Genotyping, sequencing and analysis of 140,000 adults from Mexico City.

The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.

Targeting Patient-Derived Orthotopic Gastric Cancers with a Fluorescent Humanized Anti-CEA Antibody.

BACKGROUND: Gastric cancer poses a major diagnostic and therapeutic challenge as surgical resection provides the only opportunity for a cure. Specific labeling of gastric cancer could distinguish resectable and nonresectable disease and facilitate an R0 resection, which could improve survival. METHODS: Two patient-derived gastric cancer lines, KG8 and KG10, were established from surgical specimens of two patients who underwent gastrectomy for gastric adenocarcinoma. Harvested tumor fragments were implanted into the greater curvature of the stomach to establish patient-derived orthotopic xenograft (PDOX) models. M5A (humanized anti-CEA antibody) or IgG control antibodies were conjugated with the near-infrared dye IRDye800CW. Mice received 50 µg of M5A-IR800 or 50 µg of IgG-IR800 intravenously and were imaged after 72 hr. Fluorescence imaging was performed by using the LI-COR Pearl Imaging System. A tumor-to-background ratio (TBR) was calculated by dividing the mean fluorescence intensity of the tumor versus adjacent stomach tissue. RESULTS: M5A-IR800 administration resulted in bright labeling of both KG8 and K10 tumors. In the KG8 PDOX models, the TBR for M5A-IR800 was 5.85 (SE ± 1.64) compared with IgG-IR800 at 0.70 (SE ± 0.17). The K10 PDOX models had a TBR of 3.71 (SE ± 0.73) for M5A-IR800 compared with 0.66 (SE ± 0.12) for IgG-IR800. CONCLUSIONS: Humanized anti-CEA (M5A) antibodies conjugated to fluorescent dyes provide bright and specific labeling of gastric cancer PDOX models. This tumor-specific fluorescent antibody is a promising potential clinical tool to detect the extent of disease for the determination of resectability as well as to visualize tumor margins during gastric cancer resection.

Humanized Anti-Carcinoembryonic Antigen Antibodies Brightly Target and Label Gastric Cancer in Orthotopic Mouse Models.

INTRODUCTION: Gastric cancer poses a major therapeutic challenge. Improved visualization of tumor margins at the time of gastrectomy with fluorescent tumor-specific antibodies could improve outcomes. The present report demonstrates the potential of targeting gastric cancer with a humanized anti-carcinoembryonic antigen (CEA) antibody in orthotopic mouse models. METHODS: MKN45 cells were injected subcutaneously into nude mice to establish xenograft models. Tumor fragments collected from subcutaneous models were then implanted into the greater curvature of the stomach to establish orthotopic models. For tumor labeling, a humanized anti-CEA antibody (M5A) and IgG as a control, were conjugated with the near-infrared dye IRDye800CW. Time (24-72 h) and dose (50-100 µg) response curves were performed in subcutaneous models. Orthotopic models received 50 µg of M5A-IR800 or 50 µg IgG-IR800 as a control and were imaged after 72 h. Fluorescence imaging was performed on the mice using the LI-COR Pearl Imaging System. RESULTS: In subcutaneous models, tumor to background ratios (TBRs) reached 8.85 at 72 h. Median TBRs of orthotopic model primary tumors were 6.25 (interquartile range [IQR] 6.03-7.12) for M5A-IR800 compared to 0.42 (IQR 0.38-0.54) for control. Abdominal wall metastasis median TBRs were 13.52 (IQR 12.79-13.76) for M5A-IR800 and 3.19 (IQR 2.65-3.73) for the control. Immunohistochemistry confirmed CEA expression within tumors. CONCLUSIONS: Humanized anti-CEA antibodies conjugated to near-infrared dyes provide specific labeling of gastric cancers in mouse models. Orthotopic models demonstrated bright and specific labeling with TBRs greater than ten times that of control. This tumor-specific fluorescent antibody is a promising potential clinical tool for improving visualization of gastric cancer margins at time of surgical resection.

