Part 2: Current Concepts in Radiologic Imaging & Intervention in Acute Biliary Tract Diseases.

Acute cholangitis is encountered commonly in critically ill, often elderly, patients. The most common causes of cholangitis include choledocholithiasis, biliary strictures, and infection from previous endoscopic, percutaneous, or surgical intervention of the biliary tract. Rare causes of acute cholangitis in the United States include sclerosing cholangitis and recurrent pyogenic cholangitis, the latter predominantly occurring in immigrants of Asian descent. Multidisciplinary management of these conditions is essential, with intensivists, surgeons, diagnostic radiologists, interventional radiologists, gastroenterologists, endoscopists, and infectious disease physicians typically involved in the care of these patients. In this paper intended for intensivists predominantly, we will review the imaging findings and radiologic interventional management of critically ill patients with acute cholangitis, primary and secondary sclerosing cholangitis, and recurrent pyogenic cholangitis.

Part 1: Current Concepts in Radiologic Imaging and Intervention in Acute Cholecystitis.

Acute calculous cholecystitis and acute acalculous cholecystitis are encountered commonly among critically ill, often elderly, patients. Multidisciplinary management of these conditions is essential, with intensivists, surgeons, diagnostic radiologists, interventional radiologists, infectious disease physicians, gastroenterologists, and endoscopists able to contribute to patient care. In this article intended predominantly for intensivists, we will review the imaging findings and radiologic treatment of critically ill patients with acute calculous cholecystitis and acute acalculous cholecystitis.

Challenges of COVID-19 Case Forecasting in the US, 2020-2021.

During the COVID-19 pandemic, forecasting COVID-19 trends to support planning and response was a priority for scientists and decision makers alike. In the United States, COVID-19 forecasting was coordinated by a large group of universities, companies, and government entities led by the Centers for Disease Control and Prevention and the US COVID-19 Forecast Hub (https://covid19forecasthub.org). We evaluated approximately 9.7 million forecasts of weekly state-level COVID-19 cases for predictions 1-4 weeks into the future submitted by 24 teams from August 2020 to December 2021. We assessed coverage of central prediction intervals and weighted interval scores (WIS), adjusting for missing forecasts relative to a baseline forecast, and used a Gaussian generalized estimating equation (GEE) model to evaluate differences in skill across epidemic phases that were defined by the effective reproduction number. Overall, we found high variation in skill across individual models, with ensemble-based forecasts outperforming other approaches. Forecast skill relative to the baseline was generally higher for larger jurisdictions (e.g., states compared to counties). Over time, forecasts generally performed worst in periods of rapid changes in reported cases (either in increasing or decreasing epidemic phases) with 95% prediction interval coverage dropping below 50% during the growth phases of the winter 2020, Delta, and Omicron waves. Ideally, case forecasts could serve as a leading indicator of changes in transmission dynamics. However, while most COVID-19 case forecasts outperformed a naïve baseline model, even the most accurate case forecasts were unreliable in key phases. Further research could improve forecasts of leading indicators, like COVID-19 cases, by leveraging additional real-time data, addressing performance across phases, improving the characterization of forecast confidence, and ensuring that forecasts were coherent across spatial scales. In the meantime, it is critical for forecast users to appreciate current limitations and use a broad set of indicators to inform pandemic-related decision making.

Transitioning from interventional radiology: ideas for the inevitable.

BACKGROUND: Interventional Radiology (IR) is a highly rewarding specialty, both for its salutary effects for patients, as will as the satisfaction it provides for the operating radiologists. Nonetheless, arduous work and long hours have led to numerous reports of burnout amongst interventional radiologists (IRs). MATERIALS AND METHODS: Six long-term academic radiologists in leadership positions briefly chronicle their becoming IRs, their type of transitioning from IR, and the pros and cons of those respective transitions. RESULTS: The specific transitions include reduced time in IR, switching to diagnostic radiology, becoming involved in medical school education, ceasing IR leadership, and retirement. Pros and cons of the various transition strategies are highlighted. CONCLUSION: As the taxing work and long hours are so ubiquitous for IRs, and as burnout is so common, transitioning from IR is highly likely eventually for IRs. The varied transition experiences highlighted in this report hopefully will be helpful for current and aspiring IRs.

