The distribution of COVID-19-related risks.

We document two COVID-19-related risks, viral risk and employment risk, and their distributions across the Canadian population. The measurement of viral risk is based on the VSE COVID-19 Risk/Reward Assessment Tool, created to assist policy-makers in determining the impacts of pandemic-related economic shutdowns and re-openings. Women are more concentrated in high-viral-transmission-risk occupations, which is the source of their greater employment loss over the first part of the pandemic. They were also less likely to maintain contact with their former employers, reducing employment recovery rates. Low-educated workers face the same viral risk rates as high-educated workers but much higher employment losses. This is largely due to their lower likelihood of switching to working from home. For both women and the low-educated, existing inequities in their occupational distributions and living situations have resulted in them bearing a disproportionate amount of the risk emerging from the pandemic. Assortative matching in couples has tended to exacerbate risk inequities.

Dans cet article, nous documentons deux risques associés à la COVID­19, soit le risque de contracter le virus étant donné l'emploi occupé et le risque de perdre son emploi dans le contexte de la pandémie. La répartition de ces risques dans la population canadienne est aussi documentée. La mesure du risque viral est basée sur l'outil de visualisation des risques par profession et industrie liés à la COVID­19 de la VSE, créée pour aider les décideurs à déterminer les impacts des fermetures et réouvertures des différents secteurs de l'économie durant la pandémie. On note que les femmes sont plus présentes dans les professions à haut risque viral, ce qui explique en partie leur plus grande perte d'emploi durant la première partie de la pandémie. Durant la pandémie, elles étaient également moins susceptibles de demeurer en contact avec leurs anciens employeurs, ce qui a affecté négativement leur taux de retour au travail. Le risque viral était similaire pour les travailleurs peu éduqués et les travailleurs hautement qualifiés, mais les pertes d'emplois ont été beaucoup plus importantes pour les travailleurs peu éduqués. Cette différence peut être attribuable à leur plus faible capacité à effectuer leur travail à domicile étant donné la nature de leur emploi. Tant pour les femmes que pour les personnes peu éduquées, les inégalités existantes dans leurs conditions de vie et leur répartition professionnelle les ont conduites à subir une part plus élevée du risque lié à la pandémie. Enfin, l'appariement assortatif des couples selon les professions a eu tendance à exacerber les inégalités face aux risques.

The effect of microgravity on the human venous system and blood coagulation: a systematic review.

NEW FINDINGS: What is the central question of this study? Recently, an internal jugular venous thrombus was identified during spaceflight: does microgravity induce venous and/or coagulation pathophysiology, and thus an increased risk of venous thromboembolism (VTE)? What is the main finding and its importance? Whilst data are limited, this systematic review suggests that microgravity and its analogues may induce an enhanced coagulation state due to venous changes most prominent in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability in microgravity and its analogues. However, whether such changes precipitate an increased VTE risk in spaceflight remains to be determined. ABSTRACT: Recently, an internal jugular venous thrombus was identified during spaceflight, but whether microgravity induces venous and/or coagulation pathophysiology, and thus, an increased risk of venous thromboembolism (VTE) is unclear. Therefore, a systematic (Cochrane compliant) review was performed of venous system or coagulation parameters in actual spaceflight (microgravity) or ground-based analogues in PubMed, MEDLINE, Ovid EMBASE, Cochrane Library, European Space Agency, National Aeronautics and Space Administration, and Deutsches Zentrum für Luft-und Raumfahrt databases. Seven-hundred and eight articles were retrieved, of which 26 were included for evaluation with 21 evaluating venous, and five coagulation parameters. Nine articles contained spaceflight data, whereas the rest reported ground-based analogue data. There is substantial variability in study design, objectives and outcomes. Yet, data suggested cephalad venous system dilatation, increased venous pressures and decreased/reversed flow in microgravity. Increased fibrinogen levels, presence of thrombin generation markers and endothelial damage were also reported. Limited human venous and coagulation system data exist in spaceflight, or its analogues. Nevertheless, data suggest spaceflight may induce an enhanced coagulation state in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability. Whether such changes precipitate an increased VTE risk in spaceflight remains to be determined.

COVID-19 and the Economic Importance of In-Person K-12 Schooling.

The extent to which elementary and secondary (K-12) schools should remain open is at the forefront of discussions on long-term pandemic management. In this context, little mention has been made of the immediate importance of K-12 schooling for the rest of the economy. Eliminating in-person schooling reduces the amount of time parents of school-aged children have available to work and therefore reduces income to those workers and the economy as a whole. We discuss two measures of economic importance and how they can be modified to better reflect the vital role played by K-12 education. The first is its size, as captured by the fraction of gross domestic product produced by that sector. The second is its centrality, reflecting how essential the sector is to the network of economic activity. Using data from Canada's Census of Population and Symmetric Input-Output Tables, we show how accounting for this role dramatically increases the importance of K-12 schooling.