Small Arteriovenous Anastomosis in Fistula Creation: Establishing a Functional Vascular Access while Minimizing Steal Syndrome.

BACKGROUND: The size selection of the arteriovenous (AV) anastomosis in dialysis access creation requires a careful balance: the diameter must be large enough to accommodate sufficient flow for hemodialysis but small enough to minimize the complication of steal syndrome. Steal syndrome affects up to 10% of patients after creation of dialysis access with sometimes devastating consequences. Conventional teaching recommends a 7-10 mm anastomosis. We sought to assess the efficacy of using a smaller (5-6 mm) anastomosis in new arteriovenous fistula (AVF) creation. METHODS: We conducted a comparative retrospective analysis of patients who underwent fistula creation with a small versus regular size anastomosis at any upper extremity anatomic site between March 2019 and October 2020 at our institution. Anatomic sites included radiocephalic, brachiocephalic, and brachiobasilic. All AV anastomoses were measured intraoperatively to be 5-6 mm in diameter for the small size groups and 8-10 mm for the regular size group. Endpoints included steal syndrome, functional patency, primary patency, and secondary patency. RESULTS: Out of 110 patients who underwent an AVF creation, 59.1% received a 5-6 mm anastomosis with a median follow-up time of 10 ± 6 months. Patients' demographics and comorbidities were relatively similar between the 2 groups except for a higher rate of hyperlipidemia (55.4% vs. 28.9%, P = 0.008) in the small size group. Patients in the small size group were more likely to undergo a radiocephalic fistula (40% vs. 4.5%, P < 0.001) and to have a smaller mean vein diameter on preoperative duplex ultrasound (3.2±1 mm vs. 3.9±1 mm, P = 0.0016) when compared to their regular size counterparts. During follow-up, none of the patients in the small group developed steal syndrome (0% vs. 9%, P = 0.015). At 1 year, patients in the regular size group achieved higher rates of primary patency (67.9% vs. 46.9%, P = 0.02); however, no difference was seen in 1-year primary-assisted patency (84.9% vs. 73.6%, P = 0.3), secondary patency (89.6% vs. 79.5%, P = 0.3), or functional patency (87.7% vs. 82.2%, P = 0.64) between the small and regular size groups, respectively. CONCLUSIONS: The use of a 5-6 mm anastomosis in the creation of new AVFs of the upper extremities appears to be a technically safe option for dialysis access. Our experience suggests that smaller anastomosis still creates enough flow to maintain a functional AV access while minimizing the incidence of steal syndrome. Additionally, even with smaller vein sizes preoperative, adequate dialysis access can be created via a small sized anastomosis, including distal arm access. Larger studies with longer follow-up are needed to evaluate long-term outcomes of small anastomosis fistulas.

Specific Targeting and Labeling of Colonic Polyps in CPC-APC Mice with Mucin 5AC Fluorescent Antibodies: A Model for Detection of Early Colon Cancer.

Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 µg PBR was 1.70 (±0.56); the mean 50 µg PBR was 2.64 (±0.97); the mean 100 µg PBR was 3.32 (±1.33); and the mean 150 µg PBR was 3.38 (±0.87). The mean PBR of the dye-only control was 2.22 (±1.02), significantly less than the 150 µg arm (p-value 0.008). The present study demonstrates the ability of fluorescent anti-MUC5AC antibodies to specifically target and label colonic polyps containing high-grade dysplasia and intramucosal adenocarcinoma in CPC-APC mice. This technology can potentially improve the detection rate and decrease the miss rate of advanced colonic neoplasia and early cancer at colonoscopy.

Foliar water uptake enables embolism removal in excised twigs of Avicennia marina.

