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The repeated failure to treat patients chronically infected with hepatitis E (HEV) and C (HCV) viruses, despite the absence of resistance-associated substitutions (RAS), particularly in response to prolonged treatments with the mutagenic agents of HEV, suggests that quasispecies structure may play a crucial role beyond single point mutations. Quasispecies structured in a flat-like manner (referred to as flat-like) are considered to possess high average fitness, occupy a significant fraction of the functional genetic space of the virus, and exhibit a high capacity to evade specific or mutagenic treatments. In this paper, we studied HEV and HCV samples using high-depth next-generation sequencing (NGS), with indices scoring the different properties describing flat-like quasispecies. The significance of these indices was demonstrated by comparing the values obtained from these samples with those from acute infections caused by respiratory viruses (betacoronaviruses, enterovirus, respiratory syncytial viruses, and metapneumovirus). Our results revealed that flat-like quasispecies in HEV and HCV chronic infections without RAS are characterized by numerous low-frequency haplotypes with no dominant one. Surprisingly, these low-frequency haplotypes (at the nucleotide level) exhibited a high level of synonymity, resulting in much lower diversity at the phenotypic level. Currently, clinical approaches for managing flat-like quasispecies are lacking. Here, we propose methods to identifying flat-like quasispecies, which represents an essential initial step towards exploring alternative treatment protocols for viruses resistant to conventional therapies.
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INTRODUCTION: There are several treatment options for plaque psoriasis (PsO), but uncertainty remains around the optimal sequencing of treatments. The aims of this study were to investigate how adopting a best-treatment-first treatment sequence impacts patient outcomes and healthcare systems and to quantify the cost of treatment failure to the healthcare system. METHODS: A 3-year state-transition treatment-sequencing model which identifies all possible treatment sequences in PsO was adapted to the Italian healthcare setting. Treatments considered in the model are those with European Medicines Agency marketing authorization and reimbursement in Italy as of December 2022. Italian market share data (2019-2021) and list prices (2022) informed the current prescribed sequences; these sequences were compared against all possible sequences to determine opportunities for improvement. Both the national perspective in Italy as well as the local perspective from seven regions were considered. The cost of treatment failure was informed through a questionnaire circulated to Italian dermatologists. RESULTS: Overall, 1284 possible treatment sequences are possible when four lines of treatment are considered for patients with moderate-to-severe PsO in Italy. Within the estimated range of treatment failures across those sequences (0.97-2.56 per patient over 3 years), current prescribing behavior from the national perspective suggests patients will face 1.44 failures on average; this highlights the potential for improvement. For every treatment failure, the cost borne by the Italian National Healthcare Service (NHS) is 676.80. Overall, prescribing more optimized treatment sequences results in a 22.95% reduction in failures with a 2.27% increase in costs. The regional analyses found similar trends. CONCLUSIONS: Results suggest that selecting the most effective treatment sequences for incident patients provides the greatest opportunity to reduce treatment failures and maximize patient outcomes with a modest impact on costs. While regional variations exist, there is room for improvement across the board, which could translate to more efficient local healthcare systems.
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OBJECTIVES: Treatment failures to modern antiretroviral therapy (ART) raise concerns, as they could reduce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. METHODS: People with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as 'difficult to treat' (DTT) if they experienced ≥1 among: i) ≥2 VF (2 viral loads, VL>200 copies/mL or 1 VL>1000 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxicity/intolerance/failure; iii) ≥1 VF followed by ART change plus ≥1 TD due to toxicity/intolerance/failure. A subgroup of the DTT participants were matched to PWH that, after the same time, were non-DTT. Treatment response, analysing VF, TD, treatment failure, AIDS/death, and SNAE (Serious non-AIDS event)/death, were compared. Survival analysis by KM curves and Cox regression models were employed. RESULTS: Among 8061 PWH, 320 (4%) became DTT. Estimates of becoming DTT was 6.5% (95% CI: 5.8-7.4%) by 6 years. DTT PWH were significantly older, with a higher prevalence of AIDS and lower CD4+ at nadir than the non-DTT. In the prospective analysis, DTT demonstrated a higher unadjusted risk for all the outcomes. Once controlled for confounders, significant associations were confirmed for VF (aHR 2.23, 1.33-3.73), treatment failure (aHR 1.70, 1.03-2.78), and SNAE/death (aHR 2.79, 1.18-6.61). CONCLUSION: A total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears to be a more fragile group who may have higher risk of failure.
