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At least 19 recordsLinked to original sources
PubMed2026

Predictors of Treatment Failure in Children With HIV Starting First-line Antiretroviral Therapy in the ODYSSEY Trial.

BACKGROUND: Data on predictors of treatment failure in children starting antiretroviral therapy (ART) are limited, particularly on dolutegravir-based regimens (DTG). METHODS: ODYSSEY demonstrated superior efficacy of DTG versus standard-of-care (SOC). We assessed predictors at ART initiation of treatment failure by 96 weeks. RESULTS: Three hundred and eighty-one children started first-line ART (82% African). At ART-initiation, median age was 10.5 years (IQR: 6.5, 14.0, 67 < 3 years), CD4% 20% (IQR: 12, 28), BMI-for-age Z-score -.58 (IQR:-1.48, +.25). One hundred and eighty-nine children started DTG, 192 started SOC (91% &#x2265;3 years started efavirenz; 79% <3 years started lopinavir). Seventy-five children experienced treatment failure (24 DTG, 51 SOC). Failure risk was lower on DTG than SOC (hazard ratio [HR] = 0.47, 95% CI: 0.29-0.77, P = .002). Lower BMI-for-age Z-score (HR = 0.82 for each unit gain, 95% CI: 0.70-0.96, P = .01) and being at an African site (HR = 2.09, 95% CI: 0.82-5.31, P = .09) were associated with higher failure risk. Risk was also higher at younger ages with the steepest increase in the youngest children and increased at lower CD4%, with a stronger CD4% effect at younger ages. At CD4% = 20, HRs relative to age 10 years were 2.40 (95% CI: 1.58-3.65) at age 1 year, 1.30 (95% CI: 1.15-1.48) at age 5 years, and 0.80 (95% CI: 0.72-0.89) at age 18 years. At age 1 year, HRs relative to CD4% = 20 were 1.39 (95% CI: 1.16-1.66) at CD4% = 15, and 0.52 (95% CI: 0.36-0.75) at CD4% = 30; at age 10, corresponding estimates were 1.07 (95% CI: 0.94-1.20) at CD4% = 15, and 0.88 (95% CI: 0.69-1.13) at CD4% = 30. CONCLUSIONS: Young age, low BMI-for-age, and low CD4% at ART initiation predicted higher risk of treatment failure and can guide targeted support.

Humans↗
PubMed1978

Tuberculosis: review of treatment failure, relapse and drug resistance.

Factors affecting the success and failure of tuberculosis (TB) treatment programs are reviewed. Topics covered include incidences of primary and secondary resistance; methods and probability of bacteriologic transfer of resistance; factors affecting delivery of successful treatment of TB; and retreatment concepts, history and regimens for TB relapse and treatment failures. Isoniazid, rifampin and ethambutol hydrochloride produce a high percentage of cure in initial and retreatment TB therapy. Attention to patient compliance should be emphasized to assure effective treatment.

Aminosalicylic Acid↗
PubMed2025

Genetically distinct within-host subpopulations of hepatitis C virus persist after Direct-Acting Antiviral treatment failure.

Analysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct-Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure, and whether there were different evolutionary rates along distinct lineages where they were observed. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e., treatment failure) and had sequenced virus from multiple timepoints. Given the short-read nature of the data, we used a number of methods to identify distinct within-host lineages including tracking concordance in intra-host nucleotide variant (iSNV) frequencies, applying sequenced-based and tree-based clustering algorithms to sliding windows along the genome, and haplotype reconstruction. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates and/or different selection pressures. We endorse lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.

Humans↗
PubMed1978

Possible causes of treatment failure with the NSAID.

The clinical efficacy of non-steroidal anti-inflammatory drugs (NSAID) is often disappointing in spite of their well-known antiphlogistic actions. The reasons for this failure are probably due to irregular intake by patients on long-term treatment with such agents. These considerations inevitably point to the necessity of concomitant determination of the plasma levels of all NSAID tested, and the need to perform clinical trials in an appropriate setting in which such determinations can be conveniently carried out.

Anti-Inflammatory Agents↗
PubMed1977

New cause of penicillin treatment failure.

