Systemic anticancer therapy for urothelial carcinoma: UK oncologists' perspective.

Urothelial carcinoma (UC) is a common cancer associated with a poor prognosis in patients with advanced disease. Platinum-based chemotherapy has remained the cornerstone of systemic anticancer treatment for many years, and recent developments in the treatment landscape have improved outcomes. In this review, we provide an overview of systemic treatment for UC, including clinical data supporting the current standard of care at each point in the treatment pathway and author interpretations from a UK perspective. Neoadjuvant cisplatin-based chemotherapy is recommended for eligible patients with muscle-invasive bladder cancer and is preferable to adjuvant treatment. For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression. Among patients unable to receive platinum-based chemotherapy, immune checkpoint inhibitor (ICI) treatment is an option for those with programmed death ligand 1 (PD-L1)-positive tumours. Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non-platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.

Sphingid caterpillars conspicuous patches do not function as distractive marks or warning against predators.

To avoid predation by visual predators, caterpillars can be cryptic to decrease detectability or aposematic to warn predators of potential unpalatability. However, for some species, it is not clear if conspicuous patches are selected to avoid predation. For example, Pandora sphinx (Eumorpha pandorus, Lepidoptera: Sphingidae) caterpillars are assumed to be palatable and have both cryptic (green, brown) and conspicuous (orange, red) color morphs. Five lateral, off-white to yellow patches on either side may serve as a warning for predators or to draw attention away from the caterpillar's form to function as distractive marks. We conducted a field study in three temperate fragmented forests in Massachusetts to investigate the potential utility of E. pandorus coloration and conspicuous patches. Using four plasticine caterpillar prey model treatments, green and red with and without lateral conspicuous patches, we tested the effects of color, patch patterning, and seasonality on attack rates by a variety of taxa. We found that 43% of the prey models (n = 964) had bite marks by an array of predators including arthropods (67.5%), birds (18.2%), rodents (11.5%), and large mammals (2.8%). Arthropods as dominant predators align with conclusions from previous studies of prey models placed near ground level. Attack rates peaked for arthropods in late August and early September but were more constant across trials for vertebrates. Arthropods, a heterogeneous group, as indicated by the variety of bite marks, showed significantly higher attack rates on green colored prey models and a tendency of higher attack on solid (non-patch patterned) prey models. Vertebrates, more visually oriented predators, had significantly higher attack rates on red colored prey models and patch patterned prey models. Thus, our results did not suggest that conspicuous patch patterning reduced predation and therefore, we did not find support for the distractive mark hypothesis or warning hypothesis. Further, our study shows clear contrasting interpretations by different predators regarding visual defensive strategies.

Cabazitaxel versus docetaxel for treatment of metastatic castrate refractory prostate cancer.

Objectives: To assess cabazitaxel versus docetaxel re-challenge for the treatment of metastatic castrate refractory prostate cancer (CRPC) patients previously treated with docetaxel at inception of primary hormone therapy. Patients and Methods: The CANTATA trial was a prospective, two-arm, open-label, phase II study conducted in eight UK centres. Patients over the age of 18, with histologically proven, metastatic prostate cancer who had been previously treated with up to 6 cycles of docetaxel as part of the STAMPEDE trial (or treated with the same drug outside of the trial at primary diagnosis) and had a performance status (PS) of 0-2, were eligible. Patients who progressed during primary treatment with docetaxel or had received prior systemic chemotherapy were excluded. Cabazitaxel (25 mg/m2) or docetaxel (75 mg/m2) was administered via intravenous infusion every 3 weeks with oral prednisolone (10 mg) for up to 10 cycles, until disease progression, death or unacceptable toxicity. The primary outcome was clinical progression-free survival (PFS) as defined by either date of pain progression, date of a cancer-related skeletal-related event, or date of death from any cause. Analyses were by intention to treat. EudraCT number: 2012-003835-40. Results: Between 7 March 2013 and 4 January 2016, 15 patients with a median age of 70 years (range 54-76) were recruited; seven received cabazitaxel, eight docetaxel. The study was halted due to slow accrual. The median clinical PFS time in the cabazitaxel group was 6.2 months compared with 8.4 for the docetaxel group (95% confidence intervals were not reached due to the small number of patients). A total of 13 serious adverse events were reported. Conclusion: Due to the low number of patients recruited, meaningful comparisons could not be made. However, toxicity was in line with known outcomes for these agents, demonstrating it is feasible and safe to deliver chemotherapy to men relapsing with CRPC after upfront chemotherapy.

