Current recommendations indicate the use of HIV-1 drug resistance genotyping in the treatment of HIV-1 infection, primarily on treatment failure, and in specific instances also before the initiation of therapy. As such, HIV-1 genotyping is becoming a standard of care parameter in HIV-1 treatment monitoring and a rapidly increasing number of laboratories now use this technology routinely. A study of proficiency, using the ENVA-2 panel, was performed to evaluate the current HIV-1 resistance genotyping quality in 34 laboratories from different parts of the world. The results demonstrated extensive interlaboratory variation in the quality of genotyping and a significant underestimation of resistance mutations, even in samples expressing pure mutant genotype. The level of variation could not be attributed to the sequencing technology used and was therefore considered to be laboratory associated. The direct clinical consequences of this may be inadequate treatment of HIV-1-infected individuals and a more rapid exhaustion of therapeutic options for the patients. Drug resistance mutations are frequently missed. Therefore, quality control programs are urgently needed. Until these are widely implemented, clinicians must consider this issue and interpret the reported genotyping results with caution.

Exposure of human immunodeficiency virus to the nucleoside analogue lamivudine (3TC) rapidly selects for resistant variants with a valine at codon 184 (M184V) in the catalytic site of reverse transcriptase. In vitro, 184V demonstrated increased enzyme fidelity and suppressed zidovudine resistance. Clinical trials demonstrated that 3TC-zidovudine combination therapy results in a strong and sustained antiviral response. To investigate the role of 184V on in vivo virus evolution, the effect of zidovudine addition in 3TC-pretreated patients harboring 184V was studied. In vivo, no significant change in fidelity was observed with 184V, shown by generation of the classical pattern of zidovudine mutations. Of interest, in contrast to zidovudine monotherapy, in which just one substitution is sufficient for in vivo development of significant zidovudine resistance, multiple substitutions are required for the same level of zidovudine resistance in strains harboring 184V. This need for multiple substitutions may be one of the mechanisms explaining the sustained antiretroviral response of the 3TC-zidovudine combination.

A panel (ENVA-1) of well-defined blinded samples containing wild-type and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase was analyzed by automated DNA sequencing in 23 laboratories worldwide. Drug resistance mutations at codons 41, 215, and 184 were present in the panel samples at different ratios to the wild type. The presence of mutant genotypes was determined qualitatively and quantitatively. All laboratories reported the presence of sequence heterogeneities at codons 41, 215, and 184 in one or more of the panel samples, though not all reported the correct codon genotypes. Two laboratories reported a mutant genotype in samples containing only the wild type, whereas two and three laboratories failed to detect the mutant genotypes at codons 41 and 215, respectively, in a completely mutant DNA population. Mutations present at relative concentrations of 25% of the total DNA population were successfully identified by 13 of 23, 10 of 23, and 16 of 23 labs for codons 41, 215, and 184Val, respectively. For more than 80% of those laboratories that qualitatively detected the presence of a mutation correctly, the estimated wild type/mutant ratio was less than 25% different from the input ratio in those samples containing 25 to 50% or 75% mutant input. This first multicenter study on the quality of DNA sequencing approaches for identifying HIV-1 drug resistance mutations revealed large interlaboratory differences in the quality of the results. The application of these procedures in their current state would in several cases lead to inaccurate or even incorrect diagnostic results. Therefore, proper quality control and standardization are urgently needed.

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These data show that, in contrast to didanosine and zidovudine, the pressure exerted by 3TC is similar for SI and NSI M184 populations.

Previous research showed that an Inertial Measurement Unit (IMU) on the anterior side of the shank can accurately measure the Shank-to-Vertical Angle (SVA), which is a clinically-used parameter to guide tuning of ankle-foot orthoses (AFOs). However, in this context it is specifically important that differences in the SVA are detected during the tuning process, i.e., when adjusting heel height. This study investigated the validity of the SVA as measured by an IMU and its responsiveness to changes in AFO-footwear combination (AFO-FC) heel height in persons with incomplete spinal cord injury (iSCI). Additionally, the effect of heel height on knee flexion-extension angle and internal moment was evaluated. Twelve persons with an iSCI walked with their own AFO-FC in three different conditions: (1) without a heel wedge (refHH), (2) with 5 mm heel wedge (lowHH) and (3) with 10 mm heel wedge (highHH). Walking was recorded by a single IMU on the anterior side of the shank and a 3D gait analysis (3DGA) simultaneously. To estimate validity, a paired t-test and intraclass correlation coefficient (ICC) between the SVAIMU and SVA3DGA were calculated for the refHH. A repeated measures ANOVA was performed to evaluate the differences between the heel heights. A good validity with a mean difference smaller than 1 and an ICC above 0.9 was found for the SVA during midstance phase and at midstance. Significant differences between the heel heights were found for changes in SVAIMU (p = 0.036) and knee moment (p = 0.020) during the midstance phase and in SVAIMU (p = 0.042) and SVA3DGA (p = 0.006) at midstance. Post-hoc analysis revealed a significant difference between the ref and high heel height condition for the SVAIMU (p = 0.005) and knee moment (p = 0.006) during the midstance phase and for the SVAIMU (p = 0.010) and SVA3DGA (p = 0.006) at the instant of midstance. The SVA measured with an IMU is valid and responsive to changing heel heights and equivalent to the gold standard 3DGA. The knee joint angle and knee joint moment showed concomitant changes compared to SVA as a result of changing heel height.

The widespread use of private military and security companies (PMSCs) in United Nations peacebuilding missions often undermines the effectiveness of these missions. PMSCs tend to encourage, in unnecessary ways, what is called security risk management and promote the militarization of humanitarian efforts. They encourage humanitarian aid organizations to protect their personnel with barbed wire fences, security guards, armed convoys, and secure aid compounds, even if the security risks are relatively low. Consequently, these militarized humanitarian efforts heighten the perception of risks and intensify security measures, which create physical and psychological barriers between humanitarian aid personnel and the local communities in which they carry out their tasks. This situation undermines local ownership of peacebuilding efforts and makes them less responsive to the local communities involved in these efforts. This article provides a comparative analysis of the nature of this problem and its effects in the Global South.