Embolism refilling is thought to require relaxation of xylem tension, and it is unclear whether and how tall trees or plants growing in arid or saline soils recover from embolism. We tested whether foliar water uptake could enable embolism refilling in dehydrated twigs of the grey mangrove (Avicennia marina). Four dehydrated twigs were imaged by laboratory-based micro-computed tomography before and after wetting leaves. Emboli were observed in dehydrated stems and leaves. Embolism decreased with increasing distance from the cut end of stems, suggesting that stem emboli were caused by cutting. A significant (P = 0.026) c. 80% reduction in the embolised area was observed in leaves between the start and the end of the experiment (29 ± 10 h after wetting). Embolus diameter was unaffected by wetting. Embolism refilling occurred slowly, in stems embolised by cutting and leaves embolised by cutting and/or dehydration. The lack of response of embolus diameter to wetting suggests that capillarity was not the main mechanism for refilling. Results show that excised twigs of A. marina are able to recover from embolism by absorption of atmospheric water and call for studies under natural conditions.

Proof of Principle of Combining Fluorescence-Guided Surgery with Photoimmunotherapy to Improve the Outcome of Pancreatic Cancer Therapy in an Orthotopic Mouse Model.

BACKGROUND: Pancreatic cancer is a recalcitrant disease in which R0 resection is often not achieved owing to difficulty in visualization of the tumor margins and proximity of adjacent vessels. To improve outcomes, we have developed fluorescence-guided surgery (FGS) and photoimmunotherapy (PIT) using a fluorescent tumor-specific antibody. METHODS: Nude mice received surgical orthotopic implantation (SOI) of the human pancreatic cancer cell line BxPC-3 expressing green fluorescent protein. An anti-carcinoembryonic antigen-related cell adhesion molecule (CEACAM) monoclonal antibody (6G5j) was conjugated to the 700-nm fluorescent dye IR700DyeDX (6G5j-IR700DX). Three weeks after SOI, 16 mice received 50 µg 6G5j-IR700DX via the tail vein 24 h before surgery and were randomized to two groups: FGS-only (n = 8) and FGS + PIT (n = 8). All tumors were imaged with the Pearl Trilogy imaging system and resected under the guidance of the FLARE imaging system. The FGS + PIT group received PIT of the post-surgical bed at an intensity of 150 mW/cm2 for 30 min. Mice were sacrificed 4 weeks after initial surgery, and tumors were imaged with a Dino-Lite digital microscope, excised, and weighed. RESULTS: The 6G5j-IR700DX dye illuminated the orthotopic pancreatic tumors for FGS and PIT. The metastatic recurrence rate was 100.0% for FGS-only and 25.0% for FGS + PIT (p = 0.007). The average total recurrent tumor weight was 2370.3 ± 1907.8 mg for FGS-only and 705.5 ± 1200.0 mg for FGS + PIT (p = 0.039). CONCLUSIONS: FGS and adjuvant PIT can be combined by using a single antibody-fluorophore conjugate to significantly reduce the frequency of pancreatic cancer recurrence.

PEGylated Fluorescent Anti-carcinoembryonic Antigen Antibody Labels Colorectal Cancer Tumors in Orthotopic Mouse Models.

INTRODUCTION: Colorectal cancer (CRC) patients often develop liver metastasis. However, curative resection of liver metastasis is not always possible due to poor visualization of tumor margins. The present study reports the characterization of a humanized anti-carcinoembryonic antigen monoclonal antibody conjugated to a PEGylated near-infrared dye, that targets and brightly labels human CRC tumors in metastatic orthotopic mouse models. METHODS: The hT84.66-M5A (M5A) monoclonal antibody was conjugated with a polyethylene glycol (PEG) chain that incorporated a near infrared (NIR) IR800 dye to establish M5A-IR800 Sidewinder (M5A-IR800-SW). Nude mice with CRC orthotopic primary tumors and liver metastasis both developed from a human CRC cell line, were injected with M5A-IR800-SW and imaged with the Pearl Trilogy Imaging System. RESULTS: M5A-IR800-SW targeted and brightly labeled CRC tumors, both in primary-tumor and liver-metastasis models. M5A-IR800-SW at 75 µg exhibited highly-specific tumor labeling in a primary-tumor orthotopic model with a median tumor-to-background ratio of 9.77 and in a liver-metastasis orthotopic model with a median tumor-to-background ratio of 7.23 at 96 h. The precise labeling of the liver metastasis was due to lack of hepatic accumulation of M5A-IR800-SW in the liver. CONCLUSIONS: M5A-IR800-SW provided bright and targeted NIR images of human CRC in orthotopic primary-tumor and liver-metastasis mouse models. The results of the present study suggest the clinical potential of M5A-IR800-SW for fluorescence-guided surgery including metastasectomies for CRC. The lack of hepatic NIR signal is of critical importance to allow for precise labeling of liver tumors.