Hepatocellular Carcinoma Incidence Threshold for Surveillance in Virologically Cured Hepatitis C Individuals.

BACKGROUND & AIMS: Guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in hepatitis C individuals with cirrhosis if the HCC incidence rate is above 1.5 per 100 person-years (PY). However, the incidence threshold for surveillance in individuals who achieve a virologic cure is unknown. We estimated the HCC incidence rate above which routine HCC surveillance is cost-effective in this growing population of virologically cured hepatitis C individuals with cirrhosis or advanced fibrosis. METHODS: We developed a Markov-based microsimulation model of the natural history of HCC in individuals with hepatitis C who achieved virologic cure with oral direct-acting antivirals. We used published data on the natural history of hepatitis C, competing risk post virologic cure, HCC tumor progression, real-world HCC surveillance adherence, contemporary HCC treatment options and associated costs, and utilities of different health states. We estimated the HCC incidence above which biannual HCC surveillance using ultrasound and alpha-fetoprotein would be cost-effective. RESULTS: In virologically cured hepatitis C individuals with cirrhosis or advanced fibrosis, HCC surveillance is cost-effective if HCC incidence exceeds 0.7 per 100 PY using $100,000 per quality-adjusted life year willingness-to-pay. At this HCC incidence, routine HCC surveillance would result in 2650 and 5700 additional life years per 100,000 cirrhosis and advanced fibrosis persons, respectively, compared with no surveillance. At $150,000 willingness-to-pay, surveillance is cost-effective if HCC incidence exceeds 0.4 per 100 PY. Sensitivity analysis showed that the threshold mostly remained below 1.5 per 100 PY. CONCLUSIONS: The contemporary HCC incidence threshold is much lower than the previous 1.5% incidence value used to guide HCC surveillance decisions. Updating clinical guidelines could improve the early diagnosis of HCC.

Dataset of phase I and II immunotherapy clinical trials used for a meta-analysis to assess the role of biomarkers in treatment outcomes in diverse cancers.

We performed a literature search in PubMed to identify phase I/II clinical trials with immunotherapy drugs approved by the Food and Drug Administration (labeled, off-label, and/or combined with investigational immune checkpoint inhibitors or other treatment modalities) from 2018 to 2020. We used the following key words: clinical trials, phase 1, Phase 2; and the following filters: cancer, humans; and selected the checkpoint inhibitors that had been approved by the FDA by March 2021, i.e., "pembrolizumab", "nivolumab", "atezolizumab", "durvalumab", "cemiplimab", "avelumab", and "ipilimumab. Clinical trials with their checkpoint inhibitors as in their labeled indications, off-label use or their combinations with investigational immune checkpoint inhibitors or other treatment modalities were included. Studies describing supportive care or locoregional treatments; cellular, viral, or vaccine therapy; studies in the adjuvant or neoadjuvant setting; and pediatric studies were excluded. Overall, 173 articles reporting on relevant studies were identified. Using these articles, we compiled a data file of study-specific covariates for each study. We recorded the immunotherapeutic agent, tumor type and biomarker, and clinical outcomes (objective response rate and median values [point estimate] and confidence intervals for progression-free survival and overall survival. Using these data, we carried out meta-analyses for the three outcomes and meta-regression on study-specific covariates. The same data could be used for any alternative implementation of meta-analysis and meta-regression, using more structured inference models reflecting different levels of dependence based on the available study-specific covariates.

Using 81Kr and isotopic tracers to characterise old groundwater in the Bangkok metropolitan and vicinity areas.

Krypton-81 was applied to investigate the age of groundwater in the aquifer system in the Bangkok metropolitan and vicinity areas. Stable (2H, 18O and 13C) and radioactive (3H, 85Kr and 14C) isotopes and noble gases were applied in parallel. Low levels of 14C and significant radiogenic 4He confirm that groundwater in the deep aquifers is older than 30 ka. 81Kr analysis identified groundwater with ages ranging from 17 to 300 ka. At some sites, large age discrepancies between 81Kr and 14C indicated that inter-aquifer mixing is likely occurring. The interpretation of the noble gases suggests that groundwaters in the deeper aquifers, with apparent ages of 300 to 10 ka, have recharged in slightly colder and wetter climates than those found in the upper aquifers with apparent ages < 10 ka. Degradation of water quality from seawater intrusion was identified in the upper four aquifers. This was also evidenced by higher δ18O and δ2H values, typical of seawater. The four deeper aquifers contain high quality water characterised by less enriched 18O and 2H. This work presents new findings of very old groundwater in the Bangkok aquifer system.