La mesure dans laquelle il conviendrait de garder ouverts les établissements d'enseignement de la maternelle à la 12e année est au premier plan des discussions liées à la gestion à long terme de la pandémie. Dans ce contexte, l'importance immédiate de l'éducation de la maternelle à la 12e année pour le reste de l'économie n'a été que timidement évoquée. La suppression de l'enseignement en classe réduit le temps dont disposent les parents d'enfants d'âge scolaire pour travailler, ce qui a pour effet de réduire le revenu versé à ces travailleurs et d'affaiblir l'économie dans son ensemble. Nous traitons de deux indicateurs de cette importance économique et de la façon dont ces indicateurs peuvent être modifiés de manière à mieux refléter le rôle déterminant que joue l'éducation de la maternelle à la 12e année. Le premier indicateur est la taille du secteur, représentée par la fraction du produit intérieur brut qu'il engendre. Le second est la centralité du secteur, soit la mesure dans laquelle il est essentiel au réseau d'activité économique. À l'aide de données tirées du recensement de la population du Canada et des tableaux d'entrées-sorties symétriques, nous démontrons que la prise en compte de ce rôle crucial accroît considérablement l'importance de l'éducation de la maternelle à la 12e année.

Effect of novel short-arm human centrifugation-induced gravitational gradients upon cardiovascular responses, cerebral perfusion and g-tolerance.

KEY POINTS: The aim of this study was to determine the effect of rotational axis position (RAP and thus g-gradient) during short-arm human centrifugation (SAHC) upon cardiovascular responses, cerebral perfusion and g-tolerance. In 10 male and 10 female participants, 10 min passive SAHC runs were performed with the RAP above the head (P1), at the apex of the head (P2), or at heart level (P3), with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. We hypothesized that movement of the RAP from above the head (the conventional position) towards the heart might reduce central hypovolaemia, limit cardiovascular responses, aid cerebral perfusion, and thus promote g-tolerance. Moving the RAP footward towards the heart decreased the cerebral tissue saturation index, calf circumference and heart rate responses to SAHC, thereby promoting g-tolerance. Our results also suggest that RAP, and thus g-gradient, warrants further investigation as it may support use as a holistic spaceflight countermeasure. ABSTRACT: Artificial gravity (AG) through short-arm human centrifugation (SAHC) has been proposed as a holistic spaceflight countermeasure. Movement of the rotational axis position (RAP) from above the head towards the heart may reduce central hypovolaemia, aid cerebral perfusion, and thus promote g-tolerance. This study determined the effect of RAP upon cardiovascular responses, peripheral blood displacement (i.e. central hypovolaemia), cerebral perfusion and g-tolerance, and their inter-relationships. Twenty (10 male) healthy participants (26.2 ± 4.0 years) underwent nine (following a familiarization run) randomized 10 min passive SAHC runs with RAP set above the head (P1), at the apex of the head (P2), or at heart level (P3) with foot-level Gz at 1.0 g, 1.7 g and 2.4 g. Cerebral tissue saturation index (cTSI, cerebral perfusion surrogate), calf circumference (CC, central hypovolaemia), heart rate (HR) and digital heart-level mean arterial blood pressure (MAP) were continuously recorded, in addition to incidence of pre-syncopal symptoms (PSS). ΔCC and ΔHR increases were attenuated from P1 to P3 (ΔCC: 5.46 ± 0.54 mm to 2.23 ± 0.42 mm; ΔHR: 50 ± 4 bpm to 8 ± 2 bpm, P < 0.05). In addition, ΔcTSI decrements were also attenuated (ΔcTSI: -2.85 ± 0.48% to -0.95 ± 0.34%, P < 0.05) and PSS incidence lower in P3 than P1 (P < 0.05). A positive linear relationship was observed between ΔCC and ΔHR with increasing +Gz, and a negative relationship between ΔCC and ΔcTSI, both independent of RAP. Our data suggest that movement of RAP towards the heart (reduced g-gradient), independent of foot-level Gz, leads to improved g-tolerance. Further investigations are required to assess the effect of differential baroreceptor feedback (i.e. aortic-carotid g-gradient).

Variation in Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy Outcomes in Asian American Men: A Multicenter Study.

PURPOSE: Asian American men have distinctly different prostate cancer epidemiology than other men. To our knowledge the role of multiparametric magnetic resonance imaging and targeted biopsy for elevated prostate specific antigen in this population has not been assessed. We sought to define imaging and targeted biopsy outcomes in Asian American men compared to other men. MATERIALS AND METHODS: We accrued a multicenter, prospective cohort of men who underwent magnetic resonance imaging targeted and systematic biopsy for elevated prostate specific antigen. The outcome of interest was a diagnosis of clinically significant prostate cancer (Gleason Grade Group 2 or greater) stratified by the PI-RADS™ (Prostate Imaging-Reporting and Data System) score and a history of negative biopsy. Multivariable logistic regression was used to assess the effect of Asian American race on cancer detection. RESULTS: Of the 2,571 men 275 (11%) were Asian American. Clinically significant prostate cancer was detected in 37% of Asian American men compared to 48% of men of other races (p <0.001). Asian American men were also less likely to be diagnosed with Grade Group 1 cancer (12% vs 18%, p=0.007). Additionally, there was significantly lower detection of significant cancer using PI-RADS 3 in Asian American men vs men of other races (12% vs 21%, p=0.032). On adjusted analysis Asian American men were less likely to be diagnosed with significant cancer (OR 0.57, 95% CI 0.42-0.79, p <0.001) and Grade Group 1 cancer (OR 0.57, 95% CI 0.38-0.84, p=0.005) than nonAsian men. CONCLUSIONS: Asian American men are less likely to be diagnosed with clinically significant prostate cancer on targeted biopsy, illustrating the different performance of PI-RADS in this population. Conventional risk assessment tools should be modified when selecting Asian American men for biopsy.