Synthesis and ring-opening metathesis polymerisation of o-alkoxy benzothiadiazole paracyclophane-1,9-dienes.

ortho-Diethylhexyloxyphenylene benzothiadiazole paracyclophane-1,9-diene as a mixture of diastereomers was synthesized by a sequential benzyne-induced Stevens rearrangement, oxidation and pyrolysis of a dithia[3.3]paracyclophane. Reaction of these highly strained cyclophanedienes with the second generation Grubbs catalyst showed that they can be ring opened to alternating cis,trans-phenylenevinylene polymers. In situ NMR experiments showed that one isomer 8a polymerised to 90% conversion, whereas the other 8b gave only 9% conversion due to steric hindrance on both faces of the alkene bridges of this isomer. The resulting polymers can be readily isomerized in dilute solution using visible light to the all-trans isomer and the optical and electrochemical properties of these polymers were examined by theory and experiment.

Development of an intervention to manage benzodiazepine dependence and high-risk use in the context of escalating drug related deaths in Scotland: an application of the MRC framework.

BACKGROUND: Scotland has the highest rate of drug related deaths (DRD) in Europe. These are deaths in people who use drugs such as heroin, cocaine, benzodiazepines and gabapentinoids. It is a feature of deaths in Scotland that people use combinations of drugs which increases the chance of a DRD. Many deaths involve 'street' benzodiazepines, especially a drug called etizolam. Many of the 'street' benzodiazepines are not licensed in the UK so come from illegal sources. People who use opiates can be prescribed a safer replacement medication (e.g., methadone). While guidance on management of benzodiazepines use highlights that there is little evidence to support replacement prescribing, practice and evidence are emerging. AIM: To develop an intervention to address 'street' benzodiazepines use in people who also use opiates. METHODS: The MRC Framework for Complex Interventions was used to inform research design. Co-production of the intervention was achieved through three online workshops with clinicians, academics working in the area of substance use, and people with lived experience (PWLE). Each workshop was followed by a PWLE group meeting. Outputs from workshops were discussed and refined by the PWLE group and then further explored at the next workshop. RESULTS: After these six sessions, a finalised logic model for the intervention was successfully achieved that was acceptable to clinicians and PWLE. Key components of the intervention were: prescribing of diazepam; anxiety management, sleep, and pain; and harm reduction resources (locked box and a range of tips), personal safety conversations, as well as a virtual learning environment. CONCLUSION: A co-produced intervention was developed for next stage clinical feasibility testing.

When should an athlete retire or discontinue participating in contact or collision sports following sport-related concussion? A systematic review.

OBJECTIVE: To systematically review the scientific literature regarding factors to consider when providing advice or guidance to athletes about retirement from contact or collision sport following sport-related concussion (SRC), and to define contraindications to children/adolescent athletes entering or continuing with contact or collision sports after SRC. DATA SOURCES: Medline, Embase, SPORTSDiscus, APA PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials were searched systematically. STUDY ELIGIBILITY CRITERIA: Studies were included if they were (1) original research, (2) reported on SRC as the primary source of injury, (3) evaluated the history, clinical assessment and/or investigation of findings that may preclude participation in sport and (4) evaluated mood disturbance and/or neurocognitive deficits, evidence of structural brain injury or risk factors for increased risk of subsequent SRC or prolonged recovery. RESULTS: Of 4355 articles identified, 93 met the inclusion criteria. None of the included articles directly examined retirement and/or discontinuation from contact or collision sport. Included studies examined factors associated with increased risk of recurrent SRC or prolonged recovery following SRC. In general, these were low-quality cohort studies with heterogeneous results and moderate risk of bias. Higher number and/or severity of symptoms at presentation, sleep disturbance and symptom reproduction with Vestibular Ocular Motor Screen testing were associated with prolonged recovery and history of previous concussion was associated with a risk of further SRC. CONCLUSION: No evidence was identified to support the inclusion of any patient-specific, injury-specific or other factors (eg, imaging findings) as absolute indications for retirement or discontinued participation in contact or collision sport following SRC. PROSPERO REGISTRATION NUMBER: CRD42022155121.