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Síndrome de Inmunodeficiencia Adquirida , Fármacos Anti-VIH , Infecciones por VIH , Humanos , Fármacos Anti-VIH/efectos adversos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Insuficiencia del Tratamiento , Análisis de Supervivencia , Carga ViralRESUMEN
INTRODUCTION: Chloroquine (CQ) is the drug of choice for treating uncomplicated Plasmodium vivax (P. vivax) malaria in India. The knowledge about the exact burden of CQ resistance in P. vivax in India is scarce. Therefore, this systematic review aimed to assess the prevalence of CQ resistance in reported P. vivax cases from India. METHODS: PubMed, EMBASE, and Web of Science, were searched using the search string: 'Malaria AND vivax AND chloroquine AND (resistance OR resistant) AND India'. We systematically reviewed in-vivo and in-vitro drug efficacy studies that investigated the CQ efficacy of P. vivax malaria between January 1995 and December 2022. Those studies where patients were followed up for at least 28 days after initiation of treatment were included. RESULTS: We identified 12 eligible CQ therapeutic efficacy studies involving 2470 patients, Of these 2329 patients were assessed by in-vivo therapeutic efficacy methods and the remaining 141 were assessed by in-vitro methods. CQ resistance was found in 25/1787 (1.39%) patients from in-vivo and in 11/141 (7.8%) patients from in-vitro drug efficacy studies. CONCLUSION: Based on the available studies, the prevalence of CQ resistance in P. vivax was found to be relatively lower in India. However, continued surveillance and monitoring are crucial to identify the emergence of CQ resistance.
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OBJECTIVES: Critically ill patients frequently require continuous renal replacement therapy. Echinocandins are recommended as first-line treatment of candidemia. Preliminary results suggested echinocandin sequestration in a polyacrylonitrile filter. The present study aimed to determine whether increasing the dose might balance sequestration. METHODS: An STX filter (Baxter-Gambro) was used. A liquid chromatography-mass spectrometry method was used for dosage of caspofungin. In vitro drug disposition was evaluated by NeckEpur (Neckepur, Versailles, France) technology using a crystalloid medium instead of diluted/reconstituted blood, focusing on the disposition of the unbound fraction of drugs. Two concentrations were assessed. RESULTS: At the low dose, the mean measured initial concentration in the central compartment (CC) was 5.1 ± 0.6 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.6 ± 2.5 L/h. The mean percentages of elimination resulting from sequestration and diafiltration were 96.0 ± 5.0 and 4.0 ± 5.2%, respectively. At high dose, the mean measured initial concentration in the CC was 13.1 mg/L. One hundred percent of the initial amount was eliminated from the CC within the 6-h session. The mean total clearance from the CC was 9.5 L/h. The mean percentages of elimination resulting from sequestration and filtration were 88.5% and 11.5%, respectively. CONCLUSION: Increasing the dose does not mitigate caspofungin sequestration in the STX filter. The results raise caution about the simultaneous use of caspofungin and polyacrylonitrile-derived filters. Intermittent modes of renal replacement therapy might be considered. For sensitive species, fluconazole might be an alternative.
