Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential.

BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.

Enthusiasm, Opinion Leaders, Comparative Advantage, and the Uptake Of Laparoscopic Resection For Colorectal Cancer Liver Metastases in Ontario, Canada: A Population-Based Cohort Study.

BACKGROUND: Numerous factors likely influence adoption of surgical innovations in large regions. We considered the role of comparative advantage, surgeon enthusiasm, and opinion leaders on uptake of minimally invasive liver resection (MILR) for colorectal cancer (CRC) metastases in Ontario. METHODS: We used administrative data for patients undergoing liver resection for CRC metastases from years 2006-2015. Fourteen regions were divided into three groups based on overall rate of MILR for CRC metastases. Outcomes included postoperative complications, length of hospital stay (LOS), operative mortality, and 1-year survival. We evaluated uptake of MILR among groups and within groups between opinion leader and nonopinion leader surgeons. RESULTS: There were 2675 patients in the low-rate (n = 937), medium-rate (n = 919), and high-rate (n = 819) groups. In these same groups, the number of opinion leader surgeons was six, five, and six. Patient outcomes were similar among groups, except in the low-rate group LOS was 1 day greater (7 vs. 6 and 6; p = 0.017). The rate of MILR for CRC metastases did not change significantly among opinion leaders in any group. This rate among nonopinion leader surgeons was steady and low in the low-rate group (1.7-8.0%, p = 0.80) and increased in the mid-rate group (2.4-31.8%, p = 0.0026) and in the high-rate group (7.7-40.9%, p < 0.001). CONCLUSIONS: Greater use of MILR was associated with a 1-day shorter LOS. Relative enthusiasm for MILR for CRC metastases among a small number of opinion leader surgeons likely facilitated or dampened uptake of this complex innovation.

The Role of Deltoid Ligament Repair in Ankle Fractures With Syndesmotic Instability: A Systematic Review.

Ankle fractures are the fourth most common fracture requiring surgical management. The deltoid ligament is a primary ankle stabilizer against valgus forces. It is frequently ruptured in ankle fractures; however, there is currently no consensus regarding repair. A systematic database search was conducted with Medline, PubMed, and Embase for relevant studies discussing patients with ankle fractures involving deltoid ligament rupture and repair. Screening, quality assessment, and data extraction were performed independently and in duplicate. Data extracted included pain, range of motion (ROM), function, medial clear space (MCS), syndesmotic malreduction, and complications. After screening, 9 eligible studies from 1990 to 2018 were included (N = 508). Compared to nonrepair groups, deltoid ligament repair patients had lower syndesmotic malreduction rates (0%-9% vs 20%-35%, p ≤ .05), fewer implant removals (5.8% vs 41% p ≤ .05), and longer operating time by 16-20 minutes (p ≤ .05). There was no significant difference for pain, function, ROM, MCS, and complication rate (p ≤ .05). In conclusion, deltoid ligament repair offers lower syndesmotic malreduction rates and reduced re-operation rates for hardware removal in comparison to trans-syndesmotic screws. Repair groups demonstrated equivalent or better outcomes for pain, function, ROM, MCS, and complication rates. Other newer syndesmotic fixation methods such as suture-button fixation require further evaluation when compared to the outcomes of deltoid ligament repair. A randomized control trial is required to further examine the outcomes of ankle fracture patients who undergo deltoid ligament repair versus trans-syndesmotic screw fixation.

Predicting Indoor Concentrations of Black Carbon in Residential Environments.

Black carbon (BC) is a descriptive term that refers to light-absorbing particulate matter (PM) produced by incomplete combustion and is often used as a surrogate for traffic-related air pollution. Exposure to BC has been linked to adverse health effects. Penetration of ambient BC is typically the primary source of indoor BC in the developed world. Other sources of indoor BC include biomass and kerosene stoves, lit candles, and charring food during cooking. Home characteristics can influence the levels of indoor BC. As people spend most of their time indoors, human exposure to BC can be associated to a large extent with indoor environments. At the same time, due to the cost of environmental monitoring, it is often not feasible to directly measure BC inside multiple individual homes in large-scale population-based studies. Thus, a predictive model for indoor BC is needed to support risk assessment in public health. In this study, home characteristics and occupant activities that potentially modify indoor levels of BC were documented in 23 homes, and indoor and outdoor BC concentrations were measured twice. The homes were located in the Cincinnati-Kentucky-Indiana tristate region and measurements occurred from September 2015 through August 2017. A linear mixed-effect model was developed to predict BC concentration in residential environments. The measured outdoor BC concentrations and the documented home characteristics were utilized as predictors of indoor BC concentrations. After the model was developed, a leave-one-out cross-validation algorithm was deployed to assess the predictive accuracy of the output. The following home characteristics and occupant activities significantly modified the concentration of indoor BC: outdoor BC, lit candles and electrostatic or high efficiency particulate air (HEPA) filters in heating, ventilation and air conditioning (HVAC) systems. Predicted indoor BC concentrations explained 78% of the variability in the measured indoor BC concentrations. The data show that outdoor BC combined with home characteristics can be used to predict indoor BC levels with reasonable accuracy.

