The impact of farming on prehistoric culinary practices throughout Northern Europe.

To investigate changes in culinary practices associated with the arrival of farming, we analysed the organic residues of over 1,000 pottery vessels from hunter-gatherer-fisher and early agricultural sites across Northern Europe from the Lower Rhine Basin to the Northeastern Baltic. Here, pottery was widely used by hunter-gatherer-fishers prior to the introduction of domesticated animals and plants. Overall, there was surprising continuity in the way that hunter-gatherer-fishers and farmers used pottery. Both aquatic products and wild plants remained prevalent, a pattern repeated consistently across the study area. We argue that the rapid adaptation of farming communities to exploit coastal and lagoonal resources facilitated their northerly expansion, and in some cases, hunting, gathering, and fishing became the most dominant subsistence strategy. Nevertheless, dairy products frequently appear in pottery associated with the earliest farming groups often mixed with wild plants and fish. Interestingly, we also find compelling evidence of dairy products in hunter-gatherer-fisher Ertebølle pottery, which predates the arrival of domesticated animals. We propose that Ertebølle hunter-gatherer-fishers frequently acquired dairy products through exchange with adjacent farming communities prior to the transition. The continuity observed in pottery use across the transition to farming contrasts with the analysis of human remains which shows substantial demographic change through ancient DNA and, in some cases, a reduction in marine consumption through stable isotope analysis. We postulate that farmers acquired the knowledge and skills they needed to succeed from local hunter-gatherer-fishers but without substantial admixture.

Can the Laparoscopic Approach for Adhesive Small Bowel Obstruction be Used in Octogenarians? An Observational Study Using ACS NSQIP.

BACKGROUND: With the population of octogenarians projected to increase fourfold by 2050, we sought to compare outcomes of laparoscopic versus open approach in octogenarians requiring surgery for adhesive small bowel obstruction (SBO). METHODS/MATERIALS AND METHODS: Using 2006-2015 American College of Surgeons National Surgical Quality Improvement Project, we identified patients aged ≥80 y who underwent emergency surgery within 1 d of admission for SBO. Risk variables of interest included age, sex, race, body mass index, preoperative sepsis, and American Society of Anesthesiologists (ASA) classification. Outcomes included length of stay, mortality, and pneumonia. Univariable and multivariable analyses were performed. RESULTS: Eight hundred fifty-six patients were identified. Six hundred ninety-nine (81.7%) underwent laparotomy; 157 (18.3%) underwent laparoscopy. Twenty-four (15.3%) of laparoscopic cases were converted. There was no difference between the open and laparoscopic groups in age, and race, preoperative albumin, or preoperative sepsis. The open group had higher rates of totally dependent functional status, congestive heart failure, chronic obstructive pulmonary disease, and higher ASA class. There was no difference in operative time. Laparoscopy was associated with shorter length of stay. The open approach showed higher rates of postoperative pneumonia, myocardial infarct, and mortality. Multivariable analysis showed increased age, functional status, preoperative albumin, and ASA class associated with mortality. The operative approach was not associated with mortality. Postoperative pneumonia was associated with male sex and open approach. CONCLUSIONS: Age, preoperative functional status, low preoperative albumin, and ASA classes IV and V were associated with mortality, while the open approach and male sex were associated with postoperative pneumonia. Octogenarians who present with SBO due to adhesive disease may benefit from an initial laparoscopic exploration. Further prospective studies are warranted.

Distal Tibia Allograft Glenoid Reconstruction in Recurrent Anterior Shoulder Instability: Clinical and Radiographic Outcomes.

