Extended blood stage sensitivity profiles of Plasmodium cynomolgi to doxycycline and tafenoquine, as a model for Plasmodium vivax.

Testing Plasmodium vivax antimicrobial sensitivity is limited to ex vivo schizont maturation assays, which preclude determining the IC50s of delayed action antimalarials such as doxycycline. Using Plasmodium cynomolgi as a model for P. vivax, we determined the physiologically significant delayed death effect induced by doxycycline [IC50(96 h), 1,401 ± 607 nM]. As expected, IC50(96 h) to chloroquine (20.4 nM), piperaquine (12.6 µM), and tafenoquine (1,424 nM) were not affected by extended exposure.

Biopsychosocial Late Effects After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases from Colorectal and Appendiceal Cancer: A National Prospective Cohort Study.

BACKGROUND: Colorectal cancer with peritoneal metastases can be treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Treatment may result in biopsychosocial late effects (LEs). We explored the frequency and severity of the following biopsychosocial LEs: anxiety, depression, fear of cancer recurrence (FCR), insomnia, fatigue, cognitive impairment, and pain, and evaluated their impact on quality of life (QoL). METHOD: This was a national prospective cohort study screening for LEs during the period January 2021-May 2023. Patients completed the following questionnaires: General Anxiety Disorder-7, Patient Health Questionnaire-9, FCR Inventory-Short Form, Insomnia Severity Index, Functional Assessment of Chronic Illness Therapy-Fatigue, cognitive impairment (six items from the European Organisation for Research and Treatment of Cancer Item Library), and the Rectal Cancer Pain Score. Preregistration was completed at ClinicalTrials.gov (NCT04956107). RESULT: In total, 99 patients were included. The mean age was 61 years and 57% were women. At 3 months after surgery, the frequent LEs were fatigue (72%), FCR (58%), and pain (48%), and at 12 months after surgery, the frequent LEs were FCR (65%), fatigue (40%), and insomnia (33%). More than half of the patients (54%) reported at least two LEs after 12 months. Patients with moderate-to-severe LEs reported a lower QoL than patients with no/mild LEs. Patients with no/mild LEs had a similar QoL as the Danish norm population. CONCLUSION: Biopsychosocial LEs were prevalent. The QoL of patients reporting LEs in the worst severity categories was negatively impacted. Screening and treatment for these LEs should be a focus in cancer survivor follow-up.

KCNA2 IgG autoimmunity in neuropsychiatric diseases.

BACKGROUND: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. DESIGN / METHODS: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. RESULTS: KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. CONCLUSION: Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.

Short-term outcomes of surgical treatment for primary ileocaecal Crohn's disease: Results of the Crohn's(urg) study, a multicentre, retrospective, comparative analysis between inflammatory and complicated phenotypes.

AIM: Recent evidence challenges the current standard of offering surgery to patients with ileocaecal Crohn's disease (CD) only when they present complications of the disease. The aim of this study was to compare short-term results of patients who underwent primary ileocaecal resection for either inflammatory (luminal disease, earlier in the disease course) or complicated phenotypes, hypothesizing that the latter would be associated with worse postoperative outcomes. METHOD: A retrospective, multicentre comparative analysis was performed including patients operated on for primary ileocaecal CD at 12 referral centres. Patients were divided into two groups according to indication of surgery for inflammatory (ICD) or complicated (CCD) phenotype. Short-term results were compared. RESULTS: A total of 2013 patients were included, with 291 (14.5%) in the ICD group. No differences were found between the groups in time from diagnosis to surgery. CCD patients had higher rates of low body mass index, anaemia (40.9% vs. 27%, p < 0.001) and low albumin (11.3% vs. 2.6%, p < 0.001). CCD patients had longer operations, lower rates of laparoscopic approach (84.3% vs. 93.1%, p = 0.001) and higher conversion rates (9.3% vs. 1.9%, p < 0.001). CCD patients had a longer hospital stay and higher postoperative complication rates (26.1% vs. 21.3%, p = 0.083). Anastomotic leakage and reoperations were also more frequent in this group. More patients in the CCD group required an extended bowel resection (14.1% vs. 8.3%, p: 0.017). In multivariate analysis, CCD was associated with prolonged surgery (OR 3.44, p = 0.001) and the requirement for multiple intraoperative procedures (OR 8.39, p = 0.030). CONCLUSION: Indication for surgery in patients who present with an inflammatory phenotype of CD was associated with better outcomes compared with patients operated on for complications of the disease. There was no difference between groups in time from diagnosis to surgery.