Adrenomedullin and galanin responses to orthostasis in older persons.

BACKGROUND: Neuroendocrine responses to orthostasis may be critical in the maintenance of mean arterial pressure in healthy individuals. A greater reduction in orthostatic tolerance with age may relate to modulation of hormonal responses such as adrenomedullin and galanin. Thus, we investigated (i) whether adrenomedullin and galanin concentrations increase during orthostatic challenge in older subjects, (ii) whether adrenomedullin and galanin concentrations are higher in older females compared with older males when seated and during orthostatic challenge, and (iii) whether postural changes in plasma concentrations of galanin are correlated with levels of adrenomedullin in either older females or males. MATERIALS AND METHODS: Subjects (n = 18; 12 ♀; 55-80 years old) performed a sit-to-stand test in a 25°C sensory-minimised environment, with blood samples collected after 4 min of being seated and then when standing. Plasma adrenomedullin and galanin concentrations were determined. RESULTS: Baseline plasma concentration of adrenomedullin (5·35 ± 0·74 (n = 12, females) vs. 7·40 ± 1·06 pg/mL (n = 5, males)) and galanin (64·07 ± 9·05 vs. 98·99 ± 16·90 pg/mL, respectively) did not significantly differ between genders. Furthermore, plasma adrenomedullin and galanin concentrations were not significantly affected by adoption of the upright posture in either gender and were not correlated in females or males. CONCLUSIONS: Adrenomedullin and galanin concentrations were similar between genders and did not change following adoption of the standing posture. To further clarify the roles, these hormones play in orthostatic intolerance, adrenomedullin and galanin concentrations should be assessed in participants who show presyncopal symptoms during an orthostatic challenge.

The Effect of the Gravity Loading Countermeasure Skinsuit Upon Movement and Strength.

Carvil, PA, Attias, J, Evetts, SN, Waldie, JM, and Green, DA. The effect of the gravity loading countermeasure skinsuit upon movement and strength. J Strength Cond Res 31(1): 154-161, 2017-Effective countermeasures against musculoskeletal deconditioning induced by microgravity and disuse are required. A simple alternative to provision of artificial gravity by centrifugation is compressive axial loading. The Russian "Pingvin" suit was the first wearable suit to apply this concept using bungee cords tethered around the shoulders and feet. However, poor loading characteristics and severe thermal and movement discomfort were reported. The gravity loading countermeasure skinsuit (GLCS) uses a bidirectional weave to generate staged axial loading from shoulders to feet, better mimicking how Earth's gravity induces progressive loading head to foot. The Mk III GLCS's loading was evaluated and tolerability assessed during maximal joint motion, ambulation, and selected strength exercises. Eight subjects (5 male and 3 female; 28 ± 3 years; 179 ± 0.1 cm and 74.8 ± 2.9 kg), having given written informed consent, had an Mk III GLCS individually tailored. Axial loading imparted, body height, joint range of motion (ROM), ambulation, and strength tests (12 repetition maximum) were performed in the GLCS and gym attire, with subjective (rating of perceived exertion, thermal comfort, movement discomfort and body control) ratings recorded throughout. Gravity loading countermeasure skinsuit provided significant axial loading when standing but significantly reduced knee (-13°), spinal (-28°) and shoulder flexion/extension ROM (-34°/-13°), in addition to Sit and Reach (-12.8 cm). No thermal issues were reported but there was an increase in subjective discomfort. Gravity loading countermeasure skinsuit did not significantly impede strength exercise, with the exception of shoulder press. The GLCS (Mk III) demonstrates potential as a countermeasure by providing tolerable, static axial loading. Furthermore, it may serve as an elasticlike strength exercise adjunct, which may have utility as a rehabilitation modality after further design refinement.

Influence of bed rest on plasma galanin and adrenomedullin at presyncope.