Deep image restoration for infrared photothermal heterodyne imaging.

Infrared photothermal heterodyne imaging (IR-PHI) is an all-optical table top approach that enables super-resolution mid-infrared microscopy and spectroscopy. The underlying principle behind IR-PHI is the detection of photothermal changes to specimens induced by their absorption of infrared radiation. Because detection of resulting refractive index and scattering cross section changes is done using a visible (probe) laser, IR-PHI exhibits a spatial resolution of ∼300 nm. This is significantly below the mid-infrared diffraction limit and is unlike conventional infrared absorption microscopy where spatial resolution is of order ∼5µm. Despite having achieved mid-infrared super-resolution, IR-PHI's spatial resolution is ultimately limited by the visible probe laser's diffraction limit. This hinders immediate application to studying samples residing in spatially congested environments. To circumvent this, we demonstrate further enhancements to IR-PHI's spatial resolution using a deep learning network that addresses the Abbe diffraction limit as well as background artifacts, introduced by experimental raster scanning. What results is a twofold improvement in feature resolution from 300 to ∼150 nm.

Using Infrared Photothermal Heterodyne Imaging to Characterize Micro- and Nanoplastics in Complex Environmental Matrices.

A key challenge for addressing micro- and nanoplastics (MNPs) in the environment is being able to characterize their chemical properties, morphologies, and quantities in complex matrices. Current techniques, such as Fourier transform infrared spectroscopy, provide these broad characterizations but are unsuitable for studying MNPs in spectrally congested or complex chemical environments. Here, we introduce a new, super-resolution infrared absorption technique to characterize MNPs, called infrared photothermal heterodyne imaging (IR-PHI). IR-PHI has a spatial resolution of ∼300 nm and can determine the chemical identity, morphology, and quantity of MNPs in a single analysis with high sensitivity. Specimens are supported on CaF2 coverslips under ambient conditions from where we (1) quantify MNPs from nylon tea bags after steeping in ultrapure water at 25 and 95 °C, (2) identify MNP chemical or morphological changes after steeping at 95 °C, and (3) chemically identify MNPs in sieved road dust. In all cases, no special sample preparation was required. MNPs released from nylon tea bags at 25 °C were fiber-like and had characteristic IR frequencies corresponding to thermally extruded nylon. At 95 °C, degradation of the nylon chemical structure was observed via the disappearance of amide group IR frequencies, indicating chain scission of the nylon backbone. This degradation was also observed through morphological changes, where MNPs altered shape from fiber-like to quasi-spherical. In road dust, IR-PHI analysis reveals the presence of numerous aggregate and single-particle (<3 µm) MNPs composed of rubber and nylon.

Kingella kingae septic arthritis.

AIMS: The aim of this study was to determine the extent to which patient demographics, clinical presentation, and blood parameters vary in Kingella kingae septic arthritis when compared with those of other organisms, and whether this difference needs to be considered when assessing children in whom a diagnosis of septic arthritis is suspected. METHODS: A prospective case series was undertaken at a single UK paediatric institution between October 2012 and November 2018 of all patients referred with suspected septic arthritis. We recorded the clinical, biochemical, and microbiological findings in all patients. RESULTS: A total of 160 patients underwent arthrotomy for a presumed septic arthritis. Of these, no organism was identified in 61 and only 25 of these were both culture- and polymerase chain reaction (PCR)-negative. A total of 36 patients did not undergo PCR analysis. Of the remaining 99 culture- and PCR-positive patients, K. kingae was the most commonly isolated organism (42%, n = 42). The knee (n = 21), shoulder (n = 9), and hip (n = 5) were the three most commonly affected joints. A total of 28 cases (66%) of K. kingae infection were detected only on PCR. The mean age of K. kingae-positive cases (16.1 months) was significantly lower than that of those whose septic arthitis was due to other organisms (49.4 months; p < 0.001). The mean CRP was significantly lower in the K. kingae group than in the other organism group (p < 0.001). The mean ESR/CRP ratio was significantly higher in K. kingae (2.84) than in other infections (1.55; p < 0.008). The mean ESR and ESR/CRP were not significantly different from those in the 'no organism identified' group. CONCLUSION: K. kingae was the most commonly isolated organism from paediatric culture- and/or PCR-positive confirmed septic arthritis, with only one third of cases detected on routine cultures. It is important to develop and maintain a clinical suspicion for K. kingae infection in young patients presenting atypically. Routine PCR testing is recommended in these patients. Cite this article: Bone Joint J 2021;103-B(3):584-588.

