Primary localised laryngeal amyloidosis : an atypical presentation

Primary localised laryngeal amyloidosis is a rare disease that classically presents with dysphonia. We present a case of a 38-year-old woman who presented with a history of early morning haemoptysis, progressively worsening hoarseness and intermittent dysphagia. A bulky left false vocal cord was seen on examination. A computed tomography scan of the neck and trunk revealed thickening of the left side of the larynx with associated asymmetry. Direct laryngoscopy showed a round, well-circumscribed lesion on the left false vocal cord and histological examination of the lesion confirmed the presence of amyloid. Systemic disease was ruled out and the patient was treated with endoscopic excision of the mass through carbon dioxide laser technology. The patient’s symptoms improved and the patient is being followed up yearly to exclude disease recurrence. The report highlights the presentation, diagnosis and appropriate management of localised laryngeal amyloidosis.peer-reviewe

Back trauma resulting in commotio cordis

Commotio cordis (Latin: "agitation of the heart") is a dysrhythmia provoked by praecordial trauma during the early part of cardiac repolarisation. Recorded rhythms include ventricular tachycardia/fibrillation, bradyarrhythmias, idioventricular rhythm, complete heart block and asystole. The quoted fatality rate is 65% even with prompt CPR and defibrillation, and exceeds 80% in the absence of such interventions. Above a certain threshold of trauma/impact, structural cardiac damage may also occur (contusio cordis).peer-reviewe

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Investigating the relationship between pain indicators and observers’ judgements of pain

Background Due to the inherent subjectivity of pain, it is difficult to make accurate judgements of pain in others. Research has found discrepancies between the ways in which perceived “objective” (e.g., medical evidence of injury) and “subjective” information (e.g., self-report) influence judgements of pain. This study aims to explore which potential cues (depictions of sensory input, brain activation, self-reported pain and facial expressions) participants are most influenced by when evaluating pain in others. Methods First, 60 participants (23 women, 36 ± 10 years old) judged who was in more pain between two different pain indicators representing two different patients. These trials revealed which congruent indicator (i.e., two high pain indicators) would most influence participant decisions. Second, participants prescribed quantities of analgesia for one patient's pain based on two different pain indicators. These trials revealed which incongruent indicators (i.e., one high and one low indicator) would most influence participant decisions. Results As predicted, facial expressions were perceived as subjective and were the least likely, among all pain indicators, to influence observer's judgements of pain. Participants relied upon indicators they perceived as objective. Self-report pain ratings had the greatest influence on participants judgements about how much analgesic cream to prescribe and was perceived as objective by half of the participants. Conclusions We found that in situations where incongruent information was presented about an individual's pain, participants relied on pain indicators that they perceived to be objective. The current study provides important insights about biases that people hold when making judgements of pain in others. Significance Interpretation and assessment of pain remains one of the largest barriers to pain management and involves complex, idiosyncratic processing. This study provides insights into what information participants view as critical in making attributions of pain when presented with multiple, seemingly incongruent sources of information

S1 File -

BackgroundWomen worldwide experience challenges managing their periods. Menstrual and genital hygiene behaviours have been linked to negative health outcomes, including urogenital symptoms and confirmed infections. However, evidence testing this association has been limited and mixed. This study aimed to (1) describe the menstrual care practices and prevalence of self-reported urogenital symptoms among working women in Mukono District, Uganda, and (2) test the associations between menstrual and genital care practices, and urogenital symptoms.MethodologyWe undertook a cross-sectional survey of women aged 18–45 working in markets, schools, and healthcare facilities in Mukono District, with 499 participants who had menstruated in the past two months included in this analysis. We developed an aggregated measure of menstrual material cleanliness, incorporating material type and laundering practices. Associations with urogenital symptoms were tested using the aggregated material cleanliness measure alongside the frequency of changing materials, handwashing before menstrual tasks, and sanitation practices.ResultsAmong our sample, 41% experienced urogenital symptoms in the past month. Compared to women exclusively using disposable pads, using appropriately cleaned or non-reused improvised materials (PR = 1.33, 95%CI 1.04–1.71), or inadequately cleaned materials (improvised or commercially produced reusable pads) (PR = 1.84, 95%CI 1.46–3.42) was associated with an increased prevalence of self-reported urogenital symptoms in the last month. There was no difference between those using disposable pads and those using clean reusable pads (PR = 0.98; 95%CI 0.66–1.57). Infrequent handwashing before changing materials (PR 1.18, 95%CI: 0.96–1.47), and delaying urination at work (PR = 1.37, 95%CI: 1.08–1.73) were associated with an increased prevalence of self-reported symptoms.ConclusionPrevalence of self-reported urogenital symptoms was associated with the type and cleanliness of menstrual material used as well as infrequent handwashing and urinary restriction. There is a need for interventions to enable women to maintain cleanliness of their menstrual materials and meet their menstruation, urination and hand washing needs at home and work.</div

Participant characteristics.

BackgroundWomen worldwide experience challenges managing their periods. Menstrual and genital hygiene behaviours have been linked to negative health outcomes, including urogenital symptoms and confirmed infections. However, evidence testing this association has been limited and mixed. This study aimed to (1) describe the menstrual care practices and prevalence of self-reported urogenital symptoms among working women in Mukono District, Uganda, and (2) test the associations between menstrual and genital care practices, and urogenital symptoms.MethodologyWe undertook a cross-sectional survey of women aged 18–45 working in markets, schools, and healthcare facilities in Mukono District, with 499 participants who had menstruated in the past two months included in this analysis. We developed an aggregated measure of menstrual material cleanliness, incorporating material type and laundering practices. Associations with urogenital symptoms were tested using the aggregated material cleanliness measure alongside the frequency of changing materials, handwashing before menstrual tasks, and sanitation practices.ResultsAmong our sample, 41% experienced urogenital symptoms in the past month. Compared to women exclusively using disposable pads, using appropriately cleaned or non-reused improvised materials (PR = 1.33, 95%CI 1.04–1.71), or inadequately cleaned materials (improvised or commercially produced reusable pads) (PR = 1.84, 95%CI 1.46–3.42) was associated with an increased prevalence of self-reported urogenital symptoms in the last month. There was no difference between those using disposable pads and those using clean reusable pads (PR = 0.98; 95%CI 0.66–1.57). Infrequent handwashing before changing materials (PR 1.18, 95%CI: 0.96–1.47), and delaying urination at work (PR = 1.37, 95%CI: 1.08–1.73) were associated with an increased prevalence of self-reported symptoms.ConclusionPrevalence of self-reported urogenital symptoms was associated with the type and cleanliness of menstrual material used as well as infrequent handwashing and urinary restriction. There is a need for interventions to enable women to maintain cleanliness of their menstrual materials and meet their menstruation, urination and hand washing needs at home and work.</div