BACKGROUND: The role of hormones in reduced orthostatic tolerance following long-term immobilization remains uncertain. We have previously shown that plasma concentrations of adrenomedullin and galanin, two peptides with vasodepressor properties, rise significantly during orthostatic challenge. We tested the hypothesis that bedrest immobilization increases the rise in adrenomedullin and galanin during orthostatic challenge leading to presyncope. MATERIALS AND METHODS: We measured baseline (supine), presyncope and recovery (10 min postpresyncope, supine) levels of adrenomedullin and galanin in 8 healthy men, before and after 21 days of -6° head-down bed rest (HDBR). Presyncope was elicited using a combined head-up tilt and graded lower body negative pressure protocol. Orthostatic tolerance was defined as the time taken from the commencement of head-up tilt to the development of presyncope. RESULTS: Orthostatic tolerance time after HDBR reduced by 8·36 ± 5·39 min (P = 0·0032). HDBR increased plasma adrenomedullin concentration to orthostatic challenge (P = 0·0367). Compared to pre-HDBR, a significant rise in post-HDBR presyncopal (P < 0·001) and recovery adrenomedullin concentration (P < 0·01) was demonstrated. In contrast, we observed no change in pre- and post-HDBR galanin levels to orthostatic challenge. CONCLUSIONS: Bedrest immobilization appears to affect adrenomedullin levels in that greater increases in adrenomedullin occur at presyncope following bedrest immobilization. Due to its peripheral vasculature hypotensive effect, the greater levels of adrenomedullin at presyncope following bedrest immobilization may have contributed to the reduced orthostatic capacity postbedrest.

Lipiodol embolism following transarterial chemoembolization: an atypical case.

OBJECTIVE: Transarterial chemoembolization is a widely used therapy for the treatment of hepatocellular carcinoma. A rare adverse event is acute respiratory distress syndrome from pulmonary embolization of Lipiodol, an iodinated oil commonly used during the procedure. The objective of this report is to describe an atypical case of acute respiratory distress syndrome from Lipiodol embolization in a patient who underwent transarterial chemoembolization for hepatocellular carcinoma 9 days prior to presentation, despite having received relatively small amounts of Lipiodol (5.5 mL). Although this diagnosis has classically been based on radiological findings, we established a diagnosis after lipid-laden macrophages were detected in bronchial alveolar lavage fluid. DESIGN: Case report. SETTING: ICU of a major metropolitan academic medical center. PATIENTS: Single case. INTERVENTIONS: Diagnostic interventions included noncontrast CT scan of the chest and cytologic examination of bronchial alveolar lavage fluid with oil red O staining. Therapeutic interventions included mechanical ventilation and methylprednisolone infusions. MEASUREMENTS AND MAIN RESULTS: Noncontrast CT demonstrated nonspecific diffuse ground glass opacification, most prominent within the upper lobes. Mechanical ventilation was begun for hypoxemic respiratory failure. Cytologic examination of bronchial alveolar lavage fluid revealed a high proportion of lipid-laden macrophages, findings consistent with Lipiodol embolism. Despite infusions of methylprednisolone, the patient expired on hospital day 8. CONCLUSIONS: Acute respiratory distress syndrome from Lipiodol embolization following transarterial chemoembolization can occur even with small Lipiodol volumes. Cytologic examination of bronchial alveolar lavage fluid with oil red O staining is a useful diagnostic modality, especially when imaging studies are equivocal.

A prospective pilot study of (89)Zr-J591/prostate specific membrane antigen positron emission tomography in men with localized prostate cancer undergoing radical prostatectomy.

PURPOSE: In this pilot study we explored the feasibility of (89)Zr labeled J591 monoclonal antibody positron emission tomography of localized prostate cancer. MATERIALS AND METHODS: Before scheduled radical prostatectomy 11 patients were injected intravenously with (89)Zr-J591, followed 6 days later by whole body positron emission tomography. Patients underwent surgery the day after imaging. Specimens were imaged by ex vivo micro positron emission tomography and a custom 3 Tesla magnetic resonance scanner coil. Positron emission tomography images and histopathology were correlated. RESULTS: Median patient age was 61 years (range 47 to 68), median prostate specific antigen was 5.2 ng/ml (range 3.5 to 12.0) and median biopsy Gleason score of the 11 index lesions was 7 (range 7 to 9). On histopathology 22 lesions were identified. Median lesion size was 5.5 mm (range 2 to 21) and median Gleason score after radical prostatectomy was 7 (range 6 to 9). Eight of 11 index lesions (72.7%) were identified by in vivo positron emission tomography. Lesion identification improved with increasing lesion size for in vivo and ex vivo positron emission tomography (each p <0.0001), and increasing Gleason score (p = 0.14 and 0.01, respectively). Standardized uptake values appeared to correlate with increased Gleason score but not significantly (p = 0.19). CONCLUSIONS: To our knowledge this is the first report of (89)Zr-J591/prostate specific membrane antigen positron emission tomography in localized prostate cancer cases. In this setting (89)Zr-J591 bound to tumor foci in situ and positron emission tomography identified primarily Gleason score 7 or greater and larger tumors, likely corresponding to clinically significant disease warranting definitive therapy. A future, larger clinical validation trial is planned to better define the usefulness of (89)Zr-J591 positron emission tomography for localized prostate cancer.

Systematic review of the use of ultrasound for venous assessment and venous thrombosis screening in spaceflight.