PURPOSE: To assess the clinical and radiographic outcomes of patients with recurrent anterior shoulder instability treated with fresh distal tibia allograft (DTA) glenoid reconstruction. METHODS: Consecutive patients with a minimum 15% anterior glenoid bone loss associated with recurrent anterior instability who underwent stabilization with DTA glenoid reconstruction were retrospectively reviewed. Patients were evaluated with the American Shoulder and Elbow Society score, Western Ontario shoulder instability index, and single numerical assessment evaluation score at a minimum 2 years after surgery. All patients also underwent postoperative imaging evaluation with computed tomography where graft incorporation and allograft angle were measured. Statistical analysis was performed with paired t-tests, with P < .05 considered significant. RESULTS: A total of 27 patients (100% male) with an average age of 31 ± 5 years and an average follow-up of 45 months (range, 30-66) were included. There were significant improvements in preoperative to postoperative American Shoulder and Elbow Society score (63-91, P < .01), Western Ontario shoulder instability index (46% to 11% of normal, P < .01), and single numerical assessment evaluation score (50-90.5, P < .01) outcomes. Analysis of computed tomography data at an average 1.4 years postoperatively (available for 25 patients) showed an allograft healing rate of 89% (range, 80% to 100%), average allograft angle of 14.9° (range, 6.6° to 29.3°), and average allograft lysis of 3% (range, 0% to 25%). Grafts with lesser allograft angles (<15°) were better opposed to the anterior glenoid, showing superior healing and graft incorporation. There were no cases of recurrent instability. CONCLUSIONS: At an average follow-up of 45 months, fresh DTA reconstruction for recurrent anterior shoulder instability results in a clinically stable joint with excellent clinical outcomes and minimal graft resorption. Optimal allograft placement resulted in superior bony incorporation with the native glenoid. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

The effect of sagittal rotation of the glenoid on axial glenoid width and glenoid version in computed tomography scan imaging.

BACKGROUND: Computed tomography (CT) scans of the shoulder are often not well aligned to the axis of the scapula and glenoid. The purpose of this paper was to determine the effect of sagittal rotation of the glenoid on axial measurements of anterior-posterior (AP) glenoid width and glenoid version attained by standard CT scan. In addition, we sought to define the angle of rotation required to correct the CT scan to optimal positioning. METHODS: A total of 30 CT scans of the shoulder were reformatted using OsiriX software multiplanar reconstruction. The uncorrected (UNCORR) and corrected (CORR) CT scans were compared for measurements of both (1) axial AP glenoid width and (2) glenoid version at 5 standardized axial cuts. RESULTS: The mean difference in glenoid version was 2.6% (2° ± 0.1°; P = .0222) and the mean difference in AP glenoid width was 5.2% (1.2 ± 0.42 mm; P = .0026) in comparing the CORR and UNCORR scans. The mean angle of correction required to align the sagittal plane was 20.1° of rotation (range, 9°-39°; standard error of mean, 1.2°). CONCLUSION: These findings demonstrate that UNCORR CT scans of the glenohumeral joint do not correct for the sagittal rotation of the glenoid, and this affects the characteristics of the axial images. Failure to align the sagittal image to the 12-o'clock to 6-o'clock axis results in measurement error in both glenoid version and AP glenoid width. Use of UNCORR CT images may have notable implications for decision-making and surgical treatment.

Biceps tenodesis for long head of the biceps after auto-rupture or failed surgical tenotomy: results in an active population.

BACKGROUND: Long head of the biceps (LHB) deformity after surgical tenotomy or auto-rupture may result from attrition or injury. The purpose of this study was to describe the surgical outcomes of biceps tenodesis after failed surgical tenotomy or auto-rupture of the LHB tendon in a population of active patients. METHODS: During a 5-year period, 11 patients with a mean age of 43.3 years (range, 33-56 years) presented with symptoms of biceps cramping with activity (100%), deformity (100%), or pain (36%) at a mean of 8 months (range, 0.5-22 months) from a tenotomy (6 of 11) or an auto-rupture (5 of 11). All patients underwent a mini-open subpectoral biceps tenodesis with interference screw fixation. Patients were independently evaluated by patient-reported outcome measures (Single Assessment Numeric Evaluation [SANE] and Western Ontario Rotator Cuff Index [WORC]) and a biceps position examination. RESULTS: Of the 11 patients, 10 (91%) completed the study requirements at a mean of 2.6 years (range, 1.6-4.2 years). A total of 9 of the 10 patients (90%) returned to full activity. The mean preoperative SANE score was 61.1 (standard deviation [SD], 8.8), and the mean preoperative WORC score was 53.2 (SD, 9.2), which improved postoperatively to a SANE score of 84.2 (SD, 7.1) and a WORC score of 86 (SD, 8.2). There were no differences in LHB muscle position relative to the antecubital fossa (3.17 cm preoperatively to 3.25 cm postoperatively; P = .35). Deformity was resolved in all patients; 9 of 10 patients reported full resolution of cramping, and pain was resolved in 8 of 10. CONCLUSIONS: LHB tenodesis after auto-rupture or surgical tenotomy improved symptoms and allowed predictable return to activity and patient satisfaction. Additional work is necessary to determine the optimal treatment of primary biceps lesions.