Examining the Need to Standardize Implanted Stimulator Connectors: NANS Survey Results.

INTRODUCTION: Connectors between implanted stimulator electrodes and pulse generators allow revisions, including battery changes or generator upgrades, to proceed without disturbing uninvolved components, such as the electrode. As new devices are introduced, however, connector incompatibility, even with updated hardware from the same manufacturer, can lead to additional procedures, expense, and morbidity. MATERIALS AND METHODS: Following the example of the cardiac pacemaker/defibrillator industry, the Institute of Neuromodulation (IoN) met to explore the possibility of creating connector standards for implanted neurostimulation devices. At a subsequent meeting of the Association for the Advancement of Medical Instrumentation, which coordinates the development of such standards, industry representatives asked for data defining the need for a new standard. Accordingly, IoN prepared an online survey to be sent to the North American Neuromodulation Society mailing list regarding experience with the connectivity of spinal cord stimulation (SCS) generators and electrodes. RESULTS: The 87 respondents of 9657 surveyed included 77 clinicians, who reported a total of 42,572 SCS implants and revisions. More than a quarter of revisions (2741 of 9935) required the interconnection of devices made by separate manufacturers, in most cases (n = 1528) to take advantage of a new feature (e.g., rechargeability, new waveform) or because an original component could not be replaced (n = 642). Connector adapters provided by manufacturers were used in less than half (n = 1246) of these cases. Nearly all (94%) of the clinicians agreed that standardized connectors should be developed for SCS, and 86% opined that standardized connectors should be developed for other neurostimulation therapies. CONCLUSION: Those who responded to our survey support the development of standard connectors for implanted stimulators, with voluntary compliance by manufacturers, to mitigate the need for adapters and facilitate interchanging components when appropriate. Other advantages to patients and manufacturers might accrue from the adoption of standards, as technology evolves and diversifies.

Assessing Patient Experience and Healthcare Quality of Dental Care Using Patient Online Reviews in the United States: Mixed Methods Study.

BACKGROUND: Over the last two decades, patient review websites have emerged as an essential online platform for doctor ratings and reviews. Recent studies suggested the significance of such websites as a data source for patients to choose doctors for healthcare providers to learn and improve from patient feedback and to foster a culture of trust and transparency between patients and healthcare providers. However, as compared to other medical specialties, studies of online patient reviews that focus on dentists in the United States remain absent. OBJECTIVE: This study sought to understand to what extent online patient reviews can provide performance feedbacks that reflect dental care quality and patient experience. METHODS: Using mixed informatics methods incorporating statistics, natural language processing, and domain expert evaluation, we analyzed the online patient reviews of 204,751 dentists extracted from HealthGrades with two specific aims. First, we examined the associations between patient ratings and a variety of dentist characteristics. Second, we identified topics from patient reviews that can be mapped to the national assessment of dental patient experience measured by the Patient Experience Measures from the Consumer Assessment of Healthcare Providers and Systems (CAHPS) Dental Plan Survey. RESULTS: Higher ratings were associated with female dentists (t71881=2.45, P<.01, g=0.01), dentists at a younger age (F7, 107128=246.97, P<.001, g=0.11), and those whose patients experienced a short wait time (F4, 150055=10417.77, P<0.001, g=0.18). We also identified several topics that corresponded to CAHPS measures, including discomfort (eg, painful/painless root canal or deep cleaning), and ethics (eg, high-pressure sales, and unnecessary dental work). CONCLUSIONS: These findings suggest that online patient reviews could be used as a data source for understanding the patient experience and healthcare quality in dentistry.

