•In the last decade, resistance in HIV-DNA was 35% in Italy.•Resistance in HIV-DNA was stable over the period 2010-2021.•Complex treatment history was associated with resistance in HIV-DNA.•APOBEC ...editing was found in around one quarter of HIV-DNA sequences.
We aimed at evaluating the temporal trend of drug-resistance and APOBEC editing from HIV-DNA genotypic resistance tests (GRT) in virologically suppressed individuals.
Major resistance mutations (MRM), genotypic susceptibility score (GSS) for the current regimen and APOBEC-related mutations (APO-M) were evaluated. Potential changes in trends of MRM and APO-M over-time were assessed and predictors of MRM detection or sub-optimal GSS (GSS<2) at HIV-DNA-GRT were estimated through logistic regression analyses.
Among the 1126 individuals included, 396 (35.2%) harboured at least one MRM (23.4% to NRTI, 18.8% to NNRTI, 7.7% to PI and 1.4% to INSTI N=724); 132 (12.3%) individuals showed a GSS <2. APO-M and stop codons were found in 229 (20.3%) and 105 (9.3%) individuals, respectively. APO-DRMs were found in 16.8% of individuals and were more likely observed in those individuals with stop codons (40.0%) compared to those without (14.4%, P<0.001). From 2010 to 2021 no significant changes of resistance or APO-M were found. Positive predictors of MRM detection at HIV-DNA GRT were drug abuse, subtype B infection, and a prolonged and complex treatment history. Perinatal infection and having at least 2 stop codons were associated with a current suboptimal regimen.
In virologically suppressed individuals, resistance in HIV-DNA and the extent of APOBEC editing were generally stable in the last decade. A careful evaluation of APOBEC editing might be helpful to improve the reliability of HIV-DNA GRT. Further investigations are required to understand how to apply the estimation of APOBEC editing in refining genotypic evaluation.
Objective: In patients with systemic lupus erythematosus (SLE), hydroxychloroquine prevents disease flares and damage accrual and facilitates the response to mycophenolate mofetil in those with renal ...involvement. A study was undertaken to determine whether hydroxychloroquine also exerts a protective effect on survival. Methods: Patients with SLE from the multiethnic LUMINA (LUpus in MInorities: NAture vs nurture) cohort were studied. A case-control study was performed within the context of this cohort in which deceased patients (cases) were matched for disease duration (within 6 months) with alive patients (controls) in a proportion of 3:1. Survival was the outcome of interest. Propensity scores were derived by logistic regression to adjust for confounding by indication as patients with SLE with milder disease manifestations are more likely to be prescribed hydroxychloroquine. A conditional logistic regression model was used to estimate the risk of death and hydroxychloroquine use with and without the propensity score as the adjustment variable. Results: There were 608 patients, of whom 61 had died (cases). Hydroxychloroquine had a protective effect on survival (OR 0.128 (95% CI 0.054 to 0.301 for hydroxychloroquine alone and OR 0.319 (95% CI 0.118 to 0.864) after adding the propensity score). As expected, the propensity score itself was also protective. Conclusions: Hydroxychloroquine, which overall is well tolerated by patients with SLE, has a protective effect on survival which is evident even after taking into consideration the factors associated with treatment decisions. This information is of importance to all clinicians involved in the care of patients with SLE.
We identified the homozygous p.Arg12* variant in 5 patients with neurodevelopmental delay, but variation databases list many truncating heterozygous variants for this small 2‐exon gene. As most of ...these affect the protein’s C‐terminus, loss‐of‐function mediated pathogenicity may be confined to bi‐allelic truncating variants in exon 1 (nonsense‐mediated decay!) or in the catalytically active Nudix box.
Abstract
Objectives
To evaluate the prevalence and therapeutic relevance of drug resistance among isolates from ART-experienced HIV-1-infected patients over the past two decades in Italy.
Methods
...Dynamics of resistance to one, two and three or more antiretroviral classes were evaluated from 1999–2018. Virological success (VS) after the latest therapy switch was evaluated according to cumulative class resistance and cumulative genotypic susceptibility score (Stanford HIV_DB algorithm).