Shoulder instability in the setting of bipolar (glenoid and humeral head) bone loss: the glenoid track concept.

BACKGROUND: An assortment of variables has been used in predicting anterior shoulder instability resulting from pathologic engagement of Hill-Sachs lesions on the glenoid. The glenoid track is a unique biomechanical model that relates both Hill-Sachs and bony Bankart lesions to predict shoulder engagement. We examined the glenoid track concept to determine if it provides a model that unifies glenoid rim and humeral head bone loss in predicting engagement. QUESTIONS/PURPOSES: In this review we addressed two questions: (1) How are humeral head and glenoid rim bony defects and their interactions quantified? (2) Why is the concept of the glenoid track important? METHODS: We performed a systematic review of the literature using PubMed (MEDLINE) and OVID for biomechanical studies and peer-reviewed articles published until March 2013. Twenty-four studies fit the inclusion criteria. These were subdivided into four anatomic studies, four studies quantifying glenohumeral bone loss, nine studies biomechanically defining shoulder engagement, six studies analyzing current treatment models, and one clinical study to be included in the final review. RESULTS: Data demonstrate pathologic engagement is dependent on the medial margin of the Hill-Sachs lesion traveling outside the glenoid track. The width of the glenoid track decreases accordingly if there is a glenoid defect, making engagement more likely. Most treatment models focus on widening the glenoid track before addressing Hill-Sachs lesions. CONCLUSIONS: The glenoid track uses both glenoid and humeral head bone loss to predict subsequent risk of humeral head engagement and possible dislocation. The glenoid track shows us that restoring the track to its natural width should be among the surgeon's first priority in restoring shoulder stability. Humeral head lesions, also known as Hill-Sachs lesions, are surgically addressed when they cause clinical symptoms. Symptoms arise when the medial margin of the defect engages the glenoid track.

A quantitative analysis of Final Palaeolithic/earliest Mesolithic cultural taxonomy and evolution in Europe.

Archaeological systematics, together with spatial and chronological information, are commonly used to infer cultural evolutionary dynamics in the past. For the study of the Palaeolithic, and particularly the European Final Palaeolithic and earliest Mesolithic, proposed changes in material culture are often interpreted as reflecting historical processes, migration, or cultural adaptation to climate change and resource availability. Yet, cultural taxonomic practice is known to be variable across research history and academic traditions, and few large-scale replicable analyses across such traditions have been undertaken. Drawing on recent developments in computational archaeology, we here present a data-driven assessment of the existing Final Palaeolithic/earliest Mesolithic cultural taxonomy in Europe. Our dataset consists of a large expert-sourced compendium of key sites, lithic toolkit composition, blade and bladelet production technology, as well as lithic armatures. The dataset comprises 16 regions and 86 individually named archaeological taxa ('cultures'), covering the period between ca. 15,000 and 11,000 years ago (cal BP). Using these data, we use geometric morphometric and multivariate statistical techniques to explore to what extent the dynamics observed in different lithic data domains (toolkits, technologies, armature shapes) correspond to each other and to the culture-historical relations of taxonomic units implied by traditional naming practice. Our analyses support the widespread conception that some dimensions of material culture became more diverse towards the end of the Pleistocene and the very beginning of the Holocene. At the same time, cultural taxonomic unit coherence and efficacy appear variable, leading us to explore potential biases introduced by regional research traditions, inter-analyst variation, and the role of disjunct macroevolutionary processes. In discussing the implications of these findings for narratives of cultural change and diversification across the Pleistocene-Holocene transition, we emphasize the increasing need for cooperative research and systematic archaeological analyses that reach across research traditions.