Comparison of sample materials for S100b analysis.

Head injury is a potentially lethal and frequently occurring condition in the emergency department (ED). Reliable and fast diagnosis is important both for patients and flow in the ED. Circulating S100B is used to rule out the need for head computer tomography in low-risk patients with mild head injury. The flow of these patients through the ED would benefit from shorter turn-around time. Standard serum clotting tubes require 30-60 min clotting time, followed by an analysis time of 45 min. Here, we evaluated the performance of two alternative blood collection tubes; a rapid serum tube (RST) with a recommend clotting time of 5 min and a hirudin tube (HIR) for instant anticoagulation. S100B measurement was performed on paired blood samples from 221 subjects using a Roche Cobas 602 analyser. The performances of the alternative tubes were evaluated by method comparison to the standard serum clotting tube, repeatability and agreement of results obtained from alternative tubes compared with the standard clotting tube. Both alternative tubes had a minor positive bias (RST = 0.011 µg/L, HIR = 0.008 µg/L). The repeatability was 2% for RST and 10% for HIR, while being 4% for the standard clotting tube. In the agreement analysis, the positive and negative predictive values for RST were 62% and 100% while being 73% and 99% for HIR respectively. Our study suggests that RST is a feasible alternative to reduce laboratory turn-around time in S100b analysis.

No additive effect of creatine, caffeine, and sodium bicarbonate on intense exercise performance in endurance-trained individuals.

BACKGROUND: Athletes commonly use creatine, caffeine, and sodium bicarbonate for performance enhancement. While their isolated effects are well-described, less is known about their potential additive effects. METHODS: Following a baseline trial, we randomized 12 endurance-trained males (age: 25 ± 5 years, VO2max: 56.7 ± 4.6 mL kg-1 min-1; mean ± SD) and 11 females (age: 25 ± 3 years, VO2max: 50.2 ± 3.4 mL kg-1 min-1) to 5 days of creatine monohydrate (0.3 g kg-1 per day) or placebo loading, followed by a daily maintenance dose (0.04 g kg-1) throughout the study. After the loading period, subjects completed four trials in randomized order where they ingested caffeine (3 mg kg-1), sodium bicarbonate (0.3 g kg-1), placebo, or both caffeine and sodium bicarbonate before a maximal voluntary contraction (MVC), 15-s sprint, and 6-min time trial. RESULTS: Compared to placebo, mean power output during 15-s sprint was higher following loading with creatine than placebo (+34 W, 95% CI: 10 to 58, p = 0.008), but with no additional effect of caffeine (+10 W, 95% CI: -7 to 24, p = 0.156) or sodium bicarbonate (+5 W, 95% CI: -4 to 13, p = 0.397). Mean power output during 6-min time trial was higher with caffeine (+12 W, 95% CI: 5 to 18, p = 0.001) and caffeine + sodium bicarbonate (+8 W, 95% CI: 0 to 15, p = 0.038), whereas sodium bicarbonate (-1 W, 95% CI: -7 to 6, p = 0.851) and creatine (-6 W, 95% CI: -15 to 4, p = 0.250) had no effects. CONCLUSION: While creatine and caffeine can enhance sprint- and time trial performance, respectively, these effects do not seem additive. Therefore, supplementing with either creatine or caffeine appears sufficient to enhance sprint or short intense exercise performance.

Performance and Fatigue Patterns in Elite Cyclists During 6 h of Simulated Road Racing.

Fatigue resistance is vital for success in elite road cycling, as repeated, intense efforts challenge the athletes' ability to sustain peak performance throughout prolonged races. The present study combined recurrent performance testing and physiological measures during 6 h simulated racing with laboratory testing to investigate factors influencing fatigue resistance. Twelve male national elite cyclists (25 ± 3 years; 76 ± 6 kg and VO2max of 5.2 ± 0.5 L/min) completed incremental power and maximal fat oxidation tests. Subsequently, they underwent field testing with physiological measures and fatigue responses evaluated through peak sprint power and 5 km time trial (TT) testing after 0, 2, 4, and 6 h of exercise. Peak power declined from 1362 ± 176 W in first sprint to 1271 ± 152 W after 2 h (p < 0.01) and then stabilized. In contrast, TT mean power gradually declined from 412 ± 38 W in the first TT to 384 ± 41 W in the final trial, with individual losses ranging from 2% to 14% and moderately correlated (r2 = 0.45) to accumulated exercise time above lactate threshold. High carbohydrate intake (~90 g/h) maintained blood glucose levels, but post-TT [lactate] decreased from 15.1 ± 2 mM to 7.1 ± 2.3 mM, while fat oxidation increased from 0.7 ± 0.3 g/min at 0 h to 1.1 ± 0.1 g/min after 6 h. The study identifies fatigue patterns in national elite cyclists. Peak sprint power stabilized after an initial impairment from 0 to 2 h, while TT power gradually declined over the 6 h simulated race, with increased differentiation in fatigue responses among athletes.

