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White matter hyperintensities (WMHs) are brain white matter lesions that are hyperintense on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans. Larger WMH volumes have been associated with Alzheimer’s disease (AD) and with cognitive decline. However, the relationship between WMH volumes and cross-sectional cognitive measures has been inconsistent. We hypothesize that this inconsistency may arise from 1) the presence of AD-specific neuropathology that may obscure any WMH effects on cognition, and 2) varying criteria for creating a WMH segmentation. Manual and automated programs are typically used to determine segmentation boundaries, but criteria for those boundaries can differ. It remains unclear whether WMH volumes are associated with cognitive deficits, and which segmentation criteria influence the relationships between WMH volumes and clinical outcomes. In a sample of 260 non-demented participants (ages 55–90, 141 males, 119 females) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we compared the performance of five WMH segmentation methods, by relating the WMH volumes derived using each method to both clinical diagnosis and composite measures of executive function and memory. To separate WMH effects on cognition from effects related to AD-specific processes, we performed analyses separately in people with and without abnormal cerebrospinal fluid amyloid levels. WMH volume estimates that excluded more diffuse, lower-intensity lesions were more strongly correlated with clinical diagnosis and cognitive performance, and only in those without abnormal amyloid levels. These findings may inform best practices for WMH segmentation, and suggest that AD neuropathology may mask WMH effects on clinical diagnosis and cognition. •WMH boundary selection modifies the relationship between WMH volume and cognition.•When less hyperintense voxels were excluded, WMH volume related best to cognition.•In Aβ- participants, greater WMH volume was associated with worse clinical measures.•Alzheimer’s disease-related processes may mask the effect of WMHs on cognition.•Larger total, frontal, parietal and periventricular WMH volumes were related to worse cognition.

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer’s disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry—the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer’s disease, and microproteins.

PurposePost-craniotomy pain is a common clinical issue and its optimal management remains incompletely studied. Utilization of a regional scalp block has the potential advantage of reducing perioperative pain and opioid consumption, thereby facilitating optimal postoperative neurologic assessment. The purpose of this study was to assess the efficacy of regional scalp block on post-craniotomy pain and opioid consumption.MethodsWe performed a prospective randomized-controlled trial in adults scheduled to undergo elective supratentorial craniotomy under general anesthesia to assess the efficacy of postoperative bilateral scalp block with 0.5% bupivacaine with 1:200,000 epinephrine compared with placebo on postoperative pain and opioid consumption. The primary outcome was the visual analogue scale (VAS) for pain at 24 hr postoperatively.ResultsEighty-nine patients were enrolled (n = 44 in block group; n = 45 in control group). There was no difference in the mean (standard deviation) VAS score at 24 hr postoperatively between the treatment group and the control group [31.2 (21.4) mm vs 23.0 (19.2) mm, respectively; mean difference, 6.6; 95% confidence interval, -2.3, 15.5; P = 0.15]. There was also no significant difference in postoperative opioid consumption. Distribution of individual VAS score and opioid consumption revealed that postoperative pain was highly variable following craniotomy. Time to hospital discharge was not different between treatment and placebo groups. No adverse events associated with scalp block were identified.ConclusionThese data show that bilateral scalp blocks using bupivacaine with epinephrine did not reduce mean postoperative VAS score or overall opioid consumption at 24 hr nor the time-to-discharge from the postanesthesia care unit or from hospital.Trial registrationwww.ClinicalTrials.gov, NCT00972790; registered 9 September, 2009.

The selection of the Discovery Program InSight landing site took over four years from initial identification of possible areas that met engineering constraints, to downselection via targeted data from orbiters (especially Mars Reconnaissance Orbiter (MRO) Context Camera (CTX) and High-Resolution Imaging Science Experiment (HiRISE) images), to selection and certification via sophisticated entry, descent and landing (EDL) simulations. Constraints on elevation ( ≤ − 2.5 km for sufficient atmosphere to slow the lander), latitude (initially 15°S–5°N and later 3°N–5°N for solar power and thermal management of the spacecraft), ellipse size (130 km by 27 km from ballistic entry and descent), and a load bearing surface without thick deposits of dust, severely limited acceptable areas to western Elysium Planitia. Within this area, 16 prospective ellipses were identified, which lie ∼600 km north of the Mars Science Laboratory (MSL) rover. Mapping of terrains in rapidly acquired CTX images identified especially benign smooth terrain and led to the downselection to four northern ellipses. Acquisition of nearly continuous HiRISE, additional Thermal Emission Imaging System (THEMIS), and High Resolution Stereo Camera (HRSC) images, along with radar data confirmed that ellipse E9 met all landing site constraints: with slopes <15° at 84 m and 2 m length scales for radar tracking and touchdown stability, low rock abundance (<10 %) to avoid impact and spacecraft tip over, instrument deployment constraints, which included identical slope and rock abundance constraints, a radar reflective and load bearing surface, and a fragmented regolith ∼5 m thick for full penetration of the heat flow probe. Unlike other Mars landers, science objectives did not directly influence landing site selection.

