Randomised controlled trial of a behaviour change physiotherapy intervention to increase physical activity following hip and knee replacement: the PEP-TALK trial

OBJECTIVE: To test the effectiveness of a behaviour change physiotherapy intervention to increase physical activity compared with usual rehabilitation after Total Hip Replacement (THR) or Total Knee Replacement (TKR). DESIGN: Multicentre, pragmatic, two-arm, open, randomised controlled, superiority trial SETTING National Health Service providers in nine English hospitals. PARTICIPANTS: 224 individuals aged >18 years, undergoing a primary THR or TKR deemed “moderately inactive” or “inactive”. INTERVENTION: Participants received either six, 30-minute, weekly, group-based exercise sessions (usual care), or the same six-weekly, group-based, exercise sessions each preceded by a 30-minute cognitive behaviour discussion group aimed at challenging barriers to physical inactivity following surgery (experimental). RANDOMISATION & BLINDING: Initial 75 participants were randomised 1:1 before changing the allocation ratio to 2:1 (experimental:usual care). Allocation was based on minimisation, stratifying on comorbidities, operation type and hospital. There was no blinding. MAIN OUTCOME MEASURES: Primary: UCLA Activity Score at 12 months. Secondary: six and 12 month assessed function, pain, self-efficacy, kinesiophobia, psychological distress and quality of life. RESULTS: Of the 1254 participants assessed for eligibility, 224 were included (139 experimental:85 usual care). Mean age was 68.4 years (standard deviation: 8.7), 63% were female, 52% underwent TKR. There was no between-group difference in UCLA score (mean difference: -0.03 (95% CI: -0.52 to 0.45, p=0.89)). There were no differences observed in any of the secondary outcomes at six or 12 months. There were no important adverse events in either group. The COVID-19 pandemic contributed to the reduced intended sample size (target 260) and reduced intervention compliance. CONCLUSIONS: There is no evidence to suggest attending usual care physiotherapy sessions plus a group-based behaviour change intervention differs to attending usual care physiotherapy alone. As the trial could not reach its intended sample size, nor a proportion of participants receive their intended rehabilitation, this should be interpreted with caution

Optimization of the doxycycline-dependent simian immunodeficiency virus through in vitro evolution

<p>Abstract</p> <p>Background</p> <p>Vaccination of macaques with live attenuated simian immunodeficiency virus (SIV) provides significant protection against the wild-type virus. The use of a live attenuated human immunodeficiency virus (HIV) as AIDS vaccine in humans is however considered unsafe because of the risk that the attenuated virus may accumulate genetic changes during persistence and evolve to a pathogenic variant. We earlier presented a conditionally live HIV-1 variant that replicates exclusively in the presence of doxycycline (dox). Replication of this vaccine strain can be limited to the time that is needed to provide full protection through transient dox administration. Since the effectiveness and safety of such a conditionally live virus vaccine should be tested in macaques, we constructed a similar dox-dependent SIV variant. The Tat-TAR transcription control mechanism in this virus was inactivated through mutation and functionally replaced by the dox-inducible Tet-On regulatory system. This SIV-rtTA variant replicated in a dox-dependent manner in T cell lines, but not as efficiently as the parental SIVmac239 strain. Since macaque studies will likely require an efficiently replicating variant, we set out to optimize SIV-rtTA through in vitro viral evolution.</p> <p>Results</p> <p>Upon long-term culturing of SIV-rtTA, additional nucleotide substitutions were observed in TAR that affect the structure of this RNA element but that do not restore Tat binding. We demonstrate that the bulge and loop mutations that we had introduced in the TAR element of SIV-rtTA to inactivate the Tat-TAR mechanism, shifted the equilibrium between two alternative conformations of TAR. The additional TAR mutations observed in the evolved variants partially or completely restored this equilibrium, which suggests that the balance between the two TAR conformations is important for efficient viral replication. Moreover, SIV-rtTA acquired mutations in the U3 promoter region. We demonstrate that these TAR and U3 changes improve viral replication in T-cell lines and macaque peripheral blood mononuclear cells (PBMC) but do not affect dox-control.</p> <p>Conclusion</p> <p>The dox-dependent SIV-rtTA variant was optimized by viral evolution, yielding variants that can be used to test the conditionally live virus vaccine approach and as a tool in SIV biology studies and vaccine research.</p

