Parental experience after diagnosis of a congenital upper limb difference: a national survey.

Congenital hand and upper limb differences may be detected during antenatal ultrasonography or visually at birth. We investigated the experience of parents when they first learned that their child had an upper limb difference. This national retrospective cross-sectional quantitative and qualitative survey within the UK and Ireland received 261 responses from parents of children. Differences were first suspected antenatally among 41% of respondents and in 57% postnatally, with 2% unsure. Of the children, 54% were seen in a clinic by a specialist congenital hand surgeon within 3 months and 88% within 12 months, with 73% of respondents feeling unsupported after a diagnosis that was unexpected. Qualitative analysis outlined a broad spectrum of parental concerns about the quality of information received, especially regarding the child's future biopsychosocial needs. This study showed the need for more support for parents from frontline healthcare professionals and the need for a streamlined referral pathway.Level of evidence: IV.

Synergistic effects of inhaled aztreonam plus tobramycin on hypermutable cystic fibrosis Pseudomonas aeruginosa isolates in a dynamic biofilm model evaluated by mechanism-based modelling and whole genome sequencing.

OBJECTIVE: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P. aeruginosa strains using the CDC dynamic in vitro biofilm reactor (CBR), mechanism-based mathematical modelling (MBM) and genomic studies. METHODS: Two CF multidrug-resistant strains were investigated in a 168 h CBR (n = 2 biological replicates). Regimens were inhaled aztreonam (75 mg 8-hourly) and tobramycin (300 mg 12-hourly) in monotherapies and combination. The simulated pharmacokinetic profiles of aztreonam and tobramycin (t1/2 = 3 h) were based on published lung fluid concentrations in patients with CF. Total viable and resistant counts were determined for planktonic and biofilm bacteria. MBM of total and resistant bacterial counts and whole genome sequencing were completed. RESULTS: Both isolates showed reproducible bacterial regrowth and resistance amplification for the monotherapies by 168 h. The combination performed synergistically, with minimal resistant subpopulations compared to the respective monotherapies at 168 h. Mechanistic synergy appropriately described the antibacterial effects of the combination regimen in the MBM. Genomic analysis of colonies recovered from monotherapy regimens indicated noncanonical resistance mechanisms were likely responsible for treatment failure. CONCLUSION: The combination of aztreonam and tobramycin was required to suppress the regrowth and resistance of planktonic and biofilm bacteria in all biological replicates of both hypermutable multidrug-resistant P. aeruginosa CF isolates. The developed MBM could be utilised for future investigations of this promising inhaled combination.

UV1 telomerase vaccine with ipilimumab and nivolumab as second line treatment for pleural mesothelioma - A phase II randomised trial.

PURPOSE: The NIPU-trial investigates the effect of adding the telomerase vaccine UV1 to treatment with ipilimumab and nivolumab for patients with pleural mesothelioma (PM). METHODS: In this phase 2 open-label trial, patients with PM progressing after first-line chemotherapy were randomised to receive ipilimumab and nivolumab alone (arm B) or combined with UV1 (arm A). The primary endpoint was progression-free survival (PFS) as determined by BICR. It was estimated that 69 PFS events were needed to detect a hazard ratio (HR) of 0.60 with 80% power and a one-sided alpha level of 0.10. RESULTS: 118 patients were randomised. The median PFS determined by blinded independent central review (BICR) was 4.2 months (95%CI 2.9-9.8) in arm A and 4.7 months (95%CI 3.9-7.0) in arm B (HR 1.01, 80%CI 0.75-1.36 P = 0.979), after a median follow-up of 12.5 months (95%CI 9.7-15.6). The investigator-determined median PFS was 4.3 months (95%CI 3.0-6.8) in arm A and 2.9 months (95%CI 2.4-5.5) in arm B (HR 0.60, 80%CI 0.45-0.81 P = 0.025). Confirmed objective response rate (ORR) by BICR was 31% in arm A and 16% in arm B (odds ratio 2.44 80%CI 1.35-4.49 P = 0.056). After a median follow-up time of 17.3 months (95%CI 15.8-22.9), the OS was 15.4 months (95%CI 11.1-22.6) in arm A and 11.1 months (95%CI 8.8-18.1) in arm B, (HR 0.73, 80%CI 0.53-1.0, P = 0.197). CONCLUSION: The primary endpoint was not met. Predefined analyses of response rates are in favour of adding the vaccine.