Beyond acute concussion assessment to office management: a systematic review informing the development of a Sport Concussion Office Assessment Tool (SCOAT6) for adults and children.

OBJECTIVES: To systematically review the scientific literature regarding the assessment of sport-related concussion (SRC) in the subacute phase (3-30 days) and provide recommendations for developing a Sport Concussion Office Assessment Tool (SCOAT6). DATA SOURCES: MEDLINE, Embase, PsycINFO, Cochrane CENTRAL, CINAHL, SPORTDiscus and Web of Science searched from 2001 to 2022. Data extracted included study design, population, definition of SRC diagnosis, outcome measure(s) and results. ELIGIBILITY CRITERIA: (1) Original research, cohort studies, case-control studies, diagnostic accuracy and case series with samples >10; (2) SRC; (3) screening/technology that assessed SRC in the subacute period and (4) low risk of bias (ROB). ROB was performed using adapted Scottish Intercollegiate Guidelines Network criteria. Quality of evidence was evaluated using the Strength of Recommendation Taxonomy classification. RESULTS: Of 9913 studies screened, 127 met inclusion, assessing 12 overlapping domains. Results were summarised narratively. Studies of acceptable (81) or high (2) quality were used to inform the SCOAT6, finding sufficient evidence for including the assessment of autonomic function, dual gait, vestibular ocular motor screening (VOMS) and mental health screening. CONCLUSION: Current SRC tools have limited utility beyond 72 hours. Incorporation of a multimodal clinical assessment in the subacute phase of SRC may include symptom evaluation, orthostatic hypotension screen, verbal neurocognitive tests, cervical spine evaluation, neurological screen, Modified Balance Error Scoring System, single/dual task tandem gait, modified VOMS and provocative exercise tests. Screens for sleep disturbance, anxiety and depression are recommended. Studies to evaluate the psychometric properties, clinical feasibility in different environments and time frames are needed. PROSPERO REGISTRATION NUMBER: CRD42020154787.

Consensus statement on concussion in sport: the 6th International Conference on Concussion in Sport-Amsterdam, October 2022.

For over two decades, the Concussion in Sport Group has held meetings and developed five international statements on concussion in sport. This 6th statement summarises the processes and outcomes of the 6th International Conference on Concussion in Sport held in Amsterdam on 27-30 October 2022 and should be read in conjunction with the (1) methodology paper that outlines the consensus process in detail and (2) 10 systematic reviews that informed the conference outcomes. Over 3½ years, author groups conducted systematic reviews of predetermined priority topics relevant to concussion in sport. The format of the conference, expert panel meetings and workshops to revise or develop new clinical assessment tools, as described in the methodology paper, evolved from previous consensus meetings with several new components. Apart from this consensus statement, the conference process yielded revised tools including the Concussion Recognition Tool-6 (CRT6) and Sport Concussion Assessment Tool-6 (SCAT6, Child SCAT6), as well as a new tool, the Sport Concussion Office Assessment Tool-6 (SCOAT6, Child SCOAT6). This consensus process also integrated new features including a focus on the para athlete, the athlete's perspective, concussion-specific medical ethics and matters related to both athlete retirement and the potential long-term effects of SRC, including neurodegenerative disease. This statement summarises evidence-informed principles of concussion prevention, assessment and management, and emphasises those areas requiring more research.