Results
Among 13 663 isolates (from 6739 patients), resistance to at least one drug class decreased sharply from 1999 to 2010 (≤2001, 84.6%; 2010, 43.6%; P < 0.001), then remained relatively constant at ∼40% during 2010–18, with the proportion of resistance to three or more classes also stable (∼5%). After 2008, integrase inhibitor resistance slightly increased from 5.6% to 9.7% in 2018 and contributed to resistance, particularly in isolates with resistance to three or more classes (one class, 8.4%; two classes, 15.3%; three or more classes, 34.7%, P < 0.001). Among 1827 failing patients with an available follow-up, by 1 year after genotype-guided therapy start the probability of VS was 87.6%. Patients with cumulative resistance to three or more classes and receiving a poorly active regimen showed the lowest probability (62.6%) of VS (P < 0.001) compared with all other patients (≥81.8%). By Cox regression analysis, cumulative MDR and receiving poorly active antiretroviral regimens were associated with a lower hazard of VS compared with those without resistance.
Conclusions
A dramatic drop of HIV-1 drug resistance at failure has been achieved over the last two decades in Italy; resistance to three or more classes is low but present among currently failing patients. Its management still requires a rational and careful diagnostic and therapeutic approach.
Objective: To examine the risk factors for self-reported work disability in patients from the LUpus in MInorities: NAture vs. Nurture cohort with systemic lupus erythematosus (SLE). Methods: Patients ...with SLE of Hispanic (Texas and Puerto Rico), African American and Caucasian ethnicity were studied. Work disability was defined by patients’ self-report. Only patients known to be employed at the baseline visit were included. The probabilities of self-reporting work disability over time were examined by the Kaplan–Meier method; differences between ethnic groups were examined by the log-rank test. The relationship of baseline socioeconomic–demographic, clinical, behavioural and psychological features with work disability was examined by standard statistical tests. Variables with p⩽0.10 in these analyses were examined by logistic regression. Results: The rate of self-reported work disability among the 273 patients studied was 19% at 5 years; it was numerically higher for the African Americans (25%) than for the Hispanics from Texas (19%) and the Caucasians (18%). The rate for the Hispanics from Puerto Rico was 7% at 2 years; 5-year rates could not be estimated for this ethnic subgroup (shorter follow-up in the cohort). In the regression analysis, age, male sex, poverty, total disease duration, disease activity and damage accrual were predictors of work disability. Conclusions: The rate of work disability was 19% at 5 years. Patients with SLE with more severe disease and with lower socioeconomic status are at high risk of becoming disabled. The toll SLE imposes could possibly be reduced in patients at risk if, in addition to medical treatment, services needed to overcome their disadvantageous socioeconomic status are provided.
•Volatile fingerprint analysis of two purple basil cultivars was performed.•In vitro biomass was established and compared with in vivo young plants.•UV elicitation was studied as stress factor.•The ...calli represented the most interesting miniaturised aromatic biomass.•The calli were a safe aromatic biomass with reduced phenylpropanoid content.
Exposure to stressful environmental conditions can induce severe metabolic variations in basil (Ocimum basilicum) aroma. The aromatic profiles of Dark Opal and Red Rubim varieties (in vivo plants, in vitro shoots, callus, and suspension cultures) were investigated for the first time. The established calli represented the most interesting miniaturised aromatic plant systems, as they were able to emit many typical basil volatiles with very low amounts of phenylpropanoids (1–2%). The hydrocarbon monoterpenes and oxygenated volatiles emitted from calli of both varieties were greatly and conversely affected by UV-C and UV-B, in comparison with the non-irradiated samples. As calli of both varieties still maintained very low levels of phenylpropanoids even after UV elicitation, they might be regarded not only as efficient in vitro plant models to study volatile compounds under UV stress conditions, but also as safe aromatic biomass in comparison with in vivo basil plants.