Indications and outcomes of simultaneous high tibial osteotomy and ACL reconstruction.

PURPOSE: The purpose of this study was to systematically review the existing literature reporting surgical outcomes of simultaneous high tibial osteotomy (HTO) and anterior cruciate ligament reconstruction (ACLR) in anterior cruciate ligament deficient (ACLD) knees. METHODS: This study was conducted per the methods of the Cochrane Handbook for Systematic Reviews of Intervention, with findings reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The electronic databases MEDLINE, EMBASE, and PubMed were searched for relevant studies and pertinent data was extracted. Studies reporting post-operative outcomes following simultaneous HTO and ACLR in ACLD knees were included. RESULTS: The search identified 515 studies, of which 18 (n = 516) were included. The mean MINORS scores for non-comparative and comparative studies were 11.6 ± 1.34 and 17.3 ± 1.9, respectively. Simultaneous HTO and ACLR resulted in improved functional subjective patient outcomes across a variety of scales. Simultaneous HTO and ACLR was effective in correcting varus angulation, with the post-operative mechanical angle ranging from 0.3° valgus to 7.7° valgus. The reported complication rate ranged from 0 to 23.5%. Across six studies, a total of 13 (6.5%) patients required revision HTO; while across four studies, 20 (17.5%) patients had failure of the ACL graft, with one receiving revision ACLR. CONCLUSIONS: Combined HTO and ACLR may be indicated in patients with ACLD knees with varus angulation. This systematic review found that the combined surgery resulted in significant improvement in post-operative functional subjective outcomes. However, it remains unclear if HTO with ACLR is superior to ALCR or HTO alone due to the lack of comparative studies. Overall, HTO with ACLR was found to have low rates of complications, re-ruptures, and need for revision surgery. This review found that patients continued to have progression of OA despite combined HTO with ACLR. Future research is required to better understand the effects of combined HTO and ACLR compared to ACLR or HTO alone and to evaluate the long-term post-operative progression of medial compartment OA following combined HTO and ACLR. LEVEL OF EVIDENCE: IV.

Seasonal dependency of controlling factors on the phytoplankton production in Taihu Lake, China.

In this study, 44 profiles of gross primary productivity (GPP) and sunlight, along with water temperature, Chlorophyll-a (Chla) and nutrients, were observed in Meiliang Bay of Taihu Lake, China, in the spring, summer, and fall seasons. Effects of water temperature, light, and nutrient concentration were examined in relation to the GPP-unit-Chla (GPP of algae per Chla). The results showed that the optimum temperature for the GPP of phytoplankton was 27.9°C, the optimal PNA-unit-Chla (photon number absorbed by phytoplankton per Chla) was 0.25 (mol), and the HSCN-unit-Chla and HSCP-unit-Chla (half-saturation constants of nitrogen and phosphorus of algae per Chla) were 0.005 (mg/L) and 0.0004 (mg/L), respectively. The seasonal dependency of the effect of different factors on the GPP was analyzed. Compared with temperature and nutrients, light was found to be the most important factor affecting the GPP during the three seasons. The effect of temperature and nutrients on the GPP of phytoplankton has obvious seasonal change. In spring, temperature was the secondary factor affecting the GPP of phytoplankton, and the effect of nutrients may be negligible in the eutrophic lake on account of temperature limit, which showed that the GPP of algae was only affected by the physical process. In summer and fall, temperature didn't affect the GPP of algae, and the presence of nutrients was the secondary factor affecting the GPP of phytoplankton. From summer to fall, effect of phosphorus was weakened and effect of nitrogen was enhanced.

Intensified dust storm activity and Valley fever infection in the southwestern United States.