Electrolyte-Gated Organic Field-Effect Transistors for Quantitative Monitoring of the Molecular Dynamics of Crystallization at the Solid-Liquid Interface.

Quantitative measurements of molecular dynamics at the solid-liquid interface are of crucial importance in a wide range of fields, such as heterogeneous catalysis, energy storage, nanofluidics, biosensing, and crystallization. In particular, the molecular dynamics associated with nucleation and crystal growth is very challenging to study because of the poor sensitivity or limited spatial/temporal resolution of the most widely used analytical techniques. We demonstrate that electrolyte-gated organic field-effect transistors (EGOFETs) are able to monitor in real-time the crystallization process in an evaporating droplet. The high sensitivity of these devices at the solid-liquid interface, through the electrical double layer and signal amplification, enables the quantification of changes in solute concentration over time and the transport rate of molecules at the solid-liquid interface during crystallization. Our results show that EGOFETs offer a highly sensitive and powerful, yet simple approach to investigate the molecular dynamics of compounds crystallizing from water.

Geriatric Craniomaxillofacial Fractures: Where do They Happen and Why?

PURPOSE: The geriatric population is a constantly growing population that is especially vulnerable to trauma. The primary purpose of this study was to determine what factors are associated with increased rates of hospital admission in geriatric patients who sustain craniomaxillofacial fractures secondary to falls. MATERIALS AND METHODS: This is a 5-year retrospective cross-sectional study that was conducted using the NEISS database. There were several, heterogenous predictor variables. The primary outcome variable was admission rate, which was used as a proxy to the severity of injury. Patient and injury characteristics were compared using chi-square and independent-sample t-tests. Binary logistic regression was conducted to determine the risk of hospital admission. RESULTS: The final sample included 2,879 cases in total. The mean age of the study sample was 78.8 years (SD, 8.6 years). Most patients were white (51.6%) females (64.2%) who were injured at their respective homes (58.7%). Relative to injuries that took place at a sports center, injuries that took place at the patient's home (OR, 2.52; P < .05) independently increased the risk for admission. Relative to maxilla fracture, orbital bone fracture (OR, 3.91; P < .05) was an independent risk factor for admission. Relative to lacerations, intracranial injuries (OR, 3.76; P < .01) increased the risk of admission. CONCLUSIONS: Craniomaxillofacial fractures that took place at the patients' home were at increased risk for admission. Orbital bone fractures and intracranial injuries were at increased risk for admission. From our, and other studies findings, screening and fall prevention interventions should be implemented amongst the geriatric population.

What are the Risk Factors for Mortality Among Patients Who Suffer Le Fort III Fractures?

PURPOSE: Le Fort III fractures are the most severe subtype of the Le Fort fractures and are associated with adverse clinical outcomes. The purpose of this study was to identify risk factors for mortality among patients who suffer Le Fort III fractures. MATERIALS AND METHODS: A retrospective cohort study was completed using the 2016-2018 National Inpatient Sample. Patients with isolated Le Fort III fractures were selected. Patients who incurred bone fractures or organ injuries outside the head and neck were excluded. There were multiple, heterogenous predictor variables. The primary outcome variable was mortality. Relative risk was used to determine independent risk factors of mortality. Statistical significance was deemed for P values less than .05. RESULTS: The final sample consisted of 559 patients (mean age, 45.9 years) who suffered a Le Fort III fracture, of whom 15 patients (2.68%) died. Most patients were male (82.7%) middle-aged adults (42.9%) of White race (66.5%) within the lowest income quartile (31.7%) that lived in large metro areas (54.9%). Relative to males, females were nearly 62 times more likely to die (P < .01). Relative to privately insured subjects, uninsured subjects were 23 times (P < .05) more likely to die. Relative to weekday admissions, weekend admissions increased the risk of mortality by 8 times (P < .05). Cranial vault fractures (odds ratio, 7.24; P < .05) and upper cervical fractures (odds ratio, 63.27; P < .05) were risk factors for mortality. Relative to males, females were at an increased risk for mortality (relative risk [RR] 7.14, 95% confidence interval [CI] 2.60, 19.61). Skull base fracture (RR 2.99, 95 CI 1.04, 8.63), cranial vault fracture (RR 3.04, 95 CI 1.07, 8.65), subdural hemorrhage (RR 2.98, 95 CI 1.10, 8.05), subarachnoid hemorrhage (RR 6.73, 95 CI 2.34, 19.35), and injury of blood vessels at neck level (RR 13.24, 95 CI 2.46, 71.16) were each risk factors for mortality. CONCLUSIONS: Intracranial injury was not a risk factor for mortality. Instead, cranial vault fractures and skull base fractures increased the risk for mortality. In addition, uninsured patients and female patients were each at an increased risk for mortality.