A multimorbidity model for estimating health outcomes from the syndemic of injection drug use and associated infections in the United States.

BACKGROUND: Fatal drug overdoses and serious injection-related infections are rising in the US. Multiple concurrent infections in people who inject drugs (PWID) exacerbate poor health outcomes, but little is known about how the synergy among infections compounds clinical outcomes and costs. Injection drug use (IDU) converges multiple epidemics into a syndemic in the US, including opioid use and HIV. Estimated rates of new injection-related infections in the US are limited due to widely varying estimates of the number of PWID in the US, and in the absence of clinical trials and nationally representative longitudinal observational studies of PWID, simulation models provide important insights to policymakers for informed decisions. METHODS: We developed and validated a MultimorbiditY model to Reduce Infections Associated with Drug use (MYRIAD). This microsimulation model of drug use and associated infections (HIV, hepatitis C virus [HCV], and severe bacterial infections) uses inputs derived from published data to estimate national level trends in the US. We used Latin hypercube sampling to calibrate model output against published data from 2015 to 2019 for fatal opioid overdose rates. We internally validated the model for HIV and HCV incidence and bacterial infection hospitalization rates among PWID. We identified best fitting parameter sets that met pre-established goodness-of-fit targets using the Pearson's chi-square test. We externally validated the model by comparing model output to published fatal opioid overdose rates from 2020. RESULTS: Out of 100 sample parameter sets for opioid use, the model produced 3 sets with well-fitting results to key calibration targets for fatal opioid overdose rates with Pearson's chi-square test ranging from 1.56E-5 to 2.65E-5, and 2 sets that met validation targets. The model produced well-fitting results within validation targets for HIV and HCV incidence and serious bacterial infection hospitalization rates. From 2015 to 2019, the model estimated 120,000 injection-related overdose deaths, 17,000 new HIV infections, and 144,000 new HCV infections among PWID. CONCLUSIONS: This multimorbidity microsimulation model, populated with data from national surveillance data and published literature, accurately replicated fatal opioid overdose, incidence of HIV and HCV, and serious bacterial infections hospitalization rates. The MYRIAD model of IDU could be an important tool to assess clinical and economic outcomes related to IDU behavior and infections with serious morbidity and mortality for PWID.

Percutaneous treatment of renal tumours.

Image-guided ablation is an accepted treatment option in the management of renal cell carcinoma. Percutaneous renal ablation offers the possibility of minimally invasive treatment while attempting to preserve renal function. Over the past several years there have been advances in tools and techniques that have improved procedure safety and patient outcomes. This article provides an updated comprehensive review of percutaneous ablation in the management of renal cell carcinoma.

Correlation between biomarkers and treatment outcomes in diverse cancers: a systematic review and meta-analysis of phase I and II immunotherapy clinical trials.

BACKGROUND: Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any. METHODS: A PubMed search for phase I/II clinical trials with drugs approved by the Food and Drug Administration (labelled, off-label, combined with investigational ICIs or other treatment modalities) from 2018 to 2020 was performed. The objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between biomarker-positive and biomarker-negative groups, using studies that explored the correlation of biomarkers with outcomes. RESULTS: Overall, 174 clinical studies that included 19,178 patients were identified, and 132 studies investigated>30 correlative biomarkers that included PD-L1 expression (≥1%, 111 studies), tumour mutational burden (20 studies) and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46 and 30 cohorts (drugs, tumour types or biomarkers) with 11,692, 3065, and 2256 patient outcomes for ORR, PFS and OS, respectively, were analysed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumours were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p < 0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p < 0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p < 0.0001) compared with those with biomarker-negative tumours. Significance for ORR and PFS was retained in multivariate analysis (p < 0.001) (OS, not included owing to the small number of trials reporting OS). CONCLUSION: Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.