The validity of venous ultrasound (V-US) for the diagnosis of deep vein thrombosis (DVT) during spaceflight is unknown and difficult to establish in diagnostic accuracy and diagnostic management studies in this context. We performed a systematic review of the use of V-US in the upper-body venous system in spaceflight to identify microgravity-related changes and the effect of venous interventions to reverse them, and to assess appropriateness of spaceflight V-US with terrestrial standards. An appropriateness tool was developed following expert panel discussions and review of terrestrial diagnostic studies, including criteria relevant to crew experience, in-flight equipment, assessment sites, ultrasound modalities, and DVT diagnosis. Microgravity-related findings reported as an increase in internal jugular vein (IJV) cross-sectional area and pressure were associated with reduced, stagnant, and retrograde flow. Changes were on average responsive to venous interventions using lower body negative pressure, Bracelets, Valsalva and Mueller manoeuvres, and contralateral IJV compression. In comparison with terrestrial standards, spaceflight V-US did not meet all appropriateness criteria. In DVT studies (n = 3), a single thrombosis was reported and only ultrasound modality criterion met the standards. In the other studies (n = 15), all the criteria were appropriate except crew experience criterion, which was appropriate in only four studies. Future practice and research should account for microgravity-related changes, evaluate individual effect of venous interventions, and adopt Earth-based V-US standards.

Transperineal Versus Transrectal Magnetic Resonance Imaging-targeted and Systematic Prostate Biopsy to Prevent Infectious Complications: The PREVENT Randomized Trial.

BACKGROUND AND OBJECTIVE: The transrectal biopsy approach is traditionally used to detect prostate cancer. An alternative transperineal approach is historically performed under general anesthesia, but recent advances enable transperineal biopsy to be performed under local anesthesia. We sought to compare infectious complications of transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis. METHODS: We assigned biopsy-naïve participants to undergo transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis (rectal culture screening for fluoroquinolone-resistant bacteria and antibiotic targeting to culture and sensitivity results) through a multicenter, randomized trial. The primary outcome was post-biopsy infection captured by a prospective medical review and patient report on a 7-d survey. The secondary outcomes included cancer detection, noninfectious complications, and a numerical rating scale (0-10) for biopsy-related pain and discomfort during and 7-d after biopsy. KEY FINDINGS AND LIMITATIONS: A total of 658 participants were randomized, with zero transperineal versus four (1.4%) transrectal biopsy infections (difference -1.4%; 95% confidence interval [CI] -3.2%, 0.3%; p = 0.059). The rates of other complications were very low and similar. Importantly, detection of clinically significant cancer was similar (53% transperineal vs 50% transrectal, adjusted difference 2.0%; 95% CI -6.0, 10). Participants in the transperineal arm experienced worse periprocedural pain (0.6 adjusted difference [0-10 scale], 95% CI 0.2, 0.9), but the effect was small and resolved by 7-d. CONCLUSIONS AND CLINICAL IMPLICATIONS: Office-based transperineal biopsy is tolerable, does not compromise cancer detection, and did not result in infectious complications. Transrectal biopsy with targeted prophylaxis achieved similar infection rates, but requires rectal cultures and careful attention to antibiotic selection and administration. Consideration of these factors and antibiotic stewardship should guide clinical decision-making. PATIENT SUMMARY: In this multicenter randomized trial, we compare prostate biopsy infectious complications for the transperineal versus transrectal approach. The absence of infectious complications with transperineal biopsy without the use of preventative antibiotics is noteworthy, but not significantly different from transrectal biopsy with targeted antibiotic prophylaxis.

Urothelial carcinoma of the bladder and the upper tract: disparate twins.