Climate models have consistently projected a drying trend in the southwestern United States, aiding speculation of increasing dust storms in this region. Long-term climatology is essential to documenting the dust trend and its response to climate variability. We have reconstructed long-term dust climatology in the western United States, based on a comprehensive dust identification method and continuous aerosol observations from the Interagency Monitoring of Protected Visual Environments (IMPROVE) network. We report here direct evidence of rapid intensification of dust storm activity over American deserts in the past decades (1988-2011), in contrast to reported decreasing trends in Asia and Africa. The frequency of windblown dust storms has increased 240% from 1990s to 2000s. This dust trend is associated with large-scale variations of sea surface temperature in the Pacific Ocean, with the strongest correlation with the Pacific Decadal Oscillation. We further investigate the relationship between dust and Valley fever, a fast-rising infectious disease caused by inhaling soil-dwelling fungus (Coccidioides immitis and C. posadasii) in the southwestern United States. The frequency of dust storms is found to be correlated with Valley fever incidences, with a coefficient (r) comparable to or stronger than that with other factors believed to control the disease in two endemic centers (Maricopa and Pima County, Arizona).

Constructing a New Biomass-Based Bistatic Window for Solar Regulation.

Smart windows effectively respond to the ever-changing climatic conditions, offering a smart solution for low-carbon buildings. However, current smart windows derived from chromic materials often have inferior solar modulation ability, or showcase high haze that obstructs outdoor views. Here, instead of developing new chromic materials, a new bistatic window is proposed for ultra-high solar modulation and luminous transmission. The new developed window can reduce the indoor surface temperature for ≈11 °C, and reduce the building space cooling and heating energy consumption by 30% to 40%, providing significant energy-related advances over traditional smart windows. In detail, the bistatic window exhibits excellent solar modulation ability (ΔTsol = 61%), high visible transmittance in both bleached (Tlum,bleached = 91%) and colored (Tlum,colored = 56%) states, low haze (< 1%), rapid switching response (switching time < 1 min), high color rendering index (CRI > 80), and long-cyclic stability after 1000 cycles. With the advantages of facile fabrication and scalability, it is foreseen the developed bistatic window holds promising prospect for the next-generation low-carbon buildings, paving a new way for future advancements in the fields of smart windows.

Dust Storms, Valley Fever, and Public Awareness.

We discuss several issues raised by Comrie (2021, https://doi.org/10.1029/2021GH000504), which uses a crowdsourced data set to study dust storms and coccidioidomycosis (Valley fever). There is inconsistency in the term "dust storm" used by science communities. The dust data from National Oceanic and Atmospheric Administration Storm Events Database are from diverse sources, unsuitable for assessing dust-coccidioidomycosis relationships. Population exposure to dust or Coccidioides needs to consider the frequency, magnitude, and duration of dust events. Given abundant evidence that dust storms are a viable driver to transport pathogens, it is in best public interest to advocate dust storms may put people at risk for contracting Valley fever.

Effect of Ambient Bright Light on Behavioral and Psychological Symptoms in People With Dementia: A Systematic Review.

Background and Objectives: Behavioral and psychological symptoms of dementia (BPSD) commonly occur in persons living with dementia. Bright light (BL) interventions have shown some positive impact on BPSD. Ambient lighting is a more efficient approach to delivering BL with better compliance and less staff workload than individual-based lighting interventions. Yet, its effect has not been systematically reviewed. This review synthesized research evidence on the effect of ambient BL on BPSD. Research Design and Methods: This review searched literature from PubMed (Medline), CINAHL, Scopus, Web of Science, and Cochrane in February 2021. Original research testing the effect of ambient BL on BPSD in persons with dementia was included. Two reviewers independently screened, extracted data, and assessed the quality of each article. Results: Nine studies were reviewed with 1 randomized controlled trial and 8 quasi-experimental studies. The sample size ranged from 14 to 89 participants across care settings. While not all studies showed positive results, evidence from multiple studies revealed the positive effect of ambient BL on depressive symptoms and agitation in persons with dementia. The ambient BL that showed a positive effect targeted at approximately 350-750 lux, 4,500-9,325 K, and/or circadian stimulus = 0.375-0.4 for 10-12 hr a day for 4 weeks or longer. Evidence on other BPSD was mixed or too limited to draw conclusions. Discussion and Implications: A preponderance of evidence suggests that, when properly designed and implemented, ambient BL shows promise in reducing depressive symptoms and agitation. Future research, using more rigorous designs, is needed to further test the effect of ambient BL on BPSD with attention to lighting parameters, measurement approaches, and intervention fidelity.