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Antifúngicos , Equinocandinas , Humanos , Caspofungina , Antifúngicos/uso terapéutico , Equinocandinas/uso terapéutico , Resinas Acrílicas , LipopéptidosRESUMEN
Introduction: Infertility literature suggests widespread recourse to long-term medical treatments despite evidence of high stress, costs, and adverse effects of repeated treatment failures. However, there is a lack of research comparing predictors of stress and psychological health outcomes between members of infertile couples who - after repeated failures - persist in pursuing medical treatments (PT) with those who opted for quitting treatments and adopting (QTA). Basing on a transactional and multidimensional approach to infertility-related stress and health, the present study aims at exploring individual (socio-demographics; coping strategies) and situational (infertility-related parameters; infertility-related stressors; couple's dyadic adjustment dimensions) predictors of state-anxiety and depression in male and female partners of PT-infertile couples and of QTA-infertile couples. Methods: Participants were both members of 176 couples with duration of infertility and a history of medical treatments for at least 3 years (76 PT-infertile couples, 100 QTA-infertile couples). The study variables were compared by study group across genders. Structural equation models (SEM) were used to test main and moderating effects of study variables on state-anxiety and depression by study group and across genders. Results: Members of infertile couples quitting treatments and adopting (QTA) reported significantly lower levels of state-anxiety and depression, higher stress related to need for parenthood and rejection of childfree-lifestyle and lower stress related to social and couple's relationship concerns than those who persist in pursuing medical treatments (PT). Members of infertile couples quitting treatments and adopting (QTA) recurred to a greater extent to active coping strategies (problem-solving/social-support) and to a lower extent to passive coping strategies (avoiding/turning-to-religion), and they reported higher levels of dyadic adjustment. Specificities in main and moderating factors related to state-anxiety and depression by study group and across genders were found. Conclusion: Findings should be addressed to provide a comprehensive assessment of both members of infertile couples facing repeated treatment failures to identify risks and resources and develop tailored evidence-based interventions.
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The global health community has targeted the elimination of neglected tropical diseases (NTDs) including soil-transmitted helminthiasis by 2030. The elimination strategy has not changed from that of control using regular mass drug administration (MDA) with albendazole, WASH and education. Already doubts have been expressed about this achievement, principally because drugs do not interrupt transmission. We report here the findings of a cohort study aimed to identify host modifiable and environmental factors associated with hookworm infection and reinfection in rural communities in Kintampo North Municipality, Ghana. Faecal samples of 564 consented participants were screened for intestinal parasites at baseline, 9 months and 24 months using the Kato-Katz method. At each time point, positive cases were treated with a single dose of albendazole (400 mg) and their samples were again screened 10-14 days post-treatment to record treatment failures. The hookworm prevalence at the three-time points was 16.7%, 9.22% and 5.3% respectively, whilst treatment failure rates were 17.25%, 29.03% and 40.9% respectively. The intensities of hookworm infection (in eggs per gram) at the time points were 138.3, 40.5 and 135, which showed a likely association with wet and dry seasons. We posit that the very low intensity of hookworm infections in humans during the dry season offers a window of opportunity for any intervention that could drastically reduce the community worm burden before the rainy season.
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The current management of vestibular schwannomas (VS) includes observation, microsurgery (MS), and stereotactic radiosurgery (SRS) or radiotherapy, and treatment failures may occur with any primary modality. SRS is most often used for microsurgical failures, as it carries a low risk of adverse events. Salvage MS following previous MS is reserved for specific cases and can present certain surgical challenges. Irradiation failures can be managed with both salvage MS and repeat SRS. This article is intended to review an approach to the failure of primary interventions for VS, with a focus on the time interval between modalities, rates of tumor control, functional outcomes, and possible complications.
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Neuroma Acústico , Radiocirugia , Humanos , Resultado del Tratamiento , Neuroma Acústico/terapia , Radiocirugia/efectos adversos , Microcirugia , Procedimientos Neuroquirúrgicos , Estudios RetrospectivosRESUMEN
In diabetic foot infections (DFI), the clinical virulence of skin commensals are generally presumed to be low. In this single-center study, we divided the wound isolates into two groups: skin commensals (coagulase-negative staphylococci, micrococci, corynebacteria, cutibacteria) and pathogenic pathogens, and followed the patients for ≥ 6 months. In this retrospective study among 1018 DFI episodes (392 [39%] with osteomyelitis), we identified skin commensals as the sole culture isolates (without accompanying pathogenic pathogens) in 54 cases (5%). After treatment (antibiotic therapy [median of 20 days], hyperbaric oxygen in 98 cases [10%]), 251 episodes (25%) were clinical failures. Group comparisons between those growing only skin commensals and controls found no difference in clinical failure (17% vs. 24 %, p = 0.23) or microbiological recurrence (11% vs. 17 %, p = 0.23). The skin commensals were mostly treated with non-beta-lactam oral antibiotics. In multivariate logistic regression analysis, the isolation of only skin commensals was not associated with failure (odds ratio 0.4, 95% confidence interval 0.1-3.8). Clinicians might wish to consider these isolates as potential pathogens when selecting a targeted antibiotic regimen, which may also be based on oral non-beta-lactam antibiotic agents effective against the corresponding skin pathogens.