External validation of a lung cancer-based prediction model for two-year mortality in esophageal cancer patient cohorts.

PURPOSE/OBJECTIVE: Chemo-radiotherapy can improve the oncological outcome of esophageal cancer (EC) patients, but may cause long term radiation-induced toxicity, including an increased risk of non-cancer related death. For lung cancer patients, a model to predict 2-year total mortality using mean heart dose (MHD) and gross tumor volume (GTV) has previously been developed and validated. This project aimed to externally validate this model in EC patients. METHODS: Five EC patient cohorts from 3 different Dutch centres were used for model validation. External validity of the model was assessed separately in definitive (n = 170) and neo-adjuvant (n = 568) chemoradiotherapy (dCRT and nCRT) patients. External validity was assessed in terms of calibration by calibration plots, calibration-in-the-large (CITL) and calibration slope (CS), and discrimination by assessment of the c-statistic. If suboptimal model performance was observed, the model was further updated accordingly. RESULTS: For the dCRT patients, good calibration was found after adjustment of the intercept (CITL 0.00; CS 1.08). The c-statistic of the adjusted model was 0.67 (95%CI: 0.58 to 0.75). For nCRT patients the model needed adjustment of both the slope and the intercept because of initial miscalibration in the validation population (CITL 0.00; CS 1.72). After recalibration, the model showed perfect calibration (i.e., CITL 0, CS 1), as is common after recalibration. The c-statistic of the recalibrated model equaled 0.62 (95%CI: 0.57 to 0.67). CONCLUSION: The existing model for 2-year mortality prediction in lung cancer patients, based on the predictive factors MHD and GTV, showed good performance in EC patients after updating the intercept and/or slope of the original model.

Upper thermal limits of Rhagoletis indifferens (Diptera: Tephritidae) pupae and pteromalid parasitoids (Hymenoptera: Pteromalidae) inside fly puparia.

Determining upper thermal limits of tephritid fly pupae can have practical implications for disinfesting soils and for predicting differential impacts of global warming on flies and their parasites. Here, upper thermal limits of Rhagoletis indifferens Curran (Diptera: Tephritidae) pupae and pteromalid wasps (Hymenoptera: Pteromalidae) inside puparia were determined. Puparia receiving sufficient chill to terminate pupal diapause were exposed to temperatures ramped linearly over 6 h from 21 °C to 47.8, 49.4, 51.1, 55.0, or 60.0 °C for a 0-h hold time. Flies eclosed when pupae were exposed to 47.8 °C but not to 49.4, 51.1, 55.0, or 60.0 °C nor in a separate test to 47.8 °C for 1-3 h hold times. All fly pupae in treatments where no eclosion occurred were dead based on puparial dissections. In contrast, adult wasps eclosed when puparia were exposed to 49.4 and 51.1 °C for 0 h and to 47.8 °C for 1- and 2-h hold times. Despite the greater upper thermal limits of wasps, heat delayed eclosion times of both adult flies and wasps, in 47.8 and 51.1 °C treatments, respectively. In separate tests, longevity of flies exposed as pupae to 47.3-48.6 °C was greater than of control flies, while longevity of control wasps and wasps exposed as immatures to 47.8-51.1 °C did not differ. Flies exposed as pupae to 47.2-48.6 °C produced as many eggs and puparia as control flies. Results suggest heat could be used to disinfest soils of puparia while sparing parasitoids. In addition, extreme heat waves due to global warming might be more detrimental to fly pupae than immature wasps.

Evidence for adaptation of Rhagoletis pomonella (Diptera: Tephritidae) on large-thorn hawthorn, Crataegus macracantha, in Okanogan County, Washington State, USA.