Exploring D-Lactate as a Biomarker for Acute Intestinal Necrosis in 2958 Patients: A Prospective Cross-Sectional Study.

BACKGROUND: Timely diagnosis of acute intestinal necrosis (AIN) is lifesaving, but challenging due to unclear clinical presentation. D-lactate has been proposed as an AIN biomarker. OBJECTIVES: We aimed to test the diagnostic performance in a clinical setting. METHODS: We performed a cross-sectional prospective study, including all adult patients with acute referral to a single tertiary gastrointestinal surgical department during 2015-2016 and supplemented by enrollment of high-risk in-hospital patients suspected of having AIN during 2016-2019. AIN was verified intraoperatively, and D-lactate was analyzed using an automatic spectrophotometric set-up. A D-lactate cut-off for AIN was estimated using the receiver operating characteristic curve. The performance according to patient subgroups was estimated using the area under the receiver operating characteristic curve (AUC). Given the exploratory nature of this study, a formal power calculation was not feasible. RESULTS: Forty-four AIN patients and 2914 controls were enrolled. The D-lactate cut-off was found to be 0.0925 mM. Due to lipemic interference, D-lactate could not be quantified in half of the patients, leaving 23 AIN patients and 1456 controls for analysis. The AUC for the diagnosis of AIN by D-lactate was 0.588 (95% confidence interval 0.475-0.712), with a sensitivity of 0.261 and specificity of 0.892. Analysis of high-risk patients showed similar results (AUC 0.579; 95% confidence interval 0.422-0.736). CONCLUSION: D-lactate showed low sensitivity for AIN in both average-risk and high-risk patients. Moreover, lipemic interference precluded valid spectrophotometric assessment of D-lactate in half of the patients, further disqualifying the clinical utility of D-lactate as a diagnostic marker for AIN.

Is transanal irrigation the best treatment possibility for low anterior resection syndrome? A multicenter, randomized clinical trial: study protocol.

Background: Up to 50% of patients who undergo rectal resection suffer from various and partly severe functional problems, despite the preservation of the anal sphincter. These complaints are defined as low anterior resection syndrome (LARS). So far, there are no randomized clinical trials regarding the most effective treatment for LARS. Our aim is to evaluate whether transanal irrigation improves bowel function and quality of life in patients following low anterior resection compared to best supportive care. Methods: Patients who have undergone low anterior resection will be approached for this study. On patient's visit, complaints regarding the defecation as well as any deterioration in their overall quality of life will be assessed using questionnaires such as the Low Anterior Resection Syndromes score, Wexner score, European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QOL) CR-29, and Measure Yourself Medical Outcome Profile tool. Few additional target questions will be also asked, such as "Would you recommend the treatment to anybody; did you expect the improvement following the treatment; etc." Questionnaires and scales will be filled on follow-up visits every 3 months for 1 year. Discussion: This multicenter, randomized controlled trial will lead to a better understanding of LARS treatment. Moreover, it will be a hypothesis-generating study and will inform areas needing future prospective studies. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT05920681).

System stability and signal enhancement with analyte protectants: Gas chromatography analysis of oxygenated-polycyclic aromatic hydrocarbons.

Matrix effects can affect detection limits, precision, and accuracy and lead to signal enhancement or suppression effects in gas chromatography analysis. Analyte protectants, such as shikimic acid and gluconolactone, can imitate the effect of matrix components and reduce the differences in matrix effect between samples. This study aimed to investigate the ability of analyte protectants to enhance gas chromatography detector signals of different oxygenated-polycyclic aromatic hydrocarbons. Addition of 100 µg L-1 shikimic acid and 200 µg L-1 gluconolactone effectively enhanced detector response of the investigated target compounds. Addition of a higher content of analyte protectants did not result in any further enhancement. It was found that between four and eleven consecutive injections of a standard solution with analyte protectants were required to obtain a stable compound response. The long-term signal stability was then maintained with subsequent injections, though an overall negative drift of the system was observed over the sequence of 200 investigated injections. Analysis of the actual sample matrix instead of standards in pure solvent, as presented in this study, could also be a way to minimize the required number of injections. Shikimic acid and gluconolactone were first and foremost able to enhance signals of oxygenated-polycyclic aromatic hydrocarbons with similar functional groups (hydroxyl) in their molecular structure. It can be relevant to consider alternative analyte protectants with different functional groups according to the type of target compounds investigated.