UMOD-ulating CKD risk: untangling the relationship between urinary uromodulin, blood pressure, and kidney disease.

A new Mendelian randomization study finds evidence that genetically predicted higher levels of urinary uromodulin are associated with lower kidney function and higher blood pressure. Bidirectional and multivariable Mendelian randomization suggests the association with higher blood pressure appears to be partially through decreased kidney function, but blood pressure does not appear to mediate the association of uromodulin with low kidney function. We describe the methods used for the bidirectional and multivariable Mendelian randomization analyses and examine the validity of the assumptions and implications of the results.

Similarities and Differences between Crystal and Enzyme Environmental Effects on the Electron Density of Drug Molecules.

The crystal interaction density is generally assumed to be a suitable measure of the polarization of a low-molecular weight ligand inside an enzyme, but this approximation has seldomly been tested and has never been quantified before. In this study, we compare the crystal interaction density and the interaction electrostatic potential for a model compound of loxistatin acid (E64c) with those inside cathepsin B, in solution, and in vacuum. We apply QM/MM calculations and experimental quantum crystallography to show that the crystal interaction density is indeed very similar to the enzyme interaction density. Less than 0.1 e are shifted between these two environments in total. However, this difference has non-negligible consequences for derived properties.

A Novel Color-Coded Liver Metastasis Mouse Model to Distinguish Tumor and Adjacent Liver Segment.

BACKGROUND: It is difficult to distinguish between a tumor and its liver segment with traditional use of indocyanine green (ICG) alone. In the present study, a method was used to limit ICG to the liver segment adjacent to a tumor. A spectrally-distinct fluorescently-labeled tumor-specific antibody against human carcinoembryonic antigen-related cell-adhesion molecules was used to label the metastatic tumor in a patient-derived orthotopic xenograft mouse model to enable color-coded visualization and distinction of a colon-cancer liver metastases and its adjacent liver segment. MATERIALS AND METHODS: Nude mice received surgical orthotopic implantation in the liver of colon-cancer liver metastases derived from two patients. An anti- carcinoembryonic antigen-related cell-adhesion molecules monoclonal antibody (mAb 6G5j) was conjugated to a near-infrared dye IR700DX (6G5j-IR700DX). After three weeks, mice received 6G5j-IR700DX via tail-vein injection 48 hours before surgery. ICG was intravenously injected after ligation of the left or left lateral Glissonean pedicle resulting in labeling of the segment with preserved blood-flow in the liver. Imaging was performed with the Pearl Trilogy and FLARE Imaging Systems. RESULTS: The metastatic liver tumor had a clear fluorescence signal due to selective tumor targeting by 6G5j-IR700DX, which was imaged on the 700 nm channel. The adjacent liver segment, with preserved blood-flow in the liver, had a clear fluorescence ICG 800 nm signal, while the left or left lateral segment had no fluorescence signal. Overlay of the images showed clear color-coded differentiation between the tumor fluorescing at 700 nm and the adjacent liver segment fluorescing at 800 nm. CONCLUSIONS: Color-coding of a liver tumor and uninvolved liver segment has the potential for improved liver resection.