The apple maggot fly, Rhagoletis pomonella (Walsh) (Diptera: Tephritidae), was introduced from eastern North America into western North America via infested apples (Malus domestica Borkhausen) about 44 yr ago, where it subsequently adapted to 2 hawthorn species, Crataegus douglasii Lindley and C. monogyna Jacquin. Here, we test whether R. pomonella has also adapted to large-thorn hawthorn, Crataegus macracantha Loddiges ex Loudon, in Okanogan County, Washington State, USA. In 2020, 2021, and 2022, fruit of C. macracantha were shown to ripen in late September and were infested at rates from 0.7% to 3.0%. In laboratory rearing studies, large-thorn hawthorn flies from C. macracantha eclosed on average 9-19 days later than apple flies from earlier ripening apple (August-early September), consistent with large-thorn hawthorn flies having adapted to the later fruiting phenology of its host. In a laboratory no-choice test, significantly fewer (64.8%) large-thorn hawthorn than apple flies visited apples. In choice tests, greater percentages of large-thorn hawthorn than apple flies resided on and oviposited into C. macracantha versus apple fruit. Large-thorn hawthorn flies were also smaller in size than apple flies. Our results provide further support for the recursive adaptation hypothesis that R. pomonella has rapidly and independently specialized phenologically and behaviorally to different novel hawthorn hosts since its introduction into the Pacific Northwest of the USA, potentially leading to host race formation.

Longitudinal Doppler Assessments in Late Preterm Fetal Growth Restriction.

PURPOSE: To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). MATERIALS AND METHODS: A prospective European multicenter observational study included women with a singleton pregnancy, 32+ 0-36+ 6, at risk of FGR (estimated fetal weight [EFW] or abdominal circumference [AC] < 10th percentile, abnormal arterial Doppler or fall in AC from 20-week scan of > 40 percentile points). The primary outcome was a composite of abnormal condition at birth or major neonatal morbidity. UCR was categorized as normal (< 0.9) or abnormal (≥ 0.9). UCR was assessed by gestational age at measurement interval to delivery, and by individual linear regression coefficient in women with two or more measurements. RESULTS: 856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. CONCLUSION: An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR.

The association between trauma and paediatric trigger thumb deformity; experience from a single tertiary referral hospital.

Whilst the natural history and management of trigger thumb have been thoroughly investigated, the aetiology of the condition remains poorly understood. There are suggestions that this could be a congenital or acquired condition, but evidence remains limited. A history of trauma has repeatedly been noted in a proportion of patients presenting with trigger thumb. This retrospective study reviewed the presentations of 75 cases of trigger thumb in 65 consecutive children who underwent surgery for trigger thumb. We found that 28% of affected digits presented with a traumatic history to the thumb, of those 90% presented immediately post-injury with a flexion deformity. Those who presented with a traumatic history were typically younger at presentation (median age 27.0 months compared to 37.5 months for traumatic and atraumatic presentations respectively) but also tended to present earlier than the atraumatic group (one day compared to 12.17 months respectively). We conclude that a single traumatic event is unlikely to be the causative factor in the development of trigger thumb in children but it may expediate the development of individuals who are predisposed.

Comparison of Prevalence of Osteoarthritis in the Hand: A Multicenter Retrospective Cohort Study.

Introduction Several studies have previously been undertaken to investigate the prevalence of radiologic hand osteoarthritis (OA) in Caucasian, Japanese, Chinese, and Arabic populations. To date, there has been no direct international comparison study on the prevalence of radiologic hand OA between a Western and a Southeast Asian population. We hypothesize that there is difference in the pattern of joint involvement among individuals of both populations. Materials and Methods Consecutive hand radiographs from individuals aged 60 years and above were reviewed. Radiographic evidence of osteoarthritis in the various joints in the hands was graded using Kellgren-Lawrence (K-L) score. Chi-square test, Fisher's exact test, or Student's t -test was used as appropriate. Multiple logistic regression analysis was performed to evaluate the associations and relationships of radiographic hand OA between joints. Results A total of 194 patients exhibited radiographic OA. Singaporean patients were more likely to have radiographic OA of the thumb interphalangeal joint (IPJ) (65.1%) compared with the thumb carpometacarpal joint (CMCJ; 40.2%); British patients were more likely to have CMCJ (43.3%) OA than thumb IPJ (21.0%). The difference was statistically significant ( p = 0.00026). In the Singapore population, it was more likely that a patient had concurrent OA of both thumb and finger joints, whereas in the British population, this was apparent in only the above-80-year-old group. The most commonly affected joint was the left thumb IPJ (joint specific prevalence of 35%) in the Singapore population, and the right index finger distal interphalangeal joint (DIPJ; joint specific prevalence of 41.5%) in the British population. Conclusion Our study, the first study to compare between Singaporean and British populations, showed statistically significant difference in the prevalence of OA in the hands. These findings suggest ethnic and cultural factors play a part in such a distribution trend.