A comprehensive examination of the immediate recovery of children following tonsillectomy and adenoidectomy.

OBJECTIVES: Using multiple well-validated measures and a large sample size, the goal of this paper was to describe the immediate clinical and behavioral recovery of children following tonsillectomy with or without an adenoidectomy (T&A) during the first two weeks following surgery. STUDY DESIGN: Observational, longitudinal study. SETTING: Four major pediatric hospitals in the U.S. consisting of Children's Hospital of Orange County, Children's Hospital of Los Angeles, Lucile Packard Children's Hospital, and Children's Hospital Colorado. SUBJECTS: and Methods: Participants included 827 patients between 2 and 15 years of age who underwent tonsillectomy with or without adenoidectomy surgery. Baseline and demographic information were gathered prior to surgery, and measures of clinical, behavioral, and physical recovery were recorded immediately following and up through two weeks after surgery. RESULTS: Pain following T&A was clinically significant through the first post-operative week and nearly resolved by the end of the second week. Negative behavioral changes were highly prevalent after surgery (75.6% of children at Day 0) through the first week (63.9% at Week 1), and over 20% of children continued to evidence new onset negative behavioral changes at two weeks post-operatively. Children were rated as experiencing significant functional impairment in the immediate three days following surgery and most children returned to baseline functioning by the end of the second week. CONCLUSIONS: Results of this study suggest that children show immediate impairment in functioning and experience clinically significant pain throughout the first week following T&A, and new onset maladaptive behavioral changes persisting even up to the two-week assessment period.

Impairment of wound healing by reactive skin decontamination lotion (RSDL®) in a Göttingen minipig® model.

Reactive Skin Decontamination Lotion (RSDL®) is an FDA-approved skin decontamination kit carried by service members for removal and neutralisation of vesicants and nerve agents. The RSDL kit, comprised of a lotion-impregnated sponge, was shown to be the superior medical decontamination device for chemical warfare agent (CWA) exposure on intact skin. In the event of a chemical exposure situation (i.e. terrorism, battlefield) physical injuries are probable, and preservation of life will outweigh the risk associated with application of RSDL to compromised skin. The purpose of this study was to quantify the rate and quality of wound healing in epidermal skin wounds treated with RSDL in a porcine model. Degree of wound healing was assessed using bioengineering methods to include ballistometry, colorimetry, evaporimetry, and high-frequency ultrasonography. Clinical observation, histopathology and immunohistochemistry were also utilised. All pigs received four bilateral superficial abdominal wounds via a pneumatic dermatome on their ventral abdomen, then were treated with the following dressings over a seven-day period: RSDL sponge, petroleum based Xeroform® gauze, 3 M™ Tegaderm™ Film, and 3 M™ Tegaderm™ Foam. Two additional non-wounded sites on the flank were used as controls. Two groups of pigs were then evaluated for a 21- or 56-day time period, representing short- and long-term wound-healing progression. Our findings indicated RSDL had a negative impact on wound-healing progression at both 21 and 56 days post-injury. Wounds receiving RSDL demonstrated a decreased skin elasticity, significant transepidermal water loss, and altered skin colouration and thickness. In addition, the rate of wound healing was delayed, and return to a functional skin barrier was altered when compared to non-RSDL-treated wounds. In conclusion, wound management care and clinical therapeutic intervention plans should be established to account for a prolonged duration of healing in patients with RSDL-contaminated wounds.

Separation of overlapping sources in bioacoustic mixtures.

Source separation is an important step to study signals that are not easy or possible to record individually. Common methods such as deep clustering, however, cannot be applied to signals of an unknown number of sources and/or signals that overlap in time and/or frequency-a common problem in bioacoustic recordings. This work presents an approach, using a supervised learning framework, to parse individual sources from a spectrogram of a mixture that contains a variable number of overlapping sources. This method isolates individual sources in the time-frequency domain using only one function but in two separate steps, one for the detection of the number of sources and corresponding bounding boxes, and a second step for the segmentation in which masks of individual sounds are extracted. This approach handles the full separation of overlapping sources in both time and frequency using deep neural networks in an applicable manner to other tasks such as bird audio detection. This paper presents method and reports on its performance to parse individual bat signals from recordings containing hundreds of overlapping bat echolocation signals. This method can be extended to other bioacoustic recordings with a variable number of sources and signals that overlap in time and/or frequency.