PURPOSE: Urothelial carcinoma of the bladder is the 4th most common malignancy in men and the 8th most common cause of male cancer death in the United States. Conversely, upper tract urothelial carcinoma accounts for only 5% to 10% of all urothelial carcinoma. Due to the relative preponderance of urothelial carcinoma of the bladder, much of the clinical decision making regarding upper tract urothelial carcinoma is extrapolated from evidence that is based on urothelial carcinoma of the bladder cohorts. In fact, only 1 major urological organization has treatment guidelines specific for upper tract urothelial carcinoma. While significant similarities exist between these 2 diseases, ignoring the important differences may be preventing us from optimizing therapy in patients with upper tract urothelial carcinoma. Therefore, we explored these dissimilarities, including the differential importance of gender, anatomy, staging, intracavitary therapy, surgical lymphadenectomy and perioperative systemic chemotherapy on the behavior of urothelial carcinoma of the bladder and upper tract urothelial carcinoma. MATERIALS AND METHODS: A nonsystematic literature search using the MEDLINE/PubMed® database was conducted to identify original articles, review articles and editorials. Searches were limited to the English language and studies in humans and in adults, and used the key words urothelial carcinoma, upper tract urothelial carcinoma or transitional cell carcinoma combined with several different sets of key words to identify appropriate publications for each section of the manuscript. The key words, broken down by section, were 1) epidemiology, sex, gender; 2) location, tumor location; 3) staging, stage; 4) intracavitary, intravesical, topical therapy; 5) lymphadenectomy, lymph node, lymph node dissection and 6) adjuvant, neoadjuvant, chemotherapy. RESULTS: Women who present with urothelial carcinoma of the bladder do so with less favorable tumor characteristics and have worse survival than men. However, gender does not appear to be associated with survival outcomes in upper tract urothelial carcinoma. The prognostic effect that urothelial carcinoma tumor location has on outcomes prediction is a matter of debate, and the influence of tumor location may reflect our technical ability to accurately stage and treat the disease more than the actual tumor biology. Moreover, technical limitations of upper tract urothelial carcinoma sampling compared to transurethral resection for urothelial carcinoma of the bladder are the most important source of staging differences between the 2 diseases. Intravesical chemotherapy and immunotherapy are essential components of standard of care for most nonmuscle invasive bladder cancer, while adjuvant intracavitary therapy for patients with upper tract urothelial carcinoma treated endoscopically or percutaneously has been sparsely used and without any clear guidelines. The widespread adoption of the use of intracavitary therapy in the upper tract will likely not only require additional data to support its efficacy, but will also require a less cumbersome means of administration. Lymphadenectomy at the time of radical cystectomy is widely accepted while lymphadenectomy at the time of radical nephroureterectomy is performed largely at the discretion of the surgeon. Among other reasons, this may be due in part to the variable lymphatic drainage along the course of the ureter compared to the relatively confined lymphatic landing sites for the bladder. Level I evidence has demonstrated a clear survival benefit for systemic chemotherapy before radical surgery or radiation in patients with clinical T2-4N0M0 urothelial carcinoma of the bladder. Such data are not available in the population with upper tract urothelial carcinoma. However, the use of neoadjuvant chemotherapy may be even more important in upper tract urothelial carcinoma than in urothelial carcinoma of the bladder because of the obligatory kidney function loss that occurs at radical nephroureterectomy. CONCLUSIONS: While urothelial carcinoma of the bladder and upper tract urothelial carcinoma share many characteristics, they represent 2 distinct diseases. There are practical, anatomical, biological and molecular differences that warrant consideration when risk stratifying and treating patients with these disparate twin diseases. To overcome the challenges that impede progress toward evidence-based medicine in upper tract urothelial carcinoma, we believe that focused collaborative efforts will best augment our understanding of this rare disease and ultimately improve the care we deliver to our patients.

Predictors of survival in patients with soft tissue surgical margin involvement at radical cystectomy.

BACKGROUND: The presence of positive soft tissue surgical margins (STSM) at radical cystectomy (RC) is rare. Although some patients with STSM experience disease recurrence rapidly, some have long-term local disease control. We sought to describe the oncologic outcomes, identify predictors, and assess the impact of location and multifocality in patients with positive STSMs at RC. METHODS: We retrospectively collected the data of 4,335 patients treated with RC and pelvic lymphadenectomy at 11 academic centers from 1981 to 2008. STSM was defined as the presence of tumor at inked areas of soft tissue on the RC specimen. Univariate and multivariate Cox regression models addressed recurrence-free survival and cancer-specific survival after surgery. RESULTS: STSM were identified in 231 patients (5%). Actuarial recurrence-free survival estimates at 2 and 5 years after RC were 26 ± 3 and 21 ± 3%, respectively. Actuarial cancer-specific survival estimates at 2 and 5 years after RC were 33 ± 3 and 25 ± 4%, respectively. Higher body mass index (p = 0.050), higher tumor stage (p = 0.017), presence of grade 3 disease (p = 0.046), lymphovascular invasion (p = 0.003), and lymph node involvement (p = 0.003) were all independently associated with disease recurrence. Furthermore, higher tumor stage (p = 0.015), lymphovascular invasion (p = 0.006), and lymph node involvement (p = 0.006) were independently associated with cancer specific mortality. Location and multifocality of STSM were not associated with outcomes. CONCLUSIONS: Although most patients with STSM at RC had poor outcomes, more than one-fifth had durable cancer control. Pathologic features associated with disease recurrence in the general RC population also stratify patients with STSM into differential risk groups.

Cost-effective treatment of low-risk carcinoma not invading bladder muscle.

UNLABELLED: Study Type - Therapy (cost effectiveness analysis) Level of Evidence 2a What's known on the subject? and What does the study add? Bladder cancer is one of the costliest malignancies to treat throughout the life of a patient. The most cost-effective management for low-risk non-muscle-invasive bladder cancer is not known. The current study shows that employing cystoscopic office fulguration for low-risk appearing bladder cancer recurrences can materially impact the cost-effectiveness of therapy. In a follow-up protocol where office fulguration is routinely employed for low-risk bladder cancers, peri-operative intravesical chemotherapy may not provide any additional cost-effectiveness benefit. OBJECTIVE: To examine the cost-effectiveness of fulguration vs transurethral resection of bladder tumour (TURBT) with and without perioperative intravesical chemotherapy (PIC) for managing low-risk carcinoma not invading bladder muscle (NMIBC). Low-risk NMIBC carries a low progression rate, lending support to the use of office-based fulguration for small recurrences rather than traditional TURBT. MATERIALS AND METHODS: A Markov state transition model was created to simulate treatment of NMIBC with vs without PIC, with recurrence treated by formal TURBT vs treatment with fulguration. Costing data were obtained from the Medicare Resource Based Relative Value Scale. Data regarding the success of PIC were obtained from the peer-reviewed literature, as were corresponding utilities for bladder cancer-related procedures. Sensitivity analyses were performed. RESULTS: At 5-year follow-up, a strategy of fulguration without PIC was the most cost-effective (mean cost-effectiveness = US $654.8/quality-adjusted life year), despite a lower recurrence rate with PIC. Both fulguration strategies dominated each TURBT strategy. Sensitivity analysis showed that fulguration without PIC dominated all other strategies when the recurrence rate after PIC was increased to ≥14.2% per year. Similarly, the cost-effectiveness of TURBT becomes more competitive with fulguration when the total cost of TURBT declines < US $1175. CONCLUSIONS: The present study shows that fulguration without PIC was the most cost-effective strategy for treating low-risk NMIBC. The effectiveness of PIC and the cost of TURBT can materially impact the cost-effectiveness of the different management strategies. These results should be considered in treatment decisions in the context of preserving oncological control.