A large empyema infected with a penicillin-sensitive haemolytic group B streptococcus failed to respond to high doses of penicillin. After two weeks' treatment the pus aspirated was found not only to contain no penicillin, but also to inactivate penicillin added to it. We believe that the inactivating agent is an enzyme that may destroy various penicillins and cephalosporins but has no effect on other common antibiotics. When treatment was changed to doxycycline the patient made a rapid recovery.

Empyema↗
PubMed1977

Minocycline treatment failure in pneumonia caused by minocycline-sensitive Streptococcus pneumoniae.

A previously healthy 23-year-old white woman had fulminant pneumococcal pneumonia complicated by empyema and bilateral pneumothoraces. Despite early treatment with the recommended doses of minocycline, the disease progressed. The S pneumoniae isolate was resistant to a 30microgram tetracycline disk and showed an MIC of 3.13microgram/ml for minocycline and 12.5 microgram/ml for tetracycline; these levels are considered by the manufacturer to indicate sensitivity to minocycline and intermediate sensitivity to tetracycline. The tetracyclines, including minocycline, should not be used to treat bacterial pneumonia since resistant strains of pneumococci are not uncommon and inffective treatment can lead to rapid progression of the infection. This case suggests that the levels of minocycline considered to indicate sensitivity in vitro be reassessed.

Adult↗
PubMed1979

Carcinoma of the esophagus: pretreatment assessment, correlation of radiation treatment parameters with survival, and identification and management of radiation treatment failure.

Between January 1969 and February 1975, 344 patients with carcinoma of the esophagus were managed primarily at the Princess Margaret Hospital, Toronto. One hundred sixty-eight (168) of the patients were treated palliatively and 176 of the patients were treated by radical doses of radiation, surgical resection or both. Survival of the radical treatment group was biphasic, the steeper component being identical to the survival of the palliative treatment group, thereby representing a group of patients that did not respond to radical treatment. Analysis of pretreatment assessment parameters indicated that all patients with T1 lesions (length less than or equal to 5 cm, circumference incomplete) and all patients with Stage I disease responded to treatment. Patients who were female, age greater than or equal to 70 years, N0 or had well differentiated squamous cell histology, responded to treatment in at least 80% of cases. No patient with extralymphatic distant metastases responded to treatment. The presence of other major disease did not affect response to treatment. Thirty patients had surgical resections and their survival was not significantly greater than the 146 patients who had radical radiation alone. Survival analysis revealed an optimum range of nominal standard dose (NSD) of 1602--1714 rets (median 1679 rets) for patients treated by radiation alone. An optimum port size (area) of 100--140 cm2 was observed for patients receiving 5000 rads and supervoltage irradiation gave a significantly improved survival in comparison with megavoltage irradiation. Sixty-seven percent (67%) of patients treated by radical doses or radiation developed esophageal strictures postradiation and on the basis of radiological, endoscopic or histological evidence 75% of these strictures were considered to be associated with the persistence of malignancy. On the basis of postmortem examinations (32) and death certificates there was overall an 80% failure to control the disease locally and 95% of strictures were associated with persistence of malignancy in the esophagus. Thirty-one of the 146 patients receiving radical radiation alone had palliation for esophageal obstruction following radiotherapy. The construction of a physiological bypass (e.g., colon) resulted in a mean survival of 215 days which was much longer than the survival observed with rigid esophageal tubes (35 days) or gastrostomy tubes (58 days).

Aged↗
PubMed1977

[Failures in periodontal treatments].

Failures in periodontal therapy may be caused by a faulty choice of patients, insufficient diagnosis, prognosis and planning, faulty choice of therapy, treatment and follow-up treatment. Particularly important is the motivation of the patient, his collaboration in periodontal therapy is decisive for success or failure of the treatment. Lasting success may only be expected if patients are regularly recalled, their brushing and cleaning habits may be checked and further treatments be dispensed in time.

Attitude to Health↗
PubMed1977

Tinidazole and metronidazole in the treatment of intestinal amoebiasis.