Estimated Reductions in Opioid Overdose Deaths With Sustainment of Public Health Interventions in 4 US States.

Importance: In 2021, more than 80 000 US residents died from an opioid overdose. Public health intervention initiatives, such as the Helping to End Addiction Long-term (HEALing) Communities Study (HCS), are being launched with the goal of reducing opioid-related overdose deaths (OODs). Objective: To estimate the change in the projected number of OODs under different scenarios of the duration of sustainment of interventions, compared with the status quo. Design, Setting, and Participants: This decision analytical model simulated the opioid epidemic in the 4 states participating in the HCS (ie, Kentucky, Massachusetts, New York, and Ohio) from 2020 to 2026. Participants were a simulated population transitioning from opioid misuse to opioid use disorder (OUD), overdose, treatment, and relapse. The model was calibrated using 2015 to 2020 data from the National Survey on Drug Use and Health, the US Centers for Disease Control and Prevention, and other sources for each state. The model accounts for reduced initiation of medications for OUD (MOUDs) and increased OODs during the COVID-19 pandemic. Exposure: Increasing MOUD initiation by 2- or 5-fold, improving MOUD retention to the rates achieved in clinical trial settings, increasing naloxone distribution efforts, and furthering safe opioid prescribing. An initial 2-year duration of interventions was simulated, with potential sustainment for up to 3 additional years. Main Outcomes and Measures: Projected reduction in number of OODs under different combinations and durations of sustainment of interventions. Results: Compared with the status quo, the estimated annual reduction in OODs at the end of the second year of interventions was 13% to 17% in Kentucky, 17% to 27% in Massachusetts, 15% to 22% in New York, and 15% to 22% in Ohio. Sustaining all interventions for an additional 3 years was estimated to reduce the annual number of OODs at the end of the fifth year by 18% to 27% in Kentucky, 28% to 46% in Massachusetts, 22% to 34% in New York, and 25% to 41% in Ohio. The longer the interventions were sustained, the better the outcomes; however, these positive gains would be washed out if interventions were not sustained. Conclusions and Relevance: In this decision analytical model study of the opioid epidemic in 4 US states, sustained implementation of interventions, including increased delivery of MOUDs and naloxone supply, was found to be needed to reduce OODs and prevent deaths from increasing again.

Evaluation of 14-day Concentration-time Curves of Vitamin D3 and 25-Hydroxyvitamin D3 in Healthy Adults With Varying Body Mass Index.

BACKGROUND/AIM: To analyze the concentration-time curves of single-dose oral 25(OH)D3 in comparison with vitamin D3 in healthy adults. PATIENTS AND METHODS: The pharmacokinetics observed over two weeks after orally administering single 900 µg doses of vitamin D3 and 25(OH)D3 to six otherwise healthy vitamin D insufficient/deficient adults participating in a broader randomized, double-blind, crossover, single center trial was analyzed. The study protocol was approved by the institutional review board (H-37167). RESULTS: Individual concentration-time curves revealed that vitamin D3 took longer than 25(OH)D3 to reach its maximal concentration after ingestion in five participants. After 25(OH)D3 ingestion, 25(OH)D3 reached its maximal concentration, dropped rapidly, and plateaued before starting to decrease slowly. There were observable inter-individual variations in the bioavailability of vitamin D3 and 25(OH)D3 and the pattern of changes in 25(OH)D3 concentration after their ingestion. CONCLUSION: Pharmacokinetics of 25(OH)D3 in comparison with vitamin D3 was illustrated and described in this study.

Projecting COVID-19 Mortality as States Relax Nonpharmacologic Interventions.

