-based study, previous high tibial osteotomy did not appear to compromise the results regarding risk of revision after total knee arthroplasty compared to primary knee arthroplasty

Patient and surgical factors affecting procedure duration and revision risk due to deep infection in primary total knee arthroplasty

Abstract Background The aim of this study was to assess which patient and procedure factors affected both the risk of infection as well as procedure duration. Additionally, to assess if procedure duration affected the revision risk due to deep infection in total knee arthroplasty (TKA) patients and in a subgroup of low-risk patients. Methods 28,262 primary TKA with 311 revisions due to deep infection were included from the Norwegian Arthroplasty Register (NAR) and analysed from primary surgery from 2005 until 31st December 2015 with a 1 and 4 year follow up. The risk of revision due to deep infection was calculated in a multivariable Cox regression model including patient and procedure related risk factors, assessing Hazard Ratio (HR) with 95% confidence interval (CI). Results Multivariate analysis showed statistically significant associations with revision due to deep infection and increased procedure duration for male patients, ASA3+ (American Society of Anesthesiologists) and perioperative complications. Procedure duration ≥110 min (75 percentile) had a higher risk of deep infection compared to duration <75 min (25 percentile), in the unadjusted analysis (HR = 1.8, 95% CI 1.3-2.5, p = 0.001) and in the adjusted analysis (HR = 1.5, 95% CI 1.0-2.1, p = 0.03). For low-risk patients, procedure duration did not increase the risk of infection. Conclusion Male patients, ASA 3+ patients and perioperative complications were risk factors both for longer procedure duration and for deep infection revisions. Patients with a high degree of comorbidity, defined as ASA3+, are at risk of infection with longer procedure durations. The occurrence of perioperative complications potentially leading to a more complex and lengthy procedure was associated with a higher risk of infection. Long procedure duration in itself seems to have minor impact on infection since we found no association in the low-risk patient

Patient and surgical factors affecting procedure duration and revision risk due to deep infection in primary total knee arthroplasty.

Background The aim of this study was to assess which patient and procedure factors affected both the risk of infection as well as procedure duration. Additionally, to assess if procedure duration affected the revision risk due to deep infection in total knee arthroplasty (TKA) patients and in a subgroup of low-risk patients. Methods 28,262 primary TKA with 311 revisions due to deep infection were included from the Norwegian Arthroplasty Register (NAR) and analysed from primary surgery from 2005 until 31st December 2015 with a 1 and 4 year follow up. The risk of revision due to deep infection was calculated in a multivariable Cox regression model including patient and procedure related risk factors, assessing Hazard Ratio (HR) with 95% confidence interval (CI). Results Multivariate analysis showed statistically significant associations with revision due to deep infection and increased procedure duration for male patients, ASA3+ (American Society of Anesthesiologists) and perioperative complications. Procedure duration ≥110 min (75 percentile) had a higher risk of deep infection compared to duration <75 min (25 percentile), in the unadjusted analysis (HR = 1.8, 95% CI 1.3-2.5, p = 0.001) and in the adjusted analysis (HR = 1.5, 95% CI 1.0-2.1, p = 0.03). For low-risk patients, procedure duration did not increase the risk of infection. Conclusion Male patients, ASA 3+ patients and perioperative complications were risk factors both for longer procedure duration and for deep infection revisions. Patients with a high degree of comorbidity, defined as ASA3+, are at risk of infection with longer procedure durations. The occurrence of perioperative complications potentially leading to a more complex and lengthy procedure was associated with a higher risk of infection. Long procedure duration in itself seems to have minor impact on infection since we found no association in the low-risk patient