Sixty adult patients with symptomatic intestinal amoebiasis and with Entamoeba histolytica present in stools were allocated at random to treatment with tinidazole or metronidazole, both administered in a dose of 2 g once daily for 3 consecutive days. The treatment period was extended in patients with stools positive for Entamoeba histolytica on the day following the last treatment day. Fifty-six patients, 29 on tinidazole and 27 on metronidazole, completed the trial as per the protocol. Twenty-eight patients (96.5%) on tinidazole and 15 (55.5%) on metronidazole were cured. Parasitological cure with partial relief of symptoms was obtained in 1 (3.5%) and 5 (18.5%) patients on tinidazole and metronidazole, respectively. Seven patients (26%) on metronidazole were treatment failures. Treatment had to be extended beyond 3 day in 53% of patients (8/15) on metronidazole as opposed to 11% (3/28) on tinidazole (p less than 0.01). The total number of side-effects, their severity, and the types were more in the metronidazole group. No toxic effects due to either drug were recorded. Tinidazole provided significantly higher cure rates than metronidazole in the treatment of symptomatic intestinal amoebiasis (p less than 0.01), and was better tolerated than metronidazole.

Adult↗
PubMed1979

Gonorrhea. Center for Disease Control recommended treatment schedules, 1979.

These recommendations specify appropriate treatment, including dosage of antibiotics for uncomplicated gonococcal infections in adults, infections with penicillinase-producing Neisseria gonorrhoeae, acute salpingitis, acute epididymitis, disseminated gonococcal infections, and gonococcal infections in pediatric patients (including neonatal infections). Special attention is given to important diagnostic considerations, relation of gonococcal infections to concomitant venereal infections, treatment of sexual partners, follow-up, treatment failures, treatments not recommended, allergic problems in treatment, needs for hospitalization, and prevention of gonococcal ophthalmia. Attention is called to the importance of using no less than the recommended dosages of antibiotics.

Amoxicillin↗
PubMed1978

Afterload reduction in the treatment of cardiac failure.

The vasodilators produce disparate modifications of cardiac function depending on the differing alterations of preload versus impedance: nitrates principally cause venodilation; nitroprusside, phentolamine and prazosin produce balanced arterial and venous dilation; while hydralazine predominantly effects arterial dilation. Combined nitroprusside and dopamine or dobutamine synergistically enhance low cardiac output and decrease raised left ventricular end-diastolic pressure. Ambulatory oral vasodilator therapy is provided by long-acting nitrates, hydralazine and prazosin alone, combined nitrate-hydralazine and combined prazosin-hydralazine. It is truly remarkable how quickly systemic vasodilators have become established as an important new medical advance in acute and chronic congestive heart failure treatment. In the future, as more experience is gained with the vasodilators and as newer such agents become available, the systemic vasodilators likely will be utilized as often as digitalis in the standard treatment of congestive heart failure.

Blood Pressure↗
PubMed1977

Formaldehyde induced anti-N: a possible cause of renal graft failure.

Treatment of human red cells with low concentrations of formaldehyde induces an antigenic change which makes them react very strongly with the anti-N sera found in certain patients treated by haemodialysis. This supports the idea that formaldehyde sterilisation of reusable home dialysers leads to the development of anti-N in these patients' sera. The clinical problems produced by this antibody are discussed together with ways of overcoming them.

Antibody Formation↗
PubMed2025

Machine learning detection of heteroresistance in Escherichia&#xa0;coli.

BACKGROUND: Heteroresistance (HR) is a significant type of antibiotic resistance observed for several bacterial species and antibiotic classes where a susceptible main population contains small subpopulations of resistant cells. Mathematical models, animal experiments and clinical studies associate HR with treatment failure. Currently used susceptibility tests do not detect heteroresistance reliably, which can result in misclassification of heteroresistant isolates as susceptible which might lead to treatment failure. Here we examined if whole genome sequence (WGS) data and machine learning (ML) can be used to detect bacterial HR. METHODS: We classified 467&#xa0;Escherichia coli clinical isolates as HR or non-HR to the often used &#x3b2;-lactam/inhibitor combination piperacillin-tazobactam using pre-screening and Population Analysis Profiling tests. We sequenced the isolates, assembled the whole genomes and created a set of predictors based on current knowledge of HR mechanisms. Then we trained several machine learning models on 80% of this data set aiming to detect HR isolates. We compared performance of the best ML models on the remaining 20% of the data set with a baseline model based solely on the presence of &#x3b2;-lactamase genes. Furthermore, we sequenced the resistant sub-populations in order to analyse the genetic mechanisms underlying HR. FINDINGS: The best ML model achieved 100% sensitivity and 84.6% specificity, outperforming the baseline model. The&#xa0;strongest predictors of HR were the total number of &#x3b2;-lactamase genes, &#x3b2;-lactamase gene variants and presence of IS elements flanking them. Genetic analysis of HR strains confirmed that HR is caused by an increased copy number of resistance genes via gene amplification or plasmid copy number increase. This aligns with the ML model's findings, reinforcing the hypothesis that this mechanism underlies HR in Gram-negative bacteria. INTERPRETATION: We demonstrate that a combination of WGS and ML can identify HR in bacteria with perfect sensitivity and high specificity. This improved detection would allow for better-informed treatment decisions and potentially reduce the occurrence of treatment failures associated with HR. FUNDING: Funding provided to DIA from the Swedish Research Council (2021-02091) and NIH (1U19AI158080-01).