Construction of a doxycycline-dependent simian immunodeficiency virus reveals a nontranscriptional function of tat in viral replication

In the quest for an effective vaccine against human immunodeficiency virus (HIV), live attenuated virus vaccines have proven to be very effective in the experimental model system of simian immunodeficiency virus (SIV) in macaques. However, live attenuated HIV vaccines are considered unsafe for use in humans because the attenuated virus may accumulate genetic changes during persistence and evolve to a pathogenic variant. As an alternative approach, we earlier presented a conditionally live HIV-1 variant that replicates exclusively in the presence of doxycycline (DOX). Replication of this vaccine strain can be limited to the time that is needed to provide full protection through transient DOX administration. Since the effectiveness and safety of such a conditionally live AIDS vaccine should be tested in macaques, we constructed a similar DOX-dependent SIVmac239 variant in which the Tat-TAR (trans-acting responsive) transcription control mechanism was functionally replaced by the DOX-inducible Tet-On regulatory mechanism. Moreover, this virus can be used as a tool in SIV biology studies and vaccine research because both the level and duration of replication can be controlled by DOX administration. Unexpectedly, the new SIV variant required a wild-type Tat protein for replication, although gene expression was fully controlled by the incorporated Tet-On system. This result suggests that Tat has a second function in SIV replication in addition to its role in the activation of transcriptio

Who should pay for global health, and how much?

Roman Carrasco and colleagues propose a "cap and trade" system for global health involving a cost-effectiveness criterion and a DALY global credit market, mirroring global carbon emission permits trading markets to mitigate climate change

Optimization of the doxycycline-dependent simian immunodeficiency virus through in vitro evolution-1

From 13 independent cultures at different times and the LTR region was subsequently PCR amplified and sequenced. The number of the culture (#) and the day of sampling are indicated on the left. The -90 to +130 U3/R region is shown with +1 indicating the transcription initiation site. The Sp1 and TATA box are shown in grey. The mutations that were introduced in TAR to abolish Tat-responsiveness are underlined. The additional nucleotide substitutions and deletions (Δ) observed in the SIV-rtTA cultures are indicated.<p><b>Copyright information:</b></p><p>Taken from "Optimization of the doxycycline-dependent simian immunodeficiency virus through in vitro evolution"</p><p>Retrovirology 2008;5():44-44.</p><p>Published online 5 Jun 2008</p><p>PMCID:PMC2443169.</p><p></p

Optimization of the doxycycline-dependent simian immunodeficiency virus through in vitro evolution-3

Constructs corresponding to the original and evolved SIV-rtTA variants and an rtTA-expressing plasmid. After two days of culturing with 0 to 1000 ng/ml dox, the intracellular luciferase level, which reflects promoter activity, was measured. The error bar represents the standard deviation (SD) for 3 to 8 experiments (B) To assay Tat responsiveness, C33A cells were transfected with the promoter/luciferase plasmids and 0 to 50 ng SIV Tat-expressing plasmid. Two days after transfection, the promoter activity was analyzed by measuring the intracellular luciferase activity. The error bar represents the SD for 2 to 4 experiments. (C) 293T cells were transfected with the SIV-rtTA proviral constructs and cultured for two days with or without dox. Virus production was quantified by measuring the CA-p27 level in the culture supernatant. The error bar represents the standard deviation for 2 experiments.<p><b>Copyright information:</b></p><p>Taken from "Optimization of the doxycycline-dependent simian immunodeficiency virus through in vitro evolution"</p><p>Retrovirology 2008;5():44-44.</p><p>Published online 5 Jun 2008</p><p>PMCID:PMC2443169.</p><p></p