Design and development of a low-cost glazing measurement system.

Knowledge of the properties and performance level of a glazing or translucent component system is necessary for assessing the operational energy use of building or greenhouse structures and proposing potential strategies for saving energy. The study of in situ measurements of the thermal and optical performance of glazing systems has not yet been thoroughly examined. To accomplish this task, a portable and easy-to-use in situ measurement system for key glazing properties that uses the inexpensive Arduino platform and compatible sensors was designed, 3D-printed, and fabricated. The glazing properties that can now be measured include the center-of-glass U-factor, solar transmittance, and visible transmittance. In this method-focused paper, we present the step-by-step development procedure in detail, as well as describe the necessary hardware and codes. One can use the shared files to 3D-print the sensor cases and follow the described procedure to achieve the measuring system hardware. Subsequently, the shared codes, including the calibration functions for the associated hardware and the "self-examination" procedure can be applied to achieve a working system for measurement. In brief, this new method is:•Based on thermodynamic equations and easy-to-use.•Open source, low cost, and simple to assemble.•Able to automatically determine the effectiveness of the output via the developed diagnostic algorithms.

Laparoscopic hepatectomy is safe and effective for the management of patients with colorectal cancer liver metastases in a population-based analysis in Ontario, Canada. A retrospective cohort study.

BACKGROUND: Laparoscopic hepatectomy (LH) has been deemed safe, and, in the case of minor hepatectomy, the standard of care. Short-, long-term outcomes and costs of LH compared with open hepatectomy (OH) in patients with colorectal cancer liver metastases have not been well described at the population level. MATERIALS AND METHODS: Patients diagnosed with colorectal cancer undergoing hepatectomy were included in this population-based retrospective cohort study from 2006- to 2014. Postoperative complications (per Clavien-Dindo) and survival were analyzed using a linear mixed model and Cox-Proportional hazards model respectively. Costs of surgery and the 90-day postoperative period were considered in 2018 Canadian dollars and compared from the perspective of a third-party payer. RESULTS: Over a median follow-up of 56 months, 95% confidence interval (CI): 51 to 68), there were 2991 hepatectomies (OH: 2551 (85%) and LH: 440 (15%)). LH compared to OH was more common for patients >70 years-old (30% vs. 22%, p = 0.004) and for minor hepatectomy (52% vs. 32%, p < 0.001) respectively. By multivariable analyses, OH was associated with similar 90-day mortality (Odds Ratio (OR) 1.05, 95% CI: 0.56-1.97), and overall survival (Hazard Ratio (HR) 1.08, 95% CI: 0.90-1.29), but higher rates of major postoperative complications (OR 1.34, 95% CI: 1.03-1.76), higher cost (median difference $6,163, 95% CI: $3229 to $9096), and longer length of hospital stay (LOS) (mean difference 3.04 days, 95% CI: 2.7 to 3.91). CONCLUSION: LH was associated with lower postoperative complications, shorter LOS, which translated into lower costs to the healthcare system, without differences in postoperative mortality and survival.

Simultaneous versus staged resection for synchronous colorectal liver metastases: A population-based cohort study.

BACKGROUND: Synchronous liver metastases from colorectal cancer may be resected simultaneously with the primary or as a second staged operation. We evaluated trends of resection for synchronous colorectal cancer liver metastases and associated patient outcomes. METHODS: This is a retrospective cohort study that included patients undergoing resection for synchronous colorectal cancer liver metastases from 2006 to 2015 in the province of Ontario, Canada (population 13 million). Simultaneous resections occurred on the same admission, while staged resections occurred less than 6 months apart. Outcomes included postoperative complications, length of hospital stay, and overall survival. Kaplan Meier survival estimates, Cox proportional hazard models and logistic regression were used. RESULTS: Among 2,738 patients undergoing resection for colorectal cancer liver metastases, 1168 (42%) had synchronous disease. Of these, 442 resections were simultaneous (38%) and 776 were staged (62%). The proportion of synchronous disease among patients undergoing resection increased on average 3% per year (p = 0.02). For simultaneous versus staged resection, respectively, median length of hospital stay was shorter (8 vs. 11 days, p < 0.001); rate of major liver resections was lower (17% vs. 65%, p < 0.001), major postoperative complications were similar (28% vs. 23%, p = 0.067), and 90-day post-operative mortality was higher (6% vs. 1%, p < 0.001). Chemotherapy was administered more commonly among patients undergoing staged resections (91% vs. 76%, p < 0.001). Simultaneous resection was associated with a lower median overall survival (40 months, 95%CI 35-46 vs. 78 months, 95%CI 59-86). Risk factors for lower survival included higher comorbidities, right-sided primary and simultaneous resection. CONCLUSION: Simultaneous resection was associated with similar postoperative complications, higher postoperative mortality and poorer long-term survival. Prospective randomized trials can inform the role of simultaneous versus staged resection for synchronous colorectal cancer liver metastases.