Children and their parents' assessment of postoperative surgical pain: Agree or disagree?

OBJECTIVE: The purpose of this study is to compare postoperative pain scores between children undergoing tonsillectomy and adenoidectomy (T&A) surgery and their parents, identify potential predictors for this disagreement, and determine possible impact on analgesic administration. METHODS: This is a prospective longitudinal study conducted with children undergoing outpatient T&A in 4 major tertiary hospitals and their parents. Children and their parents were enrolled prior to surgery and completed baseline psychological instruments assessing parental anxiety (STAI), parental coping style (MBSS), child temperament (EAS) and parental medication administration attitude questionnaire (MAQ). Postoperatively, parents and children completed at-home pain severity ratings (Faces Pain Scale-Revised, children; Numeric Rating Scale, parents) on postoperative recovery days 1, 2, and 3, reflecting an overall pain level for the past 24 h. Parents also completed a log of analgesic administration. Based on postoperative pain scores, parent-child dyads were classified as overestimators (i.e., parents rated their child's pain higher than children rated their own pain), in agreement (i.e., rating in agreement), or underestimators (i.e., parents rated their child's pain lower than children rated their own pain). RESULTS: A significant proportion of parent-child pairs disagreed on pain ratings on postoperative days 1-3 (30.05%-35.95%). Of those pairs in disagreement, the majority of parents overestimated their child's pain on all three postoperative days, specifically such that a total of 24-26% parents overestimated their child's pain on postoperative days 1, 2, and 3. Repeated measures ANOVA demonstrated that parents in the overestimator group administered higher, though still within safe limits, amounts of ibuprofen and oxycodone (mg/day) than did the underestimator or agreement groups. Multiple regression models showed hospital site as the only independent predictor for postoperative pain rating disagreement between children and parents. CONCLUSIONS: Since parents overestimate their child's postoperative pain and may administer more analgesics to their child, it is essential to develop a standardized method of child pain assessment and a tailored recommended postoperative analgesic regimen amongst medical providers for children undergoing T&A.

Changing healthcare provider and parent behaviors in the pediatric post-anesthesia-care-unit to reduce child pain: Nurse and parent training in postoperative stress.

BACKGROUND: Children who undergo surgery experience significant pain in the post anesthesia care unit. Nurse and parent behaviors in the post anesthesia care unit directly impact child postoperative pain. Therefore, we have developed and evaluated (Phase 1) and then tested (Phase 2) the feasibility of a new intervention (Nurse and Parent Training in Postoperative Stress) to alter parent and nurse behaviors in a way consistent with reducing child postoperative pain. METHODS: In Phase 1, a multidisciplinary team of experts (physicians, nurses, and psychologists) developed an empirically-based intervention which was then evaluated by experienced nurses (N = 8) and parents (N = 9) during focus groups. After revising the intervention based on focus group feedback, it was tested in Phase 2 using a pre-post study design. Nurses (N = 23) who worked in the recovery room were recruited to be part of both pre- and post-intervention data collection periods. Parents were recruited to be part of either the pre- (N = 52) or post-intervention (N = 60) data collection periods. Nurses and parent-child dyads were recorded in the post anesthesia care unit and videos were coded for the desired (ie, behaviors that may decrease child pain) and non-desired (ie, behaviors that may increase child pain) behaviors. Pain data was collected from the children's medical records to assess pain after surgery. The intervention was given to the nurses and parents in the post-intervention data collection period. RESULTS: Nurses significantly increased their rate of desired behaviors by 231% (P = 0.001; Somer's D = 1) and significantly decreased their rate of non-desired behaviors by 62% (P = 0.004, Somer's D = -0.88, 95% CI [-1.74, -0.03]). Parents significantly increased their rate of desired behaviors by 124% (P = 0.033). Moreover, the intervention significantly decreased child pain in the post anesthesia care unit (b = -2.19, SE = 0.63, z = -3.46, P = 0.001, 95%CI [-3.43, -0.95]). CONCLUSION: The intervention was effective in changing nurse and parent behaviors as well as child pain after surgery.