Hypomyelinating leukodystrophies (HLDs) affect the white matter of the central nervous system and manifest as neurological disorders. They are genetically heterogeneous. Very recently, biallelic ...variants in NKX6‐2 have been suggested to cause a novel form of autosomal recessive HLD. Using whole‐exome or whole‐genome sequencing, we identified the previously reported c.196delC and c.487C>G variants in NKX6‐2 in 3 and 2 unrelated index cases, respectively; the novel c.608G>A variant was identified in a sixth patient. All variants were homozygous in affected family members only. Our patients share a primary diagnosis of psychomotor delay, and they show spastic quadriparesis, nystagmus and hypotonia. Seizures and dysmorphic features (observed in 2 families each) represent an addition to the phenotype, while developmental regression (observed in 3 families) appears to be a notable and previously underestimated clinical feature. Our findings extend the clinical and mutational spectra associated with this novel form of HLD. Comparative analysis of our 10 patients and the 15 reported previously did, however, not reveal clear evidence for a genotype‐phenotype correlation.
Recurrent Bell’s palsy (RBP) has been reported to range from 2.6 to 15.2% of primary Bell’s palsy (BP) and has been associated with systemic comorbidities such as diabetes and hypertension. A ...retrospective analysis of patients affected by BP and RBP were performed to define the signs and symptoms associated with recurrence and the outcomes. Clinical and subjective characteristics of 341 patients affected by facial palsy were analysed. Facial function was assessed via House-Brackmann and Sunnybrook grading system. Characteristics of the palsy and systemic comorbidities (diabetes, hypertension, herpetic infections, autoimmunity disorders, audio-vestibular symptoms) were analysed in BP and RBP patients applying Fisher exact and the Mann-Whitney U tests, while time to recovery was explored with univariate and multivariate analysis. Twenty-four patients presented two or more episodes of facial palsy, representing a recurrence rate of 7%. Associated symptoms (e.g. retroauricular pain, taste disorder, dry eye etc.) were similar between BP and RBP patients. RBP occurred at older age than primary episode (p = 0.03). Recurrence was a risk factor for delayed recovery (p = 0.02), although final facial function was similar between the two groups. In conclusion, no significant differences were found between primary BP patients and RBP patients in terms of symptoms, palsy severity and presence of comorbidities. Delayed facial nerve function recovery in RBP did not affect the final outcome. Treatment of facial nerve recurrences must be the same of the primary episode, although the presence of prodromal symptoms may alert the patient and early corticosteroid treatment may be commenced even before the onset of paresis.
La enfermedad relacionada con IgG4 (ER-IgG4) es una entidad multisistémica poco frecuente,caracterizada por lesiones con un denso infiltrado linfoplasmocítico con abundantes células positivas ...parainmunoglobulina G (IgG)4, fibrosis estoriforme, flebitis obliterativa y niveles séricos elevados de IgG4. Laafectación torácica incluye al parénquima pulmonar, las vías respiratorias, el mediastino y la pleura y seobserva en aproximadamente el 40% de los pacientes. Se presenta el caso de un varón de 66 años conmúltiples comorbilidades e historia de derrame pleural a repetición. La biopsia pleural demostró pleuritiscrónica con flebitis obliterativa y un denso infiltrado linfoplasmocitario, sin fibrosis estoriforme. Lainmunofijación evidenció ≥40 células IgG4+ por campo de alto poder y relación: IgG4+/IgG+ >50%. Eldosaje plasmático de subclases de IgG reveló niveles elevados de IgG4. Se inició tratamiento con pulsosde metilprednisolona por tres días con lo cual se obtuvo una respuesta favorable, sin recaídas en controlesposteriores. Se destaca la importancia de considerar esta afección dentro de los diagnósticos diferencialesen pacientes con derrame pleural, teniendo en cuenta la respuesta generalmente favorable a los corticoidesy las secuelas irreversibles que puede generar el retraso en su tratamiento.
Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson’s disease. Objective: To study recurrent ...LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson’s disease. Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson’s disease phenotype and a broad range of onset age (34 to 73 years). Conclusions: G2019S is the most common genetic determinant of Parkinson’s disease identified so far. It is especially frequent among cases with familial Parkinson’s disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson’s disease.
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