Cells sense and respond to changes in oxygen concentration through gene regulatory processes that are fundamental to survival. Surprisingly, little is known about how anemia affects hypoxia signaling. Because nitric oxide synthases (NOSs) figure prominently in the cellular responses to acute hypoxia, we defined the effects of NOS deficiency in acute anemia. In contrast to endothelial NOS or inducible NOS deficiency, neuronal NOS (nNOS)–/– mice demonstrated increased mortality during anemia. Unlike wild-type (WT) animals, anemia did not increase cardiac output (CO) or reduce systemic vascular resistance (SVR) in nNOS–/– mice. At the cellular level, anemia increased expression of HIF-1α protein and HIF-responsive mRNA levels (EPO, VEGF, GLUT1, PDK1) in the brain of WT, but not nNOS–/– mice, despite comparable reductions in tissue PO2. Paradoxically, nNOS–/– mice survived longer during hypoxia, retained the ability to regulate CO and SVR, and increased brain HIF-α protein levels and HIF-responsive mRNA transcripts. Real-time imaging of transgenic animals expressing a reporter HIF-α(ODD)-luciferase chimeric protein confirmed that nNOS was essential for anemia-mediated increases in HIF-α protein stability in vivo. S-nitrosylation effects the functional interaction between HIF and pVHL. We found that anemia led to nNOS-dependent S-nitrosylation of pVHL in vivo and, of interest, led to decreased expression of GSNO reductase. These findings identify nNOS effects on the HIF/pVHL signaling pathway as critically important in the physiological responses to anemia in vivo and provide essential mechanistic insight into the differences between anemia and hypoxia.

PurposeHemodilutional anemia is associated with acute kidney injury (AKI) and mortality in patients undergoing cardiac surgery by mechanisms that may include tissue hypoxia. Our hypothesis was to assess if changes in the potential hypoxic biomarkers, including methemoglobin and erythropoietin, correlated with a decrease in hemoglobin (Hb) concentration following hemodilution on cardiopulmonary bypass (CPB).MethodsArterial blood samples were taken from patients (n = 64) undergoing heart surgery and CPB at baseline, during CPB, following CPB, and in the intensive care unit (ICU). Potential hypoxic biomarkers were measured, including methemoglobin, plasma Hb, and erythropoietin. Data were analyzed by repeated measures one-way analysis of variance on ranks and linear regression.ResultsHemoglobin levels decreased following CPB and methemoglobin increased in the ICU (P < 0.001 for both). No correlation was observed between the change in Hb and methemoglobin (P = 0.23). By contrast, reduced Hb on CPB correlated with increased lactate, reduced pH, and increased erythropoietin levels following CPB (P ≤ 0.004 for all). Increased plasma Hb (P < 0.001) also correlated with plasma erythropoietin levels (P < 0.001).ConclusionThese data support the hypothesis that erythropoietin rather than methemoglobin is a potential biomarker of anemia-induced tissue hypoxia. The observed relationships between decreased Hb during CPB and the increase in lactate, reduced pH, and increase in erythropoietin levels suggest that early changes in plasma erythropoietin may be a pragmatic early biomarker of anemia-induced renal hypoxia. Further study is required to determine if anemia-induced increases in erythropoietin may predict AKI in patients undergoing cardiac surgery.Trial registrationwww.clinicaltrials.gov (NCT01883713). Registered 21 June 2013.