Accurate preoperative prediction of non-organ-confined bladder urothelial carcinoma at cystectomy.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Upstaging to non-organ-confined (NOC) disease is frequent at the time of radical cystectomy for urothelial carcinoma of the bladder (UCB). Pre-surgical models that can accurately predict which patients are likely to have more extensive disease are sparse. The present study developed an accurate nomogram for the prediction of NOC-UCB based on a cohort of patients with clinically organ-confined disease. Adoption of such a tool into daily clinical decision-making may lead to more appropriate integration of perioperative chemotherapy, thereby potentially improving survival in patients with UCB. OBJECTIVE: To create an accurate pre-cystectomy decision-making tool that allows for the accurate identification of patients with clinically organ-confined urothelial carcinoma of the bladder (UCB) who have non-organ-confined UCB (NOC-UCB) at cystectomy, as identification of patients with UCB most likely to benefit from neoadjuvant chemotherapy (NACTx) is hampered by inaccurate clinical staging. PATIENTS AND METHODS: A prospectively maintained single-institution database containing 201 patients who underwent cystectomy and pelvic lymph node (LN) dissection without NACTx for UCB was analysed. Predictive variables for NOC-UCB included, among others, age, gender, transurethral resection of bladder tumour (TURBT) findings (stage, grade, histology, size, presence of carcinoma in situ, lymphovascular invasion [LVI], multifocality), history of intravesical therapy, time from TURBT to cystectomy, and cross-sectional imaging findings. RESULTS: Clinical stage distribution was 19 patients with Ta, 15 with Tis, 67 with T1, and 100 with T2. At the time of cystectomy, NOC-UCB and LN-positive disease were found in 71 (35%) and 38 (19%) of patients, respectively; 81 (40%) of patients had NOC-UCB (≥pT3/Nany or pTany/N+). Tumour stage (P [trend] <0.001), presence of LVI (odds ratio [OR] 5.2; P = 0.02), and radiographic evidence of NOC-UCB or hydronephrosis (OR 3.2; P = 0.01) were independently associated with ≥pT3 Nany UCB. Tumour stage (P [trend] < 0.001) and presence of LVI (OR 6.64; P = 0.01) were independently associated with (≥pT3/Nany or pTany/N+) UCB. A nomogram to predict (≥pT3/Nany or pTany/N+) based on all three variables was highly accurate (area under the curve 0.828) and well calibrated, deviating <8% from ideal prediction. Decision curve analysis showed net benefit across all threshold probabilities. CONCLUSIONS: NOC-UCB can be predicted with high accuracy by integrating standard clinicopathological factors with imaging information. This model may help to identify patients with NOC-UCB who may benefit from NACTx.

Predictors of cancer-specific mortality after disease recurrence following radical cystectomy.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Outcomes after disease recurrence in patients with urothelial carcinoma of the bladder treated with radical cystectomy are variable, but the majority of patients die from the disease within 2 years after disease recurrence. Knowledge about prognostic factors that may influence survival after disease recurrence is limited. We found that outcomes after disease recurrence in patients with urothelial carcinoma of the bladder are significantly affected by common clinicopathological factors. In addition, a shorter time from surgery to disease recurrence is significantly associated with poor outcomes. These factors should be considered when scheduling salvage chemotherapy protocols/clinical trials. OBJECTIVE: To describe the natural history following disease recurrence after radical cystectomy (RC) and to identify prognostic factors that influence cancer-specific survival with special focus on time from RC to disease recurrence. METHODS: We identified 1545 patients from 16 international institutions who experienced disease recurrence after RC and bilateral lymphadenectomy. None of the patients received preoperative chemotherapy; 549 patients received adjuvant chemotherapy. A multivariable Cox regression model addressed time to cancer-specific mortality after disease recurrence. RESULTS: The median cancer-specific survival time after disease recurrence was 6.9 months (95% CI 6.3-7.4). Overall, 1254 of 1545 patients died from urothelial carcinoma of the bladder and 47 patients died from other causes. The actuarial cancer-specific survival estimate at 12 months after disease recurrence was 32%. On multivariable analysis, non-organ-confined tumour stages (hazard ratio [HR] 1.38, P= 0.002), lymph node metastasis (HR 1.25, P < 0.001), positive soft tissue surgical margin (HR 1.32, P= 0.002), female gender (HR 1.21, P= 0.003), advanced age (HR 1.16, P < 0.001) and a shorter interval from surgery to disease recurrence (P < 0.001) were significantly associated with cancer-specific mortality. The adjusted risk of death from cancer within 1 year after disease recurrence for patients who recurred 6, 12 and 24 months after surgery was 70%, 64% and 60%, respectively. CONCLUSIONS: Over two-thirds of patients who experience disease recurrence of urothelial carcinoma of the bladder after RC die within 12 months. Common clinicopathological factors are strongly associated with cancer-specific mortality. A shorter time from surgery to disease recurrence is significantly associated with poor outcomes. Accurate risk stratification could help in patient counselling and decision-making regarding salvage treatment.