Community richness of amphibian skin bacteria correlates with bioclimate at the global scale.

Animal-associated microbiomes are integral to host health, yet key biotic and abiotic factors that shape host-associated microbial communities at the global scale remain poorly understood. We investigated global patterns in amphibian skin bacterial communities, incorporating samples from 2,349 individuals representing 205 amphibian species across a broad biogeographic range. We analysed how biotic and abiotic factors correlate with skin microbial communities using multiple statistical approaches. Global amphibian skin bacterial richness was consistently correlated with temperature-associated factors. We found more diverse skin microbiomes in environments with colder winters and less stable thermal conditions compared with environments with warm winters and less annual temperature variation. We used bioinformatically predicted bacterial growth rates, dormancy genes and antibiotic synthesis genes, as well as inferred bacterial thermal growth optima to propose mechanistic hypotheses that may explain the observed patterns. We conclude that temporal and spatial characteristics of the host's macro-environment mediate microbial diversity.

Marijuana Lollipop-Induced Myocardial Infarction.

A 70-year-old man with known coronary artery disease presented with crushing chest pain, diaphoresis, and pallor after consuming a marijuana lollipop; the pain began within 30 minutes of consumption. His troponin T increased from 94 ng/L to 216 ng/L, with slight ST changes but no gross ST elevations. Discharge diagnosis was non-ST-elevation myocardial infarction, and subsequent nuclear medicine wall motion studies showed worsening ejection fraction (40% to 31%). He also described worsening functional status and exercise capacity after the event. The outcome of this case is important with new marijuana legalization-hopefully with marijuana use no longer criminalized, more research into the cardiovascular side effects will emerge.

Parental satisfaction of child's perioperative care.

BACKGROUND: Satisfaction in the hospital setting is an important component of both hospital funding and patient experience. When it comes to a child's hospital experience, parent satisfaction of their child's perioperative care is also necessary to understand. However, little research has been conducted on the predictors of this outcome. Therefore, the purpose of this current study was to validate a priori selected predictors for parental satisfaction in their child's perioperative process. METHODS: Eight hundred and ten pediatric patients who underwent tonsillectomy and adenoidectomy surgery and their parents were included in this study. The primary outcome was assessed using a 21-item parent satisfaction questionnaire resulting in three satisfaction scores: overall care satisfaction, OR/induction satisfaction, and total satisfaction. RESULTS: Descriptive statistics and correlational analysis found that sedative-premedication, parental presence at anesthesia induction, child social functioning, parental anxiety, and language were all significant predictors of various components of the satisfaction score. Regression models, however, revealed that only parent anxiety and child social functioning remained significant predictors such that parents who reported lower state anxiety (OR/induction satisfaction: OR = 0.975, 95% CI [0.957, 0.994]; total satisfaction: OR = 0.968, 95% CI [0.943, 0.993]) and who had higher socially functioning children (overall care satisfaction: OR = 1.019, 95% CI [1.005, 1.033]; OR/induction satisfaction: OR = 1.011, 95% CI [1.000, 1.022]) were significantly more satisfied with the perioperative care they received. CONCLUSION: Lower parent anxiety and higher child social functioning were predictive of higher parental satisfaction scores.

Evolution of Stereotactic Ablative Radiotherapy in Lung Cancer and Birmingham's (UK) Experience.

Stereotactic ablative radiotherapy (SABR) has taken a pivotal role in early lung cancer management particularly in the medically inoperable patients. Retrospective studies have shown this to be well tolerated with comparable results to surgery and no significant increase in toxicity. Paucity of randomized evidence has dictated initiation of several trials to provide good quality evidence to steer future practice. This review summaries salient developments in lung SABR, comparisons to surgery and other platforms and our local experience at University Hospitals Birmingham, UK of lung SABR since its initiation in June 2013.