Extracorporeal membrane oxygenation in the surgical management of large mediastinal masses: a narrative review.

Background and Objective: The management of large mediastinal tumors requires a complex multidisciplinary approach, particularly in the perioperative setting due to increased risk of hemodynamic compromise. The utilization of extracorporeal membrane oxygenation (ECMO) provides a useful adjunct in the surgical management for biopsy and resection of these mediastinal masses. The objective of this article is to review indications and implementation of ECMO in the surgical management of mediastinal disease. Methods: A literature review of the PubMed database was completed evaluating articles discussing 'extracorporeal circulation', 'cardiopulmonary bypass', 'anesthesia', 'mediastinal disease', and 'mediastinal cancer'. These articles were evaluated for contribution to the discussion of indications and implementation of ECMO in the management of these patients. Key Content and Findings: Large mediastinal tumors place patients at risk of hemodynamic collapse on induction of anesthesia due to compression of vascular structures, tracheobronchial tree and creation of V/Q mismatch. Patients may be stratified regarding their risk of perioperative complications by evaluation of postural symptoms, cross sectional imaging findings and pulmonary function tests. Those patients at elevated perioperative risk may benefit from the utilization of ECMO, most commonly veno-arterial (V-A) ECMO. Guidewires or ECMO cannulas may be placed under local anesthesia prior to induction. Those patients with hemodynamic compromise may receive mechanical circulatory support to allow completion of the operation. Conclusions: The use of a multidisciplinary team consisting of surgeons, anesthesiologists, perfusionists and OR team is critical to the success in the use of ECMO in the resection of mediastinal masses. With diligent preparation, these high-risk patients may be optimally managed at the time of resection.

The reciprocal interplay of physical activity and health-related quality of life in children and adolescents: Evidence for both upward and downward spirals.

OBJECTIVE: This study examines the bidirectional effect between physical activity (PA) and health-related quality of life in children and adolescents, focusing on within-person effects. METHODS: PA and health-related quality of life were assessed in children and adolescents (N = 685, age: M = 10.29 years, SD = 1.35, range = 8-14), via self-report across four waves, each 6 months apart, and a random-intercept cross-lagged panel model with time-invariant cross-lagged effects was calculated. RESULTS: Positive cross-lagged effects between prior PA and health-related quality of life 6 months later ( γ y = 0.536, 95% CI [0.016, 1.055], p = .043, d = 0.11) and vice versa ( γ x = 0.015, 95% CI [0.001, 0.030], p = .039, d = 0.12) were found. Furthermore, the random intercept correlation was significant ( T xy = 3.622, 95% CI [2.204, 5.041], p < .001, d = 0.27). CONCLUSIONS: The findings confirm known correlations between PA and health-related quality of life and extends them by indicating both an upward and downward spiral of PA and health-related quality of life in children and adolescents.

Bronchogenic cysts: a narrative review.

Background and Objective: Bronchogenic cysts represent a rare form of cystic malformation of the respiratory tract. Primarily located in the mediastinum if occurring early in gestation as opposed to the thoracic cavity if arising later in development. However, they can arise from any site along the foregut. They exhibit a variety of clinical and radiologic presentations, representing a diagnostic challenge, especially in areas with endemic hydatid disease. Endoscopic drainage has emerged as a diagnostic and potentially therapeutic option but has been complicated by reports of infection. Surgical excision remains the standard of care allowing for symptomatic resolution and definitive diagnosis via pathologic examination; minimally invasive approaches such as robotic and thoracoscopic approaches aiding treatment. Following complete resection, prognosis is excellent with essentially no recurrence. Methods: A review of the available electronic literature was performed from 1975 through 2022, using PubMed and Google Scholar, with an emphasis on more recent series. We included all retrospective series and case reports. A single author identified the studies, and all authors reviewed the selection until there was a consensus on which studies to include. Key Content and Findings: The literature consisted of relatively small series, mixed between adult and pediatric patients, and the consensus remains that all symptomatic lesions should be excised via minimally invasive approach where feasible. Conclusions: Surgical excision of symptomatic bronchogenic cysts remains the gold standard, with endoscopic drainage being reserved for diagnosis or as a temporizing measure in clinically unstable patients.