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STUDY DESIGN: Case-control study. PURPOSE: Analyze association between imaging factors related to the failure of conservative treatment in isolated subaxial cervical facet fractures. OVERVIEW OF LITERATURE: Facet fracture (F1, F2, and F3 AOSpine) may be stable or unstable depending on clinical and imaging variables, which are not well established. As a result, differences in fracture management lead to differences in surgical or conservative indications, and there is no evidence to predict conservative treatment failure. METHODS: Patients were categorized into two groups: six patients (16.2%) with conservative treatment failure (defined as the appearance of neurological symptoms, listhesis >3.5 mm, kyphotic deformation >11°, and/or non-union), and 31 patients (83.7%) with successful conservative management (defined as complete consolidation confirmed by computed tomography [CT] at the 6-month followup). All participants were fitted with rigid collars of the Miami type, and standardized follow-up was performed until consolidation or failure. CT and magnetic resonance imaging (MRI) was used to examine imaging characteristics. Sagittal balance parameters were assessed using CT, and signs of acute disc injury, prevertebral edema, facet synovitis, and interspinous hyperintense signal were assessed using MRI. RESULTS: Thirty-seven patients were diagnosed with unilateral cervical facet fractures between 2009 and 2020. In this sample, acute disc injury had a significative association to failure of conservative treatment in F2 and F3 AOSpine facet fractures, 100% of the failure group presented with traumatic disc injury compared to 9.7% of the successful group, for the other variables: prevertebral edema, 83.7% vs. 41.9%; facet synovitis, 100% vs. 77.4%; and interspinous hyperintensity, 71.4% vs. 38.7%, respectively. With conservative management, all F1 fractures healed successfully. Conservative treatment failed in 20% of F2 fractures and 50% of F3 fractures, respectively. In terms of cervical sagittal balance parameters, there were no significant differences between groups. CONCLUSIONS: Conservative management was successful in all F1 fractures. In F2 and F3 types, there was a significant association between acute disc injury and conservative treatment failure.
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OBJECTIVE: To evaluate outcomes following salvage microsurgery (MS) and salvage stereotactic radiosurgery (SRS) after failure of primary treatment for vestibular schwannomas (VS). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. METHODS: Patients with more than 1 intervention for their VS were divided into 4 groups: MS followed by SRS (n = 61), MS followed by MS (n = 9), SRS followed by MS (n = 7), and SRS followed by SRS (n = 7), and outcomes were evaluated. RESULTS: A total of 77 patients were included (84 procedures). In group 1 (MS then SRS), 3% developed a decline in facial function, 3% developed trigeminal sensory loss, and 13% patients had gradual improvement of facial nerve function following SRS. Group 2 (MS then MS) had the highest rates of facial nerve deterioration, although all but 1 patient achieved a House-Brackmann score of II or III. Gross-total resection (GTR) was achieved in 56% of patients. When a different approach was used for salvage resection, GTR occurred more commonly, and facial nerve outcomes were similar. In group 3 (SRS then MS), GTR occurred in 43% of cases, and 2 of 7 patients developed worsened facial function. In group 4 (SRS then SRS), no patient developed facial weakness after reirradiation, and 1 developed a trigeminal nerve deficit. CONCLUSIONS: For MS recurrences/residuals, SRS is the mainstay of treatment and does not preclude facial function recovery. If salvage microsurgery is required, an alternate approach should be considered. For SRS failures, when MS is required, less-than GTR may be preferable, and reirradiation is a potential safe alternative.
