Klinička praksa temeljena na dokazima: pregled prijetnji valjanosti dokaza i kako ih spriječiti

Using the best quality of clinical research evidence is essential for choosing the right treatment for patients. How to identify the best research evidence is, however, difficult. In this narrative review we summarise these threats and describe how to minimise them. Pertinent literature was considered through literature searches combined with personal files. Treatments should generally not be chosen based only on evidence from observational studies or single randomised clinical trials. Systematic reviews with meta-analysis of all identifiable randomised clinical trials with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment represent the highest level of evidence. Even though systematic reviews are trust worthier than other types of evidence, all levels of the evidence hierarchy are under threats from systematic errors (bias); design errors (abuse of surrogate outcomes, composite outcomes, etc.); and random errors (play of chance). Clinical research infrastructures may help in providing larger and better conducted trials. Trial Sequential Analysis may help in deciding when there is sufficient evidence in meta-analyses. If threats to the validity of clinical research are carefully considered and minimised, research results will be more valid and this will benefit patients and heath care systems.Primjena najkvalitetnijih dokaza kliničkih istraživanja ključna je u odabiru ispravnog liječenja pacijenata. No, način na koji će se odabrati najbolji dokazi predstavlja često poteškoću. Ovim preglednim člankom prikazujemo opasnosti navedenog odabira, kao i načine kako ih umanjiti. Relevantni izvori razmatrani su pretragom literature u kombinaciji s osobnim datotekama. Izbor liječenja uglavnom se ne bi smio temeljiti isključivo na opservacijskim ili pojedinačnim randomiziranim kliničkim studijama. Sustavni pregledi s metaanalizom svih identificiranih randomiziranih kliničkih studija procijenjenih sustavom stupnjevanja procjene, razvoja i evaluacije preporuka (engl. Grading of Recommendations Assessment, Development and Evaluation; GRADE) predstavljaju najvišu razinu dokaza. Iako su sustavni pregledi pouzdaniji od drugih vrsta dokaza, sve razine hijerarhije dokaza ugrožene su sustavnim pogreškama (engl. bias); pogreškama dizajna studije (zloupotreba surogatnih ishoda, složenih ishoda itd.) i slučajnim pogreškama (igra slučaja). Kliničke istraživačke infrastrukture mogu pomoći u pružanju većih i adekvatnije provedenih ispitivanja. Sekvencijska analiza studija može pomoći pri odlučivanju kada postoji dovoljna razina dokaza u metaanalizama. Ako se prijetnje valjanosti kliničkih istraživanja pažljivo razmatraju i minimiziraju, rezultati istraživanja bit će vrjedniji i korisniji pacientima i zdravstvenim sustavima

A Phase I Double Blind, Placebo-Controlled, Randomized Study of a Multigenic HIV-1 Adenovirus Subtype 35 Vector Vaccine in Healthy Uninfected Adults

<div><h3>Background</h3><p>We conducted a phase I, randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of escalating doses of two recombinant replication defective adenovirus serotype 35 (Ad35) vectors containing gag, reverse transcriptase, integrase and nef (Ad35-GRIN) and env (Ad35-ENV), both derived from HIV-1 subtype A isolates. The trial enrolled 56 healthy HIV-uninfected adults.</p> <h3>Methods</h3><p>Ad35-GRIN/ENV (Ad35-GRIN and Ad35-ENV mixed in the same vial in equal proportions) or Ad35-GRIN was administered intramuscularly at 0 and 6 months. Participants were randomized to receive either vaccine or placebo (10/4 per group, respectively) within one of four dosage groups: Ad35-GRIN/ENV 2×10⁹ (A), 2×10¹⁰ (B), 2×10¹¹ (C), or Ad35-GRIN 1×10¹⁰ (D) viral particles.</p> <h3>Results</h3><p>No vaccine-related serious adverse event was reported. Reactogenicity events reported were dose-dependent, mostly mild or moderate, some severe in Group C volunteers, all transient and resolving spontaneously. IFN-γ ELISPOT responses to any vaccine antigen were detected in 50, 56, 70 and 90% after the first vaccination, and in 75, 100, 88 and 86% of Groups A–D vaccine recipients after the second vaccination, respectively. The median spot forming cells (SFC) per 10⁶ PBMC to any antigen was 78–139 across Groups A–C and 158–174 in Group D, after each of the vaccinations with a maximum of 2991 SFC. Four to five HIV proteins were commonly recognized across all the groups and over multiple timepoints. CD4+ and CD8+ T-cell responses were polyfunctional. Env antibodies were detected in all Group A–C vaccinees and Gag antibodies in most vaccinees after the second immunization. Ad35 neutralizing titers remained low after the second vaccination.</p> <h3>Conclusion/Significance</h3><p>Ad35-GRIN/ENV reactogenicity was dose-related. HIV-specific cellular and humoral responses were seen in the majority of volunteers immunized with Ad35-GRIN/ENV or Ad35-GRIN and increased after the second vaccination. T-cell responses were broad and polyfunctional.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/results?term=NCT00851383">NCT00851383</a></p> </div