Accelerating TB diagnosis during the COVID-19 pandemic.

SETTING: The COVID-19 pandemic has caused significant disruption worldwide to economies and healthcare systems, even those with well-developed infrastructure.OBJECTIVE: To examine the effects of COVID-19 on TB diagnosis in Singapore, and to identify any factors that could facilitate early detection of TB among persons screened.DESIGN: To assess the impact of testing and diagnosis of the pandemic on TB, the number of TB-related tests from January 2018 to December 2020 were collected. We also conducted a retrospective case-control study of all adult patients admitted for COVID-19, TB or coinfection from 23 January to 31 May 2020.RESULTS: Nationwide testing for TB from 2018 to 2020 increased by 24.2%. We analysed 253 adult inpatients, of whom 107 (42.3%) were diagnosed with COVID-19, 134 (53.0%) had TB, while 12 (4.7%) had co-infection. Patients with TB were more likely to have chest X-ray abnormalities than those with COVID-19 (89.9% vs. 76.0%; P < 0.01). Patients with TB were more likely to have prolonged cough vs. those with COVID-19 infection (28 vs. 5 days; P < 0.01).CONCLUSION: Early screening for TB, even among patients with COVID-19, could lead to earlier diagnosis and treatment, thereby breaking the chain of transmission.

Evaluation of Organic, Food-Grade Hydrophobic Coatings for Suppressing Oviposition and Increasing Mortality of Western Cherry Fruit Fly (Diptera: Tephritidae).

Newer organic options for protecting fruit from tephritid fruit fly attack are needed to reduce extensive insecticide use. Here, we evaluated organic, food-grade hydrophobic coatings that help protect sweet cherries (Prunus avium L.) from water-induced cracking for suppressing attack on cherries by western cherry fruit fly, Rhagoletis indifferens Curran (Diptera: Tephtitidae), as well as for their effects on fly mortality. Three formulations of coatings called HydroShield 13.20, 13.22, and 13.28 that form invisible elastic barriers on cherries and that consist of complex carbohydrates, fatty acids and occlusive agents, solvents, emulsifiers, emollients, surfactants, and other ingredients were tested. In the laboratory, fly visits on and oviposition in HydroShield-coated cherries were 66.1-92.8% and 59.1-99.5% lower, respectively, than in controls. The mean number of dead female flies exposed to HydroShield-coated cherries was 69.4-94.6% greater than of females exposed to control cherries. In the field, three sprays of HydroShield 13.22 and 13.20 on sweet cherry trees in 2020, when fly densities were high, reduced larval infestations in cherries by 32.1% and 31.8%, respectively. In the field in 2021, when fly densities were lower, three sprays of HydroShield 13.22 and 13.28 reduced infestations in cherries by 90.5% and 86.8%, respectively, but sprays also reduced cherry size and toughened cherries. HydroShield formulations show promise in protecting sweet cherry from attack by R. indifferens, but further testing is needed to improve formulations so that they suppress fly oviposition without affecting cherry quality.

Sensitivities to Chill Durations and No-Chill Temperatures Regulating Eclosion Responses Differ Between Rhagoletis zephyria (Diptera: Tephritidae) and its Braconid Parasitoids (Hymenoptera: Braconidae).