A narrative on diversity, equity, and inclusion in surgery: insights from the European Society of Coloproctology and identification of points for action.

The focus of the 2022 European Society of Coloproctology (ESCP) annual campaign was diversity, equity, and inclusion (DEI) in surgery. The ESCP "Operation Equal Access" campaign sought to interview key-opinion leaders and trainees, to raise awareness on inequalities, inform the community of the status of the topic, and to identify future areas for improvement. The ESCP Social Media Working Group interviewed experts who have made significant contributions to DEI in colorectal surgery and were acknowledged opinion leaders in the field. The interviews focused on their career, professional life, experiences, and opportunities during their training, and their views on DEI in colorectal surgery. DEI principles, education, and values need further promotion to reduce and address bias within the profession and overall improve the experience of minority community including health professionals and patients. International Societies are working to facilitate training opportunities and overcome DEI, and networking have contributed to that. Collaborations between societies will be pivotal to contribute to offering research and leadership opportunities equally. Access to advanced workshops including cadaveric training and simulation can be consistently promoted and provided globally via societies through telemonitoring. Involving patients in research should be encouraged, as it brings the perspective of a living experience.

Low Energy Availability Followed by Optimal Energy Availability Does Not Benefit Performance in Trained Females.

PURPOSE: Short periods of reduced energy availability are commonly undertaken by athletes to decrease body mass, possibly improve the power-to-mass ratio, and enhance physical performance. Our primary aim was to investigate the impact of 10 d of low energy availability (LEA) followed by 2 d of optimal energy availability (OEA) on physical performance parameters in trained females. Second, physiological markers at the whole-body and molecular level related to performance were evaluated. METHODS: Thirty young trained eumenorrheic females were matched in pairs based on training history and randomized to a 10-d intervention period of LEA (25 kcal·fat-free mass (FFM) -1 ·d -1 ) or OEA (50 kcal·FFM -1 ·d -1 ) along with supervised exercise training. Before the intervention, participants underwent a 5-d run-in period with OEA + supervised exercise training. After the LEA intervention, 2 d of recovery with OEA was completed. Participants underwent muscle biopsies, blood sampling, physical performance tests, body composition measurements, and resting metabolic rate measurements. A linear mixed model was used with group and time as fixed effects and subject as random effects. RESULTS: Compared with OEA, LEA resulted in reduced body mass, muscle glycogen content, repeated sprint ability, 4-min time-trial performance, and rate of force development of the knee extensors (absolute values; P < 0.05). Two days of recovery restored 4-min time-trial performance and partly restored repeated sprint ability, but performance remained inferior to the OEA group. When the performance data were expressed relative to body mass, LEA did not enhance performance. CONCLUSIONS: Ten days of LEA resulted in impaired performance (absolute values), with concomitant reductions in muscle glycogen. Two days of recovery with OEA partially restored these impairments, although physical performance (absolute values) was still inferior to being in OEA. Our findings do not support the thesis that LEA giving rise to small reductions in body mass improves the power-to-mass ratio and thus increases physical performance.

Investigation of Escherichia coli isolates from pigs and humans for colistin resistance in Lao PDR- a cross-sectional study.