Importance: A key question for policy makers and the public is what to expect from the COVID-19 pandemic going forward as states lift nonpharmacologic interventions (NPIs), such as indoor mask mandates, to prevent COVID-19 transmission. Objective: To project COVID-19 deaths between March 1, 2022, and December 31, 2022, in each of the 50 US states, District of Columbia, and Puerto Rico assuming different dates of lifting of mask mandates and NPIs. Design Setting and Participants: This simulation modeling study used the COVID-19 Policy Simulator compartmental model to project COVID-19 deaths from March 1, 2022, to December 31, 2022, using simulated populations in the 50 US states, District of Columbia, and Puerto Rico. Projected current epidemiologic trends for each state until December 31, 2022, assuming the current pace of vaccination is maintained into the future and modeling different dates of lifting NPIs. Exposures: Date of lifting statewide NPI mandates as March 1, April 1, May 1, June 1, or July 1, 2022. Main Outcomes and Measures: Projected COVID-19 incident deaths from March to December 2022. Results: With the high transmissibility of current circulating SARS-CoV-2 variants, the simulated lifting of NPIs in March 2022 was associated with resurgences of COVID-19 deaths in nearly every state. In comparison, delaying by even 1 month to lift NPIs in April 2022 was estimated to mitigate the amplitude of the surge. For most states, however, no amount of delay was estimated to be sufficient to prevent a surge in deaths completely. The primary factor associated with recurrent epidemics in the simulation was the assumed high effective reproduction number of unmitigated viral transmission. With a lower level of transmissibility similar to those of the ancestral strains, the model estimated that most states could remove NPIs in March 2022 and likely not see recurrent surges. Conclusions and Relevance: This simulation study estimated that the SARS-CoV-2 virus would likely continue to take a major toll in the US, even as cases continued to decrease. Because of the high transmissibility of the recent Delta and Omicron variants, premature lifting of NPIs could pose a substantial threat of rebounding surges in morbidity and mortality. At the same time, continued delay in lifting NPIs may not prevent future surges.

What is the prevalence of and trend in opioid use disorder in the United States from 2010 to 2019? Using multiplier approaches to estimate prevalence for an unknown population size.

Opioid-related overdose deaths have increased since 2010 in the U.S., but information on trends in opioid use disorder (OUD) prevalence is limited due to unreliable data. Multiplier methods are a classical epidemiological technique to estimate prevalence when direct estimation is infeasible or unreliable. We used two different multiplier approaches to estimate OUD prevalence from 2010 to 2019. First, we estimated OUD in National Survey on Drug Use and Health (NSDUH), and based on existing capture-recapture studies, multiplied prevalence by 4.5x. Second, we estimated the probability of drug poisoning death among people with OUD (Meta-analysis indicates 0.52/100,000), and divided the number of drug poisoning deaths in the US by this probability. Estimates were weighted to account for increase in drug-related mortality in recent years due to fentanyl. Estimated OUD prevalence was lowest when estimated in NSDUH with no multiplier, and highest when estimated from vital statistics data without adjustment. Consistent findings emerged with two methods: NSDUH data with multiplier correction, and vital statistics data with multiplier and adjustment. From these two methods, OUD prevalence increased from 2010 to 2014; then stabilized and slightly declined annually (survey data with multiplier, highest prevalence of 4.0% in 2015; death data with a multiplier and correction, highest prevalence of 2.35% in 2016). The number of US adolescent and adult individuals with OUD in 2019 was estimated between 6.7-7.6 million. When multipliers and corrections are used, OUD may have stabilized or slightly declined after 2015. Nevertheless, it remains highly prevalent, affecting 6-7 million US adolescents and adults.

Genetic testing to guide screening for pancreatic ductal adenocarcinoma: Results of a microsimulation model.

BACKGROUND: First-degree relatives (FDRs) of patients with pancreatic ductal adenocarcinoma (PDAC) have elevated PDAC risk, partially due to germline genetic variants. We evaluated the potential effectiveness of genetic testing to target MRI-based screening among FDRs. METHODS: We used a microsimulation model of PDAC, calibrated to Surveillance, Epidemiology, and End Results (SEER) data, to estimate the potential life expectancy (LE) gain of screening for each of the following groups of FDRs: individuals who test positive for each of eight variants associated with elevated PDAC risk (e.g., BRCA2, CDKN2A); individuals who test negative; and individuals who do not test. Screening was assumed to take place if LE gains were achievable. We simulated multiple screening approaches, defined by starting age and frequency. Sensitivity analysis evaluated changes in results given varying model assumptions. RESULTS: For women, 92% of mutation carriers had projected LE gains from screening for PDAC, if screening strategies (start age, frequency) were optimized. Among carriers, LE gains ranged from 0.1 days (ATM+ women screened once at age 70) to 510 days (STK11+ women screened annually from age 40). For men, LE gains were projected for all mutation carriers, ranging from 0.2 days (BRCA1+ men screened once at age 70) to 620 days (STK11+ men screened annually from age 40). For men and women who did not undergo genetic testing, or for whom testing showed no variant, screening yielded small LE benefit (0-2.1 days). CONCLUSIONS: Genetic testing of FDRs can inform targeted PDAC screening by identifying which FDRs may benefit.