Machine Learning↗
PubMed2026

Artemether-lumefantrine for the treatment of Plasmodium falciparum malaria in Laos: a therapeutic efficacy study coupled with genomic and in vitro phenotypic analyses.

BACKGROUND: Artemisinin-based combination therapies (ACTs) have played a crucial role in decreasing the impact of malaria worldwide. Since 2005, artemether-lumefantrine (AL) has been the main first-line treatment for uncomplicated Plasmodium falciparum malaria in Laos. Herein, we aimed to study the efficacy of AL in the context of malaria elimination in Laos. METHODS: Between Aug 1, 2019, and June 11, 2023, AL efficacy was evaluated in four provinces of southern Laos: Attapeu, Champassack, Salavan, and Savannakhet. Adults and children (aged 1-60 years) with microscopically confirmed P falciparum malaria received oral AL twice a day for 3 days, with follow-up on days 7, 14, 21, and 28. The primary outcome was PCR-adjusted adequate clinical and parasitological response (ACPR) by day 28. Resistance to dihydroartemisinin (DHA) and lumefantrine (LM) was assessed by an in vitro phenotypic analysis, and mutations in P falciparum kelch13 (pfkelch13), P falciparum multidrug resistance 1 (pfmdr1), P falciparum plasmepsin 2 (pfpm2), and P falciparum chloroquine resistant transporter (pfcrt) were characterised in parasites collected from enrolled patients. Safety outcomes included the frequency and nature of adverse events and serious adverse events. FINDINGS: A total of 198 patients (median age 16 years [IQR 10-28]; 124 [63%] male and 74 [37%] female) were initially enrolled, of whom three were lost to follow-up, resulting in 195 patients who received the 3-day AL regimen. At day 28, the PCR-adjusted ACPR was 96% (95% CI 92-98), with a treatment failure rate of 2% (1-5) and a reinfection rate of 2% (1-5). Among the four PCR-confirmed recrudescent isolates, one showed markedly reduced LM susceptibility (LM 50% inhibitory concentration [IC50] 59&#xb7;9 nM, 2&#xb7;5 times higher than the median IC50 of other isolates) and high artemisinin resistance in vitro (ring-stage survival survival rate 35&#xb7;8%), which was associated with the pfkelch13 R539T mutation and day-3 microscopy-positive parasitaemia. Among 190 isolates with successfully determined pfkelch13 sequencing, nine (5%) carried the pfkelch13 mutation R539T and 43 (23%) carried the C580Y mutation, and both were associated with day-3 microscopy-positive parasitaemia (p=0&#xb7;044). No amplification of pfmdr1 or pfpm2, nor any mutations in pfmdr1 and pfcrt, were associated with treatment failure. INTERPRETATION: Our findings indicate the potential emergence of LM resistance in Laos. Although AL remains efficacious, vigilance for decreasing efficacy and close monitoring of LM efficacy should be considered to support the country's goal of eliminating malaria by 2030. Importantly, none of the known pfmdr1 or pfcrt haplotypes were uniquely associated with treatment failure, including the isolate with the highest LM IC50, underscoring the need to identify reliable molecular markers for LM resistance. FUNDING: Bill and Melinda Gates Foundation and The Global Fund.

Humans↗