Background: In Laos, colistin is not currently registered for use in humans. This One Health study aimed to estimate the prevalence of meat-producing pigs carrying colistin-resistant Escherichia coli, and investigate if E. coli causing invasive human infections were colistin-resistant. Methods: Between September 2022 and March 2023, rectal swabs were collected from 895 pigs from abattoirs in 9/17 Lao provinces. Pig rectal swabs and stored E. coli isolates from human blood cultures, submitted to Mahosot Hospital Microbiology laboratory between 2005 and 2022, were screened for colistin resistance on selective chromogenic agar with organism identification confirmed using MALDI-TOF MS. Suspected colistin-resistant isolates underwent colistin susceptibility testing by broth microdilution following European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Isolates with MIC values of ≥2 µg/ml were tested for plasmid-mediated colistin resistance genes (mcr-1, mcr-2, and mcr-3) by multiplex SYBR Green PCR. Results: A total of 15/620 (2.41%) invasive human E. coli isolates were phenotypically colistin-resistant by broth microdilution (MIC values 4 to 8 µg/ml). The earliest isolate was from 2015 in a patient from Phongsaly province in Northern Laos. A total of 582/895 (65.02%) pig rectal swab samples contained colistin-resistant E. coli. The detected colistin resistance genes were predominantly mcr-1 (57.8%, 346/598), followed by mcr-3 (20.23%,121/598), and 22.24% (133/598) were found to co-harbour mcr-1 and mcr-3. Among the 15 human isolates with colistin MIC values of ≥4 µg/ml, 12/15 were mcr-1. Conclusions: We found that colistin resistant E. coli is causing invasive infection in humans in Laos despite the fact it is not available for human use. Use in animals seems to be widespread, confirmed by high carriage rates of colistin-resistant E. coli in pigs. It is probable that food-producing animals are the source of colistin-resistant E. coli bloodstream infection in Laos, although these have been infrequent to date. This is a serious public health concern in the region that needs to be addressed by appropriate enforceable legislation.

Investigation of the association between foot-and-mouth disease clinical signs and abattoir serological data in large ruminants in northern Lao People's Democratic Republic.

Foot-and-mouth disease (FMD) is a highly infectious and endemic disease in Lao PDR. However, surveillance is weak, and outbreaks are not routinely reported. To address this, serum samples were routinely collected from cattle and buffalo from provincial abattoirs between November 2021 and December 2022. A total of 2,663 serum samples were collected from large ruminants (n = 1,625 cattle; n = 1,038 buffalo) from 17 provinces. Samples were tested for specific antibodies directed against FMD non-structural protein (NSP) to determine the proportion of animals exposed to FMD virus. In addition to sampling from abattoirs, further independent data was collected to report clinical signs and outcomes from 94 districts in 12 northern provinces. These incident reports were recorded by district staff using a Google Form and summarised monthly in the National Animal Disease Reporting System. Information was collected on species, incident date, herd size, location and which clinical signs the animals presented. Overall, 46% of the tested animals returned a positive result using ID Screen® FMD NSP Competition ELISA. Results from serological testing were then compared with reported clinical signs from the same district. In districts reporting 'mouth problems' (regardless of other clinical signs) the median FMD seroprevalence was 49.7%, compared to 31.6% in districts not reporting mouth problems (p = 0.021). This finding suggests that reporting clinical cases of 'mouth problems' could be a potential predictor of FMD infection at a district level in cattle and buffalo in Lao PDR. Furthermore, in districts reporting 'fever', 'mouth problems', and 'nose/mouth secretions' together, the median FMD seroprevalence was 46.2%, compared to 24.4% in districts not reporting these signs (p = 0.033). In districts reporting 'mouth problems' and 'nose/mouth secretions' the median FMD seroprevalence was 49.4%, compared to 25.5% in districts not reporting these signs (p = 0.037). In districts reporting both 'fever' and 'mouth problems,' the median FMD seroprevalence was 46.4% compared to 25% in districts not reporting these signs (p = 0.017). Based on serological data generated by abattoir surveillance, this study identified clinical signs most predictive of FMD seroprevalence. These novel findings can be used to guide passive surveillance efforts in the future specifically in northern Laos and help support improved FMD surveillance more broadly in FMD endemic countries in Southeast Asia.

Molecular dissection of an immunodominant epitope in Kv1.2-exclusive autoimmunity.

Introduction: Subgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response. Methods: Binding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers. Results: 83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes. Discussion: Systematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.

A Market for Snow: Modeling Winter Recreation Patterns Under Current and Future Climate.

Throughout the winter months across the globe, mountain communities and snow-enthusiasts alike anxiously monitor ever-changing snowpack conditions. We model the behavioral response to this climate amenity by pairing a unique panel of 12 million short-term property rental transactions with daily local weather, daily local snowpack, and daily local snowfall in every major ski resort market across the United States. Matching the spatial and temporal variation in the level of the amenity with that of related market transactions, we derive market-specific demand elasticities, explicitly accounting for substitution, to model recreation patterns throughout a typical season. Lastly, we combine downscaled projections of local snowpack under future climate scenarios to estimate within and across season trends in visitation during mid and late-century conditions. Our model predicts reductions in snow-related visitation of -40% to -60%, almost twice as large as previous estimates suggest. This translates to a lower-bound on the annual willingness to pay to avoid reductions in snowpack between $1.23 billion (RCP4.5) and $2.05 billion (RCP8.5) by the end of the century.