Achieving opioid-free discharge following robotic thoracic surgery: A single-institution experience.

Objectives: Enhanced recovery after thoracic surgery (ERATS) protocols use a combination of analgesics for pain control and have been associated with decreased opioid requirements. We investigated the impact of continual ERATS refinement on the incidence of opioid-free discharge. Methods: We retrospectively analyzed our prospectively maintained institutional database for elective, opioid-naive robotic thoracoscopic procedures. Demographics, operative outcomes, postoperative opioid dispensed (morphine milligram equivalent), and opioid discharge status were collected. Our primary outcome of interest was factors associated with opioid-free discharge; our secondary objective was to determine the incidence of new persistent opioid users. Results: In total, 466 patients from our optimized ERATS protocol were included; 309 (66%) were discharged without opioids. However, 34 (11%) of patients discharged without opioids required a prescription postdischarge. Conversely, 7 of 157 patients (11%), never filled their opioid prescriptions given at discharge. Factors associated with opioid-free discharges were nonanatomic resections, mediastinal procedures, minimal pain, and lack of opioid usage on the day of discharge. More importantly, 3.2% of opioid-free discharge patients became new persistent opioid users versus 10.8% of patients filling opioid prescriptions after discharges (P = .0013). Finally, only 2.3% of opioid-naive patients of the entire cohort became chronic opioid users; there was no difference in the incidence of chronic use by opioid discharge status. Conclusions: Optimized opioid-sparing ERATS protocols are highly effective in reducing opioid prescription on the day of discharge. We observed a very low rate of new persistent or chronic opioid use in our cohort, further highlighting the role ERATS protocols in combating the opioid epidemic.

The essential role of non-steroidal anti-inflammatory drugs in pain control following robotic thoracoscopic lung resections.

Background: Enhanced recovery after thoracic surgery (ERATS) protocols use a combination of analgesics for pain control. We investigated the effect of non-steroidal analgesic drugs (NSAIDs) on pain control by comparing patient levels and opioid requirements after robotic pulmonary resections. Methods: We retrospectively analyzed our prospectively maintained institutional database for elective, opioid-naïve robotic thoracoscopic pulmonary resections. All patients received postoperative NSAIDs unless contraindicated or at the discretion of the attending surgeons. Our original protocol (ERATS-V1) was modified to optimize opioid-sparing effect without affecting pain control (ERATS-V2). Demographics, operative outcomes, and postoperative opioid dispensed [morphine milligram equivalent (MME)] were collected. Results: A total of 491 patients (147 ERATS-V1; 344 ERATS-V2) were included in this study. There was no difference in patient characteristics or operative outcomes between ERATS cohorts. Protocol optimization was associated with a 2- to 10-fold reduction of postoperative opioid use without compromising pain control. In ERATS-V1 cohort, there was no difference in pain levels and opioid requirements with NSAID usage. In ERATS-V2 cohort, while pain levels were similar, higher in-hospital opioid consumption was observed in no-NSAID subgroup {MME: 20.5 [interquartile range (IQR), 4.8-40.5] vs. 12.0 (IQR, 2.0-32.2), P=0.0096, schedule II: 14.2 (IQR, 3.0-36.4) vs. 6.8 (IQR, 1.4-24.0), P=0.012} as well as total postoperative schedule II opioid requirement [17.8 (IQR, 3.0-43.5) vs. 8.8 (IQR, 1.5-30), P=0.032]. Conclusions: The opioid-sparing effect of NSAIDs was observed only in optimized ERATS patients. Modifications of our pre-existing ERATS was associated with a significant reduction of opioid consumption without affecting pain levels. This revealed the role of NSAIDs in postoperative pain management otherwise masked by excessive opioids use.