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Neuroma Acústico , Radiocirugia , Estudios de Seguimiento , Humanos , Neuroma Acústico/radioterapia , Neuroma Acústico/cirugía , Radiocirugia/efectos adversos , Radiocirugia/métodos , Estudios Retrospectivos , Terapia Recuperativa , Resultado del TratamientoRESUMEN
Recently, Gansané and colleagues published an article on inadequate efficacy of two different forms of artemisinin-based combination therapy (ACT) in Burkina Faso. The development of Plasmodium falciparum resistance to different ACT partner drugs at levels that could affect the efficacy of two ACT would both be startling and a cause for great concern. In reviewing the available data collected since 2008 on ACT efficacy in Burkina Faso, the analysis shows that the reported efficacy of the tested ACT varies greatly. Most of the studies have considerable methodological deviations and challenges, especially in PCR correction done to distinguish between recrudescence and re-infection, and in the failure to omit re-infections in the calculation of efficacy rates. So far, there is no convincing evidence in the articles reviewed that multidrug resistance has emerged in Burkina Faso. However, the potential consequence of failing ACT means that the results published by Gansané et al. urgently need to be confirmed. Furthermore, articles reporting on efficacy data need to include an examination of the potential consequences of any methodological deviations.
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Antimaláricos/farmacología , Artemisininas/farmacología , Resistencia a Múltiples Medicamentos , Lactonas/farmacología , Plasmodium falciparum/efectos de los fármacos , Burkina Faso , Combinación de Medicamentos , Plasmodium falciparum/fisiologíaRESUMEN
Background: Smoking by cancer patients and survivors causes adverse cancer treatment outcomes, but little information is available about how smoking can affect cancer treatment costs. Methods: We developed a model to estimate attributable cancer treatment failure because of continued smoking after a cancer diagnosis (afs). Canadian health system data were used to determine the additional treatment cost for afs for the most common cancers in Canada. Results: Of 206,000 patients diagnosed with cancer annually, an estimated 4789 experienced afs. The annual incremental cost associated with treating patients experiencing afs was estimated at between $198 million and $295 million (2017 Canadian dollars), reflecting an added incremental cost of $4,810-$7,162 per patient who continued to smoke. Analyses according to disease site demonstrated higher incremental costs where the smoking prevalence and the cost of individual second-line cancer treatment were highest. Of breast, prostate, colorectal, and lung cancers, lung cancer was associated with the highest incremental cost for treatment after afs. Conclusions: The costs associated with afs in Canada after a cancer diagnosis are considerable. Populations in which the smoking prevalence and treatment costs are high are expected to benefit the most from efforts aimed at increasing smoking cessation capacity for patients newly diagnosed with cancer.
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Neoplasias Pulmonares , Cese del Hábito de Fumar , Canadá/epidemiología , Análisis Costo-Beneficio , Humanos , Masculino , Fumar/epidemiologíaRESUMEN
INTRODUCTION: Cervical dystonia is the most frequent form of focal dystonia. It is characterised by involuntary muscular contractions resulting in abnormal head/neck and shoulder movements and postures, which can be associated with tremor and pain. Local intramuscular injections of botulinum toxin type A (BoNT-A) is the treatment of choice, being both effective and well-tolerated. However, a considerable number (c. 30%) of patients discontinue this treatment. The aim of this review was to analyse the factors possibly responsible for treatment failures of cervical dystonia (CD), with special regard to the new classification known as the 'Col-Cap' concept and non-motor symptoms. CLINICAL IMPLICATIONS: Several factors analysed in this review are responsible for effective treatment: proper diagnosis of dystonia and exclusion of pseudodystonias, correct recognition of dystonia pattern and identification of new patterns according to the Col-Cap concept, muscle selection and precise injections under electromyography (EMG) and/or ultrasonography (US) guidance. Furthermore, concomitant diagnosis and treatment of non-motor symptoms such as depression, anxiety, fatigue, sleep problems, phobias and stigmatisation are crucial in obtaining the best overall effect of the treatment. Primary and secondary immunisation and non-responsiveness seem to be marginal problems nowadays due to a low potential of new BoNT-A formulations to produce neutralising antibodies. FUTURE DIRECTIONS: There is a need for new and relevant scales combining the Col-Cap concept patterns with non-motor symptoms and quality of life. There is also a lack of specific rehabilitation protocols which could enhance BoNT-A treatment results.