Duration and cost-effectiveness of hepatocellular carcinoma surveillance in hepatitis C patients after viral eradication.

BACKGROUND & AIMS: Successful treatment of chronic hepatitis C with oral direct-acting antivirals (DAAs) leads to virological cure, however, the subsequent risk of hepatocellular carcinoma (HCC) persists. Our objective was to evaluate the cost-effectiveness of biannual surveillance for HCC in patients cured of hepatitis C and the optimal age to stop surveillance. METHODS: We developed a microsimulation model of the natural history of HCC in individuals with hepatitis C and advanced fibrosis or cirrhosis who achieved virological cure with oral DAAs. We used published data on HCC incidence, tumor progression, real-world HCC surveillance adherence, and costs and utilities of different health states. We compared biannual HCC surveillance using ultrasound and alpha-fetoprotein for varying durations of surveillance (from 5 years to lifetime) vs. no surveillance. RESULTS: In virologically cured patients with cirrhosis, the incremental cost-effectiveness ratio (ICER) of biannual surveillance remained below $150,000 per additional quality-adjusted life year (QALY) (range: $79,500-$94,800) when surveillance was stopped at age 70, irrespective of the starting age (40-65). Compared with no surveillance, surveillance detected 130 additional HCCs in 'very early'/early stage and yielded 51 additional QALYs per 1,000 patients with cirrhosis. In virologically cured patients with advanced fibrosis, the ICER of biannual surveillance remained below $150,000/QALY (range: $124,600-$129,800) when surveillance was stopped at age 60, irrespective of the starting age (40-50). Compared with no surveillance, surveillance detected 24 additional HCCs in 'very early'/early stage and yielded 12 additional QALYs per 1,000 patients with advanced fibrosis. CONCLUSION: Biannual surveillance for HCC in patients cured of hepatitis C is cost-effective until the age of 70 for patients with cirrhosis, and until the age of 60 for patients with stable advanced fibrosis. LAY SUMMARY: Individuals who are cured of hepatitis C using oral antiviral drugs remain at risk of developing liver cancer. The value of lifelong screening for liver cancer in these individuals is not known. By simulating the life course of hepatitis C cured individuals, we found that ultrasound-based biannual screening for liver cancer is cost-effective up to age 70 in those with cirrhosis and up to age 60 in those with stable advanced fibrosis.

Biota-mediated carbon cycling-A synthesis of biotic-interaction controls on blue carbon.

Research into biotic interactions has been a core theme of ecology for over a century. However, despite the obvious role that biota play in the global carbon cycle, the effects of biotic interactions on carbon pools and fluxes are poorly understood. Here we develop a conceptual framework that illustrates the importance of biotic interactions in regulating carbon cycling based on a literature review and a quantitative synthesis by means of meta-analysis. Our study focuses on blue carbon ecosystems-vegetated coastal ecosystems that function as the most effective long-term CO2 sinks of the biosphere. We demonstrate that a multitude of mutualistic, competitive and consumer-resource interactions between plants, animals and microbiota exert strong effects on carbon cycling across various spatial scales ranging from the rhizosphere to the landscape scale. Climate change-sensitive abiotic factors modulate the strength of biotic-interaction effects on carbon fluxes, suggesting that the importance of biota-mediated carbon cycling will change under future climatic conditions. Strong effects of biotic interactions on carbon cycling imply that biosphere-climate feedbacks may not be sufficiently represented in current Earth system models. Inclusion of new functional groups in these models, and new approaches to simplify species interactions, may thus improve the predictions of biotic effects on the global climate.