Postoperative day 1 discharge following robotic thoracoscopic pulmonary anatomic resections in the era of enhanced recovery protocol: A single-institution experience.

Objective: Implementation and continuing optimization of enhanced recovery protocol after thoracic surgery results in significant improvement of postoperative outcomes. We observed a 10-fold increase in the rate of postoperative day (POD) 1 discharges following robotic thoracoscopic anatomic resections over time. We aimed to determine factors associated with safe POD1 discharges. Methods: We performed a retrospective analysis of a prospectively maintained database of robotic anatomic pulmonary resections between July 1, 2012, and June 30, 2022, with patients of the last 2.5 years forming the basis of this study. Data collected included demographics, insurance types, Area Deprivation Index (indicator of poverty), and operative and postoperative variables including length of stay, opioid use, daily pain levels, readmissions, and outpatient interventions. Factors associated with POD1 were analyzed using a logistic regression module. Result: In total, 279 patients met inclusion criteria (91 POD1 discharges, 32.6%; none discharged with a pleural catheter). There was neither an increase of postdischarge interventions for pleural complications nor readmission in early discharge patients. After adjusting for relevant factors, younger age, right middle lobectomy, lower opioid use on POD1, operating room finish before 4 PM, and low Area Deprivation Index were significantly associated with POD1 discharge. A subanalysis of 49 patients, who could have been discharged on POD1, identified hypoxemia requiring home oxygen, atrial fibrillation, and poorly controlled pain being common mitigatable clinical factors delaying POD1 discharge. Conclusions: Safe POD1 discharge following robotic thoracoscopic anatomic resection was achieved in 32% of cases. Identification of positive and negative factors affecting early discharge provides guidance for further modifications to increase the number of POD1 discharges.

Magnetogenetic cell activation using endogenous ferritin.

The ability to precisely control the activity of defined cell populations enables studies of their physiological roles and may provide therapeutic applications. While prior studies have shown that magnetic activation of ferritin-tagged ion channels allows cell-specific modulation of cellular activity, the large size of the constructs made the use of adeno-associated virus, AAV, the vector of choice for gene therapy, impractical. In addition, simple means for generating magnetic fields of sufficient strength have been lacking. Toward these ends, we first generated a novel anti-ferritin nanobody that when fused to transient receptor potential cation channel subfamily V member 1, TRPV1, enables direct binding of the channel to endogenous ferritin in mouse and human cells. This smaller construct can be delivered in a single AAV and we validated that it robustly enables magnetically induced cell activation in vitro . In parallel, we developed a simple benchtop electromagnet capable of gating the nanobody-tagged channel in vivo . Finally, we showed that delivering these new constructs by AAV to pancreatic beta cells in combination with the benchtop magnetic field delivery stimulates glucose-stimulated insulin release to improve glucose tolerance in mice in vivo . Together, the novel anti-ferritin nanobody, nanobody-TRPV1 construct and new hardware advance the utility of magnetogenetics in animals and potentially humans.

A pan-European dataset revealing variability in lithic technology, toolkits, and artefact shapes ~15-11 kya.

Comparative macro-archaeological investigations of the human deep past rely on the availability of unified, quality-checked datasets integrating different layers of observation. Information on the durable and ubiquitous record of Paleolithic stone artefacts and technological choices are especially pertinent to this endeavour. We here present a large expert-sourced collaborative dataset for the study of stone tool technology and artefact shape evolution across Europe between ~15.000 and 11.000 years before present. The dataset contains a compendium of key sites from the study period, and data on lithic technology and toolkit composition at the level of the cultural taxa represented by those sites. The dataset further encompasses 2D shapes of selected lithic artefact groups (armatures, endscrapers, and borers/perforators) shared between cultural taxa. These data offer novel possibilities to explore between-regional patterns of material culture change to reveal scale-dependent processes of long-term technological evolution in mobile hunter-gatherer societies at the end of the Pleistocene. Our dataset facilitates state-of-the-art quantitative analyses and showcases the benefits of collaborative data collation and synthesis.