Outcomes and prognostic factors in patients with a single lymph node metastasis at time of radical cystectomy.

OBJECTIVES: To identify clinicopathological factors that predict outcomes in patients with a single lymph node (LN) metastasis (pN1) treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). LN metastasis is an established predictor of clinical outcomes in patients. While most patients with large LN burden experience disease recurrence, lymphadenectomy can be curative in patients with pN1 disease. PATIENTS AND METHODS: We analysed 381 patients with pN1 UCB from a multi-institutional cohort of 4335 patients with UCB treated with RC and lymphadenectomy without preoperative chemo- or radiotherapy. Subgroup analyses were performed for patients with ≥9 LNs removed and according to adjuvant chemotherapy administration (n = 215). RESULTS: The median (interquartile range, IQR) LN number was 15 (19) and the median (IQR) LN density was 6.7 (7.5)%. Within a median follow-up of 41 months, the mean (+/- SD) 2- and 5-year cancer-specific survival (CSS) rates were 55 (3)% and 46 (3)%, respectively. On multivariable analysis that adjusted for the effects of standard clinicopathological features, female gender (hazard ratio [HR] 1.48, P = 0.023), higher tumour stage (HR 1.68, P = 0.007), positive soft tissue surgical margin (STSM; HR 2.06, P = 0.004), higher LN density (HR 2.99, P = 0.025) and absence of adjuvant chemotherapy (HR 0.70, P = 0.026) were independently associated with CSS. In subgroup analyses of patients with ≥9 LNs removed, tumour stage and STSM status remained independent predictors for CSS (P = 0.009 and P < 0.001, respectively). CONCLUSIONS: About half of the patients with pN1 UCB died from UCB within 5 years of RC. Pathological stage and STSM status are strong predictors for outcomes. Accurate prediction of the individual risk of CSS may help risk stratifying pN1 UCB in order to help improve clinical-decision making. Patients with pN1 UCB presenting with additional unfavourable risk factors need a closer follow-up scheduling and might receive adjuvant therapy.

Effects of body size and countermeasure exercise on estimates of life support resources during all-female crewed exploration missions.

Employing a methodology reported in a recent theoretical study on male astronauts, this study estimated the effects of body size and aerobic countermeasure (CM) exercise in a four-person, all-female crew composed of individuals drawn from a stature range (1.50- to 1.90-m) representative of current space agency requirements (which exist for stature, but not for body mass) upon total energy expenditure (TEE), oxygen (O2) consumption, carbon dioxide (CO2) and metabolic heat (Hprod) production, and water requirements for hydration, during space exploration missions. Assuming geometric similarity across the stature range, estimates were derived using available female astronaut data (mean age: 40-years; BMI: 22.7-kg·m-2; resting VO2 and VO2max: 3.3- and 40.5-mL·kg-1·min-1) on 30- and 1080-day missions, without and with, ISS-like countermeasure exercise (modelled as 2 × 30-min aerobic exercise at 75% VO2max, 6-day·week-1). Where spaceflight-specific data/equations were not available, terrestrial equivalents were used. Body size alone increased 24-h TEE (+ 30%), O2 consumption (+ 60%), CO2 (+ 60%) and Hprod (+ 60%) production, and water requirements (+ 17%). With CM exercise, the increases were + 25-31%, + 29%, + 32%, + 38% and + 17-25% across the stature range. Compared to the previous study of theoretical male astronauts, the effect of body size on TEE was markedly less in females, and, at equivalent statures, all parameter estimates were lower for females, with relative differences ranging from -5% to -29%. When compared at the 50th percentile for stature for US females and males, these differences increased to - 11% to - 41% and translated to larger reductions in TEE, O2 and water requirements, and less CO2 and Hprod during 1080-day missions using CM exercise. Differences between female and male theoretical astronauts result from lower resting and exercising O2 requirements (based on available astronaut data) of female astronauts, who are lighter than male astronauts at equivalent statures and have lower relative VO2max values. These data, combined with the current move towards smaller diameter space habitat modules, point to a number of potential advantages of all-female crews during future human space exploration missions.