Seasonal temperatures select for eclosion timing of temperate insects and their parasitoids. In western North America, the fruit fly Rhagoletis zephyria Snow (Diptera: Tephritidae) is parasitized by the hymenopterous wasps Utetes lectoides (Gahan), an egg parasite, and Opius downesi Gahan, a larval parasite (both Braconidae). Eclosion of wasps should be timed with the presence of susceptible fly stages, but reports indicate U. lectoides ecloses in the absence of flies under no-chill conditions. Based on this, we tested the hypotheses that chill durations and no-chill temperatures both differentially regulate eclosion times of R. zephyria and its parasitic wasps. When fly puparia were chilled at ~3°C for 130-180 d, U. lectoides and O. downesi always eclosed on average later than flies. However, after 180-d chill, flies eclosed on average earlier than after 130- and 150-d chill, whereas eclosion times of U. lectoides and O. downesi were less or not affected by chill duration. When fly puparia were exposed to 20-22°C (no chill), U. lectoides eclosed before flies, with 88.9% of U. lectoides versus only 0.61% of flies eclosing. Taken together, findings show that eclosion times of flies are more sensitive to changes in chill duration than those of wasps. Flies are less sensitive than wasps to no-chill in that most flies do not respond by eclosing after no-chill while most wasps do. Our results suggest that shorter winters and longer summers due to climate change could cause mismatches in eclosion times of flies and wasps, with potentially significant evolutionary consequences.

Heat Treatments for Killing Apple Maggot Fly (Diptera: Tephritidae) Puparia for Application in Disinfesting Organic Yard Waste.

Organic yard waste from western Washington, U.S. that may contain puparia of apple maggot fly, Rhagoletis pomonella (Walsh) (Diptera: Tephritidae), had been moved to central Washington for composting, threatening the $3 billion apple industry concentrated in that region. Heating waste to kill fly puparia before it is transported could be a solution to this problem. Here, we report results of studies in 2016-2021 that sought to identify a minimum heat treatment simulating that obtained using a low-pressure steam generator for maximizing kill of R. pomonella puparia. In two experiments, puparia were exposed to temperatures ramped linearly over 6 h from 21°C to 47.8, 51.1, 55.0, or 60.0°C in an oven. The 47.8, 51.1, and 55°C treatments did not achieve 100% mortality, although only one adult fly from 4,000 puparia was found in the 55°C treatment, while no puparia survived the 60°C treatment. In a third, similar experiment, no puparia out of 2,400 exposed to 55°C survived. In a fourth and final experiment conducted over 3 years, no puparia out of 61,223 exposed to a 6-h ramp from 21°C to 55°C followed by a 1-h hold time at 55°C produced flies. In addition, all puparia in this treatment died. Based on 42.3 to 69.8% control survival, 31,217 puparia were killed by this treatment with no survivors, for a probit 8.7190 level of security. Results suggest that the 55°C and 1-h hold time treatment here is close to the minimum heat regime needed for disinfesting organic waste of R. pomonella puparia.

Radiomics biopsy signature for predicting survival in patients with spinal bone metastases (SBMs).

STUDY DESIGN: Retrospective analysis of a registered cohort of patients treated and irradiated for metastases in the spinal column in a single institute. OBJECTIVE: This is the first study to develop and internally validate radiomics features for predicting six-month survival probability for patients with spinal bone metastases (SBM). BACKGROUND DATA: Extracted radiomics features from routine clinical CT images can be used to identify textural and intensity-based features unperceivable to human observers and associate them with a patient survival probability or disease progression. METHODS: A study was conducted on 250 patients treated for metastases in the spinal column irradiated for the first time between 2014 and 2016, at the MAASTRO clinic in Maastricht, the Netherlands. The first 150 available patients were used to develop the model and the subsequent 100 patient were considered as a test set for the model. A bootstrap (B = 400) stepwise model selection, which combines both the forward and backward variable elimination procedure, was used to select the most useful predictive features from the training data based on the Akaike information criterion (AIC). The stepwise selection procedure was applied to the 400 bootstrap samples, and the results were plotted as a histogram to visualize how often each variable was selected. Only variables selected more than 90 % of the time over the bootstrap runs were used to build the final model.A prognostic index (PI) called radiomics score (radscore) and clinical score (clinscore) was calculated for each patient. The prognostic index was not scaled, the original values were used which can be extracted from the model directly or calculated as a linear combination of the variables in the model multiplied by the respective beta value for each patient. RESULTS: The clinical model had a good discrimination power. The radiomics model, on the other hand, had an inferior performance with no added predictive power to the clinical model. The internal imaging characteristics do not seem to have a value in the prediction of survival. However, the Shape features were excluded from further analyses in our study since all biopsies had a standard shape hence no variability.