Limited historical admixture between European wildcats and domestic cats.

Domestic cats were derived from the Near Eastern wildcat (Felis lybica), after which they dispersed with people into Europe. As they did so, it is possible that they interbred with the indigenous population of European wildcats (Felis silvestris). Gene flow between incoming domestic animals and closely related indigenous wild species has been previously demonstrated in other taxa, including pigs, sheep, goats, bees, chickens, and cattle. In the case of cats, a lack of nuclear, genome-wide data, particularly from Near Eastern wildcats, has made it difficult to either detect or quantify this possibility. To address these issues, we generated 75 ancient mitochondrial genomes, 14 ancient nuclear genomes, and 31 modern nuclear genomes from European and Near Eastern wildcats. Our results demonstrate that despite cohabitating for at least 2,000 years on the European mainland and in Britain, most modern domestic cats possessed less than 10% of their ancestry from European wildcats, and ancient European wildcats possessed little to no ancestry from domestic cats. The antiquity and strength of this reproductive isolation between introduced domestic cats and local wildcats was likely the result of behavioral and ecological differences. Intriguingly, this long-lasting reproductive isolation is currently being eroded in parts of the species' distribution as a result of anthropogenic activities.

Vesicular uptake blockade generates the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde in PC12 cells: relevance to the pathogenesis of Parkinson's disease.

Parkinson's disease entails profound loss of nigrostriatal dopaminergic terminals, decreased vesicular uptake of intraneuronal catecholamines, and relatively increased putamen tissue concentrations of the toxic dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). The objective of this study was to test whether vesicular uptake blockade augments endogenous DOPAL production. We also examined whether intracellular DOPAL contributes to apoptosis and, as α-synuclein oligomers may be pathogenetic in Parkinson's disease, oligomerizes α-synuclein. Catechols were assayed in PC12 cells after reserpine to block vesicular uptake, with or without inhibition of enzymes metabolizing DOPAL-daidzein for aldehyde dehydrogenase and AL1576 for aldehyde reductase. Vesicular uptake was quantified by a method based on 6F- or (13) C-dopamine incubation; DOPAL toxicity by apoptosis responses to exogenous dopamine, with or without daidzein+AL1576; and DOPAL--induced synuclein oligomerization by synuclein dimer production during DOPA incubation, with or without inhibition of L-aromatic-amino-acid decarboxylase or monoamine oxidase. Reserpine inhibited vesicular uptake by 95-97% and rapidly increased cell DOPAL content (p = 0.0008). Daidzein+AL1576 augmented DOPAL responses to reserpine (p = 0.004). Intracellular DOPAL contributed to dopamine-evoked apoptosis and DOPA-evoked synuclein dimerization. The findings fit with the 'catecholaldehyde hypothesis,' according to which decreased vesicular sequestration of cytosolic catecholamines and impaired catecholaldehyde detoxification contribute to the catecholaminergic denervation that characterizes Parkinson's disease.

Auto calibration of a cone-beam-CT.