PurposeAlthough intraoperative anaphylaxis during surgery is a rare event, we describe five patients who experienced perioperative anaphylactic reactions during renal transplantation and were referred for investigation.Clinical featuresSkin-prick and intradermal skin tests were done to investigate potential allergies to drugs given perioperatively prior to the development of anaphylaxis, including basiliximab, propofol, cefazolin, cis-atracurium, fentanyl, latex, remifentanil, and chlorhexidine. In addition, in vitro serologic testing for specific IgE was done in patients suspected to have had chlorhexidine anaphylaxis. All five patients were male, with a mean age of 48 yr (range 30–69). Skin testing for all drugs was non-reactive except for chlorhexidine, which was positive in four of five patients (one patient refused intradermal testing). In vitro test results for chlorhexidine-specific IgE were positive in all of the patients. Anesthetic records showed that intraoperative anaphylaxis had occurred immediately after insertion of a chlorhexidine-coated central venous catheter.ConclusionsIntraoperative insertion of chlorhexidine-coated central venous catheters can trigger life-threatening anaphylaxis in susceptible patients undergoing renal transplantation.

Palmer amaranth (Amaranthus palmeri S. Wats.) is a highly competitive weed that can be difficult to manage in many cropping systems. Research to date has not quantified the growth and development of A. palmeri in a manner that allows direct comparisons across cropping systems. Research was conducted to compare the growth, development, and seed production of A. palmeri when competing with corn (Zea mays L.), cotton (Gossypium hirsutum L.), peanut (Arachis hypogaea L.), and soybean [Glycine max (L.) Merr.] when emerging with crops or emerging three weeks after crops emerge. Regardless of when A. palmeri emerged, seed production was greatest and similar in cotton and peanut and exceeded that of corn and soybean; seed production in soybean exceeded that of corn. However, seed production was approximately 10-fold greater when A. palmeri emerged with crops compared with emergence three weeks later. These results illustrate the importance of controlling weeds during the first three weeks of the season relative to contributions of A. palmeri to the weed seed bank and is the first report comparing seed production in presence of these crops in a manner allowing a statistical comparison of seed production and highlighting the importance of crop sequence for seed bank management.

To evaluate the topography of the surface within the InSight candidate landing ellipses, we generated Digital Terrain Models (DTMs) at lander scales and those appropriate for entry, descent, and landing simulations, along with orthoimages of both images in each stereopair, and adirectional slope images. These products were used to assess the distribution of slopes for each candidate ellipse and terrain type in the landing site region, paying particular attention to how these slopes impact InSight landing and engineering safety, and results are reported here. Overall, this region has extremely low slopes at 1-meter baseline scales and meets the safety constraints of the InSight lander. The majority of the landing ellipse has a mean slope at 1-meter baselines of 3.2°. In addition, a mosaic of HRSC, CTX, and HiRISE DTMs within the final landing ellipse (ellipse 9) was generated to support entry, descent, and landing simulations and evaluations. Several methods were tested to generate this mosaic and the NASA Ames Stereo Pipeline program dem_mosaic produced the best results. For the HRSC-CTX-HiRISE DTM mosaic, more than 99 % of the mosaic has slopes less than 15°, and the introduction of artificially high slopes along image seams was minimized.

We have used high-precision, high-resolution digital terrain models (DTMs) of the NASA Mars Science Laboratory and Mars 2020 rover landing sites based on mosaicked images from the Mars Reconnaissance Orbiter High Resolution Imaging Science Experiment (MRO HiRISE) camera as a reference data set to evaluate DTMs based on Mars Express High Resolution Stereo Camera (MEX HRSC) images. The Next Generation Automatic Terrain Extraction (NGATE) matcher in the SOCET SET/GXP® commercial photogram- metric system produces DTMs with relatively good (small) horizontal resolution but high error, and results are terrain dependent, with poorer resolution and smaller errors on smoother surfaces. Multiple approaches to smoothing the NGATE DTMs give very similar tradeoffs between resolution and error. Smoothing the NGATE DTMs with a 5x5 lowpass filter is near optimal in terms of both combined resolution-error performance and local slope estimation, but smoothing with a single pass of an area-based matcher, which has been the standard approach for generating planetary DTMs at the U.S. Geological Survey to date results in similar errors and only slightly worse resolution. DTMs from the HRSC team processing pipeline fall within this same trade space but are less sensitive to terrain roughness. DTMs produced with the Ames Stereo Pipeline also fall in this space at resolutions intermediate between NGATE and the team pipeline. Although DTM resolution and error each vary by a factor of 2, the product of resolution and error is much more consistent, varying by 20% across multiple image sets and matching algorithms. Refinement of the stereo DTM by photoclinometry can yield significant quantitative improvement in resolution and some improvement in error (improving their product by as much as a factor of 2), provided that albedo variations over distances smaller than the stereo DTM resolution are not too severe.