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Toxinas Botulínicas/uso terapéutico , Tortícolis , Humanos , Dolor , Calidad de Vida , Tortícolis/tratamiento farmacológicoRESUMEN
BACKGROUND & AIMS: HCV subtypes which are unusual in Europe are more prevalent in the African region, but little is known of their response to direct-acting antivirals (DAAs). These include non-1a/1b/ non-subtypeable genotype 1 (G1) or non-4a/4d (G4). In this report we aimed to describe the genotype distribution and treatment outcome in a south London cohort of African patients. METHODS: We identified all patients born in Africa who attended our clinic from 2010-2018. Information on HCV genotype, treatment regimen and outcome were obtained. Non-subtypeable samples were analysed using Glasgow NimbleGen next-generation sequencing (NGS). Phylogenetic analysis was carried out by generating an uncorrected nucleotide p-distance tree from the complete coding regions of our sequences. RESULTS: Of 91 African patients, 47 (52%) were infected with an unusual subtype. Fourteen novel, as yet undesignated subtypes (G1*), were identified by NGS. Three individuals were infected with the same subtype, now designated as subtype 1p. Baseline sequences were available for 22 patients; 18/22 (82%) had baseline NS5A resistance-associated substitutions (RASs). Sustained virological response (SVR) was achieved in 56/63 (89%) overall, yet only in 21/28 (75%) of those with unusual G1 subtypes, with failure in 3/16 G1*, 1/2 G1p and 3/3 in G1l. Six treatment failures occurred with sofosbuvir/ledipasvir compared to 1 failure on a PI-based regimen. The SVR rate for all other genotypes and subtypes was 35/35 (100%). CONCLUSIONS: Most individuals in an unselected cohort of African patients were infected with an unusual genotype, including novel subtype 1p. The SVR rate of those with unusual G1 subtypes was 75%, raising concern about expansion of DAAs across Africa. Depending on the regimen used, higher failure rates in African cohorts could jeopardise HCV elimination. LAY SUMMARY: Direct-acting antiviral medications are able to cure hepatitis C in the majority of patients. The most common genotype of hepatitis C in Europe and the United States is genotype 1a or 1b and most clinical trials focused on these genotypes. We report that in a group of African patients, most of them had unusual (non-1a/1b) genotype 1 subtypes, and that the cure rate in these unusual genotypes was lower than in genotypes 1a and 1b.
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Bencimidazoles/farmacología , Farmacorresistencia Viral/genética , Fluorenos/farmacología , Hepacivirus , Hepatitis C Crónica , Sofosbuvir/farmacología , Proteínas no Estructurales Virales/genética , Antivirales/farmacología , Población Negra , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/etnología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Londres/epidemiología , Masculino , Persona de Mediana Edad , Respuesta Virológica Sostenida , Insuficiencia del TratamientoRESUMEN
BACKGROUND & AIMS: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. METHODS: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12â¯weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. RESULTS: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, pâ¯=â¯0.05) and those with GT3 infection (80%, pâ¯<0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. CONCLUSION: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. LAY SUMMARY: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12â¯weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.