PURPOSE: This paper introduces a novel autocalibration method for cone-beam-CTs (CBCT) or flat-panel CTs, assuming a perfect rotation. The method is based on ellipse-fitting. Autocalibration refers to accurate recovery of the geometric alignment of a CBCT device from projection images alone, without any manual measurements. METHODS: The authors use test objects containing small arbitrarily positioned radio-opaque markers. No information regarding the relative positions of the markers is used. In practice, the authors use three to eight metal ball bearings (diameter of 1 mm), e.g., positioned roughly in a vertical line such that their projection image curves on the detector preferably form large ellipses over the circular orbit. From this ellipse-to-curve mapping and also from its inversion the authors derive an explicit formula. Nonlinear optimization based on this mapping enables them to determine the six relevant parameters of the system up to the device rotation angle, which is sufficient to define the geometry of a CBCT-machine assuming a perfect rotational movement. These parameters also include out-of-plane rotations. The authors evaluate their method by simulation based on data used in two similar approaches [L. Smekal, M. Kachelriess, S. E, and K. Wa, "Geometric misalignment and calibration in cone-beam tomography," Med. Phys. 31(12), 3242-3266 (2004); K. Yang, A. L. C. Kwan, D. F. Miller, and J. M. Boone, "A geometric calibration method for cone beam CT systems," Med. Phys. 33(6), 1695-1706 (2006)]. This allows a direct comparison of accuracy. Furthermore, the authors present real-world 3D reconstructions of a dry human spine segment and an electronic device. The reconstructions were computed from projections taken with a commercial dental CBCT device having two different focus-to-detector distances that were both calibrated with their method. The authors compare their reconstruction with a reconstruction computed by the manufacturer of the CBCT device to demonstrate the achievable spatial resolution of their calibration procedure. RESULTS: Compared to the results published in the most closely related work [K. Yang, A. L. C. Kwan, D. F. Miller, and J. M. Boone, "A geometric calibration method for cone beam CT systems," Med. Phys. 33(6), 1695-1706 (2006)], the simulation proved the greater accuracy of their method, as well as a lower standard deviation of roughly 1 order of magnitude. When compared to another similar approach [L. Smekal, M. Kachelriess, S. E, and K. Wa, "Geometric misalignment and calibration in cone-beam tomography," Med. Phys. 31(12), 3242-3266 (2004)], their results were roughly of the same order of accuracy. Their analysis revealed that the method is capable of sufficiently calibrating out-of-plane angles in cases of larger cone angles when neglecting these angles negatively affects the reconstruction. Fine details in the 3D reconstruction of the spine segment and an electronic device indicate a high geometric calibration accuracy and the capability to produce state-of-the-art reconstructions. CONCLUSIONS: The method introduced here makes no requirements on the accuracy of the test object. In contrast to many previous autocalibration methods their approach also includes out-of-plane rotations of the detector. Although assuming a perfect rotation, the method seems to be sufficiently accurate for a commercial CBCT scanner. For devices which require higher dimensional geometry models, the method could be used as a initial calibration procedure.

Tumor and Tumor-Associated Macrophage Programmed Death-Ligand 1 Expression Is Associated With Adjuvant Chemotherapy Benefit in Lung Adenocarcinoma.

INTRODUCTION: Patients with stage II to III lung adenocarcinomas are treated with adjuvant chemotherapy (ACT) to target the premetastatic niche that persists after curative-intent resection. We hypothesized that the premetastatic niche is a scion of resected lung tumor microenvironment and that analysis of tumor microenvironment can stratify survival benefit from ACT. METHODS: Using tumor and tumoral stroma from 475 treatment-naive patients with stage II to III lung adenocarcinomas, we constructed a tissue microarray and performed multiplex immunofluorescent staining for immune markers (programmed death-ligand 1 [PD-L1], tumor-associated macrophages [TAMs], and myeloid-derived suppressor cells) and derived myeloid-lymphoid ratio. The association between immune markers and survival was evaluated using Cox models adjusted for pathologic stage. RESULTS: Patients with high PD-L1 expression on TAMs or tumor cells in resected tumors had improved survival with ACT (TAMs: hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.12-2.85; tumor cells: HR = 3.02, 95% CI: 1.69-5.40). Among patients with high PD-L1 expression on TAMs alone or TAMs and tumor cells, ACT survival benefit is pronounced with high myeloid-lymphoid ratio (TAMs: HR = 3.87, 95% CI: 1.79-8.37; TAMs and tumor cells: HR = 2.19, 95% CI: 1.02-4.71) or with high stromal myeloid-derived suppressor cell ratio (TAMs: HR = 2.53, 95% CI: 1.29-4.96; TAMs and tumor cells: HR = 3.21, 95% CI: 1.23-8.35). Patients with low or no PD-L1 expression on TAMs or tumor cells had no survival benefit from ACT. CONCLUSIONS: Our observation that PD-L1 expression on TAMs or tumor cells is associated with improved survival with ACT provides rationale for prospective investigation and developing chemoimmunotherapy strategies for patients with lung adenocarcinoma.