Safety and Adherence to Intermittent Pre-Exposure Prophylaxis (PrEP) for HIV-1 in African Men Who Have Sex with Men and Female Sex Workers

Background Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). Methods/Principal Findings MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a onemonth recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63–92] for daily dosing and 55% [IQR:28–78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14–50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Conclusions/Significance Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens</p

Negative bulk modulus and possibility of loss of elastic stability near tricritical transitions in thin films on substrates

Within the Landau-like approach we study anomalies of elastic moduli at phase transitions in thin films on substrates. We consider the case where, similar to many experimental cases, the first-order transition in free crystal would convert into a second order in the film if the system remained homogeneous. It is shown, however, that apart from its questionable thermodynamic advantages, the homogeneous state of low-symmetry phase may become absolutely unstable which is signaled by changing of sign of its bulk modulus

Loss of elastic stability and formation of inhomogeneous states at phase transitions in thin films on substrates

Within the Landau-like approach we study stability of homogeneous states near phase transitions in thin films on substrates. The order parameter is electrically neutral in order to exclude the effects of the depolarizing fields and concentrate on the elasticity effects. We consider the case where the first-order transition in free crystal would convert into a second order when in the film on a substrate if the system remained homogeneous. Limit of stability of the homogeneous state is found analytically, though approximately. Numerical simulations provide qualitatively similar results and reveal temperature evolution of the arising inhomogeneities

Effects of the depolarization field in a perforated film of the biaxial ferroelectric

The domain structure in a biaxial ferroelectric layer perforated by cylindrical channels has been investigated using the numerical simulation based on the phenomenological theory of ferroelectricity and the equations of electrostatics in the framework of the Gauss-Seidel iterative method. Both polar axes lie in the plane of the film, which is characteristic of thin epitaxial films of BaTiO3 and (Ba1-xSrx )TiO3 on a MgO substrate. The calculations have been performed using the parameters of BaTiO3, which does not matter because of the qualitative character of the results: the electrostatic problem is two-dimensional and formally applies to infinitely thick layers rather than to thin layers. The primary attention has been paid to the systems containing sixteen channels. Two different orientations of the polar axes with respect to the lattice channels have been considered. It has been shown that, for these orientations, the domain structure has a different character: when the line with the minimum distance between the channels is perpendicular to the bisector of the angle between the polar axes, this structure contains a single channel in the repeating motif and a polarization vortex; when one of the polar axes is perpendicular to the line with the minimum distance between the channels, the situation is less clear. There are indications that the repeating motif of the domain structure in a system of many channels contains two channels and does not contain vortices. The strong influence of the electrodes on the domain structure in this case has been noted

Electrocaloric properties of epitaxial strontium titanate films

The electrocaloric (EC) response of strontium titanate thin films is computed as a function of misfit strain, temperature, electric field strength, and electrode configuration using a nonlinear thermodynamic theory. For films in a capacitor configuration on compressive substrates, the transition between paraelectric and strain-induced ferroelectric tetragonal phases produces a large adiabatic temperature change, Delta T = 5K, at room temperature for electric field changes Delta E = 1200 kV/cm. For films on tensile substrates, the transition between the paraelectric and strain-induced ferroelectric orthorhombic phases can also be accessed using inter-digitated electrodes (IDEs). The maximum EC response occurs for IDEs with a [110] orientation

Potential barrier increase due to Gd doping of BiFeO3 layers in Nb:SrTiO3-BiFeO3-Pt structures displaying diode-like behavior

The rectifying properties of Nb:SrTiO3-Bi1-xGdxFeO3-Pt structures (x = 0, 0.05, 0.1) displaying diode-like behavior were investigated via current-voltage characteristics at different temperatures. The potential barrier was estimated for negative polarity assuming a Schottky-like thermionic emission with injection controlled by the interface and the drift controlled by the bulk. The height of the potential barrier at the Nb:SrTiO3-Bi1-xGdxFeO3 interface increases with Gd doping. The results are explained by the partial compensation of the p-type conduction due to Bi vacancies with Gd doping in addition to the shift of the Fermi level towards the middle of the bandgap with increasing dopant concentration