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Carbamatos , Hepatitis C Crónica , Compuestos Heterocíclicos de 4 o más Anillos , Cirrosis Hepática/diagnóstico , Compuestos Macrocíclicos , Sofosbuvir , Sulfonamidas , Adulto , Ácidos Aminoisobutíricos , Antivirales/administración & dosificación , Antivirales/efectos adversos , Carbamatos/administración & dosificación , Carbamatos/efectos adversos , Ciclopropanos , Combinación de Medicamentos , Monitoreo de Drogas/métodos , Farmacorresistencia Viral , Femenino , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/virología , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compuestos Macrocíclicos/administración & dosificación , Compuestos Macrocíclicos/efectos adversos , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Quinoxalinas , Sofosbuvir/administración & dosificación , Sofosbuvir/efectos adversos , España/epidemiología , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
The appropriate management of early treatment failures in patients with elbow injuries requires the identification of the cause of failure. In this work, six types of elbow injury are considered: (i) identification of early failed reduction of a dislocation or fracture-dislocation of the elbow should lead to a repeat reduction procedure, testing for elbow instability, and ligament repair, followed by the use of a hinged external fixator to allow early mobilisation. Differentiating an isolated dislocation from a dislocation combined with a fracture of the coracoid process is crucial. Re-implantation of the coronoid process allows repair of the ligaments and restoration of stability in the sagittal plane; (ii) early secondary displacement of a distal humeral fracture after internal fixation is usually due to insufficient fixation confined to a single humeral pillar. If both humeral pillars are fractured, then both must be repaired; (iii) early treatment failure of an intra-articular distal humeral fracture in an elderly patient with bone loss warrants distal humeral hemiarthroplasty or total elbow arthroplasty; (iv) in fractures of the olecranon, treatment failures are due to insufficient fixation or to a mistaken diagnosis of trans-olecranon fracture-dislocation; (v) in fractures of the radial head, causes of early revision include excessive tilting of the head in radial neck fractures, with secondary displacement due to insufficient internal fixation, and adverse effects on the wrist of radial head resection performed without assessing the ulnar variance. In patients with radial head fractures, no treatment decisions can be made before performing an anteroposterior radiograph of the wrist; (vii) in fracture-dislocations of both the radius and ulna, accurate reduction of the ulnar fracture is a pre-requisite to proper reduction of the radio-humeral and proximal radio-ulnar joints. An early postoperative assessment, within 10 days after surgery, is of paramount importance to re-evaluate the initial treatment and, if needed, to introduce modifications. Early failure of the initial treatment of an elbow injury should lead to the prompt implementation of corrective measures: follow-up anteroposterior and lateral radiographs must be obtained on day 8 to ensure the diagnosis of initial treatment failure and to allow the institution of an appropriate management strategy; the dogma stating that the elbow should never be immobilised remains valid, and every effort should be made to ensure that mobilisation starts as early as possible.
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Lesiones de Codo , Articulación del Codo/cirugía , Insuficiencia del Tratamiento , Artroplastia de Reemplazo de Codo , Fijadores Externos , Fractura-Luxación/diagnóstico , Fractura-Luxación/cirugía , Fijación de Fractura , Humanos , Fracturas del Húmero/cirugía , Luxaciones Articulares/diagnóstico , Luxaciones Articulares/cirugía , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/cirugía , Olécranon/lesiones , Olécranon/cirugía , Osteotomía , Fracturas del Radio/cirugía , Recurrencia , Reoperación , Fracturas del Cúbito/diagnóstico , Fracturas del Cúbito/cirugíaRESUMEN
AIM: To determine the most appropriate duration of antibiotic therapy for diabetic foot infections (DFIs). METHODS: Using a clinical pathway for adult patients with DFIs (retrospective cohort analysis), we created a cluster-controlled Cox regression model to assess factors related to remission of infection, emphasizing antibiotic-related variables. We excluded total amputations as a result of DFI and DFI episodes with a follow-up time of <2 months. RESULTS: Among 1018 DFI episodes in 482 patients, we identified 392 episodes of osteomyelitis, 626 soft tissue infections, 246 large abscesses, 322 episodes of cellulitis and 335 episodes of necrosis; 313 cases involved revascularization. Patients underwent surgical debridement for 824 episodes (81%), of which 596 (59%) required amputation. The median total duration of antibiotic therapy was 20 days. After a median follow-up of 3 years, 251 of the episodes (24.7%) were followed by ≥1 additional episode(s). Comparing patients with and without additional episodes, risk of recurrence was lower in those who underwent amputation, had type 1 diabetes, or underwent revascularization. On multivariate analysis including the entire study population, risk of remission was inversely associated with type 1 diabetes (hazard ratio [HR] 0.3, 95% confidence interval [CI] 0.2-0.6). Neither duration of antibiotic therapy nor parenteral treatment affected risk of recurrence (HR 1.0, 95% CI 0.99-1.01 for both). Similarly, neither >3 weeks versus <3 weeks of therapy, nor >1 week versus <1 week of intravenous treatment affected recurrence. In stratified analyses for both soft tissue DFIs or osteomyelitis separately, we did not observe associations of antibiotic duration with microbiological or clinical recurrences of DFI. The HRs were 1.0 (95% CI 0.6-1.8) for an antibiotic duration >3 weeks overall and 0.6 (95% CI 0.2-1.3) for osteomyelitis cases only. Plotting of duration of antibiotic therapy failed to identify any optimal threshold for preventing recurrences. CONCLUSIONS: Our analysis found no threshold for the optimal duration or route of administration of antibiotic therapy to prevent recurrences of DFI. These limited data might support possibly shorter treatment duration for patients with DFI.