Simultaneous versus staged resection for synchronous colorectal liver metastases: A population-based cost analysis in Ontario, Canada - Health economic evaluation.

BACKGROUND: Simultaneous compared to staged resection of synchronous colorectal cancer liver metastases is considered safe. We aimed to determine their cost implications. STUDY DESIGN: Population-based cohort was generated by linking administrative healthcare datasets in Ontario, Canada (2006-2014). Resection of colorectal cancer and liver metastases within six months was considered synchronous. Cost analysis was performed from the perspective of a third-party payer. Median costs with range were estimated using the log-normal distribution of cost using t-test with a one-year time horizon. RESULTS: Among patients undergoing staged resection (n = 678), the estimated median cost was $54,321 CAD (IQR 45,472 to 68,475) and $41,286 CAD (IQR 31,633 to 58,958) for those undergoing simultaneous resection (n = 390), median difference: $13,035 CAD (p < 0.001). Primary cost driver were all costs related to hospitalization for liver and colon resection, which was higher for the staged approach, median difference: $16,346 CAD (p < 0.001). This was mainly due to a longer median length of hospital stay in the staged vs. simultaneous group (11 vs. 8 days, p < 0.001 respectively), which was not attributable to differences in major postoperative complication rates (23% vs. 28%, p = 0.067 respectively). Other costs, including cost of chemotherapy within six months of surgery ($11,681 CAD vs. $8644 CAD, p = 0.074 respectively) and 90-day re-hospitalization cost ($2155 CAD vs. $2931 CAD, p = 0.454 respectively) were similar between groups. CONCLUSION: Cost of staged resection of synchronous colorectal cancer liver metastases is significantly higher compared to the simultaneous approach, mostly driven by a longer length of hospital stay despite similar postoperative complication rates.

Acoustic radiation force induced accumulation and dynamics of microbubbles on compliant surfaces.

Ultrasound stimulated microbubbles have been shown to be capable of breaking up blood clots through micro-scale interactions occurring near the clot surface. However, only a small fraction of bubbles circulating in the bloodstream will be in close proximity to such boundaries, where they must be to elicit therapeutic effects. Here, the accumulation and subsequent behavior of microbubbles displaced from an overlying flow channel to a boundary under radiation forces were examined. Experimental data were acquired using a novel high speed microscopy configuration and simulations were conducted to provide insight into the accumulation process. There was broad agreement between experiments and simulations, both indicating that the size distribution and number of bubbles arriving at the boundary depended on channel flow rate, applied pressure, and bubble concentration. For example, higher flow rates and lower pressures favored the accumulation of larger bubbles relative to the native agent distribution. Moreover, bubble dynamics were dependent on the surface type, exhibiting rapid translation along agarose gel surfaces whereas on fibrin surfaces, they accumulated in localized regions inducing repetitive strain cycles. The results indicate that the process of bringing bubbles from within a vessel to a boundary is complex and should be an important consideration in the development of therapeutic applications such as sonothrombolysis.

Temporal and spatial characteristics of potential energy anomaly in Lake Taihu.

In this study, water temperature and meteorological data in Lake Taihu from June 11 to July 6, 2013, are collected to calibrate and verify the unstructured grid finite-volume community ocean model (FVCOM) coupled with a heat exchange module. The spatial and temporal variations of potential energy anomalies (PEA) in the lake, simulated by the calibrated FVCOM, are analyzed to explore the stratification and de-stratification processes in water body. The temporal variation of PEA primarily follows the diurnal cycles of solar radiation, while the spatial heterogeneity of PEA is jointly determined by solar radiation and vertical shear of horizontal velocity coupled with the topography of the lake. The maxima of PEA in the lake are not greater than 4 J/m3 in the summer and even smaller along shore regions and near the Pingtaishan station. This study is helpful to improve understanding of the effect of physical processes on the algae bloom in Lake Taihu.