Asunto(s)
Antibacterianos/administración & dosificación , Pie Diabético/tratamiento farmacológico , Pie Diabético/epidemiología , Inducción de Remisión , Adulto , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica/estadística & datos numéricos , Análisis por Conglomerados , Estudios de Cohortes , Comorbilidad , Desbridamiento/estadística & datos numéricos , Pie Diabético/patología , Pie Diabético/cirugía , Vías de Administración de Medicamentos , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión/métodos , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Mebendazole (MBZ), a benzimidazole compound, has received attention in treating patients with giardiasis because it has shown beneficial effects both in vitro and in vivo. The aim of this study was to assess with a systematic review and meta-analysis of randomized controlled trials (RCTs) the efficacy of MBZ compared to other antigiardial agents in children. We searched RCTs of MBZ for the treatment of Giardia infections published in PubMed and EBSCOhost. Application of inclusion and exclusion criteria, data extraction, and assessment of methodological quality were independently performed in duplicate. The primary outcome was the parasitological cure. We included 7 RCTs in the systematic review (639 patients). There was no clinical difference in the parasitological cure between MBZ and metronidazole (MTZ). The relative risk (RR) was 0.81 [95% Confidence Interval 0.61-1.09], with high heterogeneity (4 trials, I2 = 81%). The prediction interval expected to cover the results of a new trial was wide enough (0.22-2.96) to support both a clinically relevant difference favouring either MBZ or MTZ. The decision to support any treatment should be based not only on efficacy but also safety and cost. Although our results suggest that MBZ may be an effective treatment option for children with Giardia infection, they should also be interpreted and translated into clinical practice with caution, as the evidence is based on a limited number of RCTs presenting high heterogeneity.
Asunto(s)
Antinematodos/uso terapéutico , Giardiasis/tratamiento farmacológico , Mebendazol/uso terapéutico , Niño , HumanosRESUMEN
Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. However, its efficacy for patients for whom previous direct-acting antiviral (DAA) therapy failed is not known. We analysed the efficacy of DCV/ASV/BCV treatment for HCV-infected mice and chronic hepatitis patients. Human hepatocyte chimaeric mice were injected with serum samples obtained from either a DAA-naïve patient or a DCV/ASV treatment failure and were then treated with DCV/ASV alone or in combination with BCV for 4 weeks. DCV/ASV treatment successfully eliminated the virus in DAA-naïve-patient HCV-infected mice. DCV/ASV treatment failure HCV-infected mice developed viral breakthrough during DCV/ASV treatment, with the emergence of NS5A-L31V/Y93H HCV resistance-associated variants (RAVs) being observed by direct sequencing. DCV/ASV/BCV treatment inhibited viral breakthrough in NS5A-L31V/Y93H-mutated HCV-infected mice, but HCV relapsed with the emergence of NS5B-P495S variants after the cessation of the treatment. The efficacy of the triple therapy was also analysed in HCV-infected patients; one DAA-naïve patient and four prior DAA treatment failures were treated with 12 weeks of DCV/ASV/BCV therapy. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed.