Climate change, malaria and neglected tropical diseases: a scoping review.

To explore the effects of climate change on malaria and 20 neglected tropical diseases (NTDs), and potential effect amelioration through mitigation and adaptation, we searched for papers published from January 2010 to October 2023. We descriptively synthesised extracted data. We analysed numbers of papers meeting our inclusion criteria by country and national disease burden, healthcare access and quality index (HAQI), as well as by climate vulnerability score. From 42 693 retrieved records, 1543 full-text papers were assessed. Of 511 papers meeting the inclusion criteria, 185 studied malaria, 181 dengue and chikungunya and 53 leishmaniasis; other NTDs were relatively understudied. Mitigation was considered in 174 papers (34%) and adaption strategies in 24 (5%). Amplitude and direction of effects of climate change on malaria and NTDs are likely to vary by disease and location, be non-linear and evolve over time. Available analyses do not allow confident prediction of the overall global impact of climate change on these diseases. For dengue and chikungunya and the group of non-vector-borne NTDs, the literature privileged consideration of current low-burden countries with a high HAQI. No leishmaniasis papers considered outcomes in East Africa. Comprehensive, collaborative and standardised modelling efforts are needed to better understand how climate change will directly and indirectly affect malaria and NTDs.

Neoadjuvant chemotherapy is associated with improved disease-free survival in pancreatic cancer patients undergoing pancreaticoduodenectomy with vascular resection.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (NAC) is becoming favored for all pancreatic adenocarcinoma (PDAC). Patients with seemingly resectable disease infrequently still display vascular involvement intraoperatively. Outcomes following NAC versus upfront surgery in patients undergoing pancreaticoduodenectomy (PD) with vascular resection are unknown. METHODS: We performed a retrospective cohort study of PDAC patients who underwent PD with vascular resection between January 1, 2013, to December 31, 2020, within a single academic center. Clinicopathologic characteristics and disease-free survival (DFS) were compared between NAC versus upfront surgery cohorts using the Kaplan-Meier estimate and Cox proportional-hazards regression model. RESULTS: Eighty-one patients who underwent PD with vascular resection for PDAC were included. Forty-six patients (56%) received NAC. The NAC cohort more often had pathologic N0 status (47.8% vs. 8.6%, p < 0.001), had decreased vascular invasion (11% vs. 40%, p = 0.002), and completed chemotherapy (80% vs. 40%, p < 0.01). The NAC cohort demonstrated improved DFS (40.5 vs. 14.3 months, p = 0.007). In multivariable analysis, NAC remained independently associated with increased DFS (HR = 0.48, p = 0.02). CONCLUSIONS: NAC was associated with improved clinicopathologic outcomes and DFS in PD with vascular resection. These findings demonstrate the advantage of NAC in PDAC patients undergoing PD with vascular resection.

Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.

Predictive Value of Microfilariae-Based Stop-MDA Thresholds After Triple Drug Therapy With IDA Against Lymphatic Filariasis in Treatment-Naive Indian Settings.

Mass drug administration (MDA) of antifilarial drugs is the main strategy for the elimination of lymphatic filariasis (LF). Recent clinical trials indicated that the triple-drug therapy with ivermectin, diethylcarbamazine, and albendazole (IDA) is much more effective against LF than the widely used two-drug combinations (albendazole plus either ivermectin or diethylcarbamazine). For IDA-based MDA, the stop-MDA decision is made based on microfilariae (mf) prevalence in adults. In this study, we assess how the probability of eventually reaching elimination of transmission depends on the critical threshold used in transmission assessment surveys (TAS-es) to define whether transmission was successfully suppressed and triple-drug MDA can be stopped. This analysis focuses on treatment-naive Indian settings. We do this for a range of epidemiological and programmatic contexts, using the established LYMFASIM model for transmission and control of LF. Based on our simulations, a single TAS, one year after the last MDA round, provides limited predictive value of having achieved suppressed transmission, while a higher MDA coverage increases elimination probability, thus leading to a higher predictive value. Every additional TAS, conditional on previous TAS-es being passed with the same threshold, further improves the predictive value for low values of stop-MDA thresholds. An mf prevalence threshold of 0.5% corresponding to TAS-3 results in ≥95% predictive value even when the MDA coverage is relatively low.

Reducing the Antigen Prevalence Target Threshold for Stopping and Restarting Mass Drug Administration for Lymphatic Filariasis Elimination: A Model-Based Cost-effectiveness Simulation in Tanzania, India and Haiti.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) aims to reduce and maintain infection levels through mass drug administration (MDA), but there is evidence of ongoing transmission after MDA in areas where Culex mosquitoes are the main transmission vector, suggesting that a more stringent criterion is required for MDA decision making in these settings. METHODS: We use a transmission model to investigate how a lower prevalence threshold (<1% antigenemia [Ag] prevalence compared with <2% Ag prevalence) for MDA decision making would affect the probability of local elimination, health outcomes, the number of MDA rounds, including restarts, and program costs associated with MDA and surveys across different scenarios. To determine the cost-effectiveness of switching to a lower threshold, we simulated 65% and 80% MDA coverage of the total population for different willingness to pay per disability-adjusted life-year averted for India ($446.07), Tanzania ($389.83), and Haiti ($219.84). RESULTS: Our results suggest that with a lower Ag threshold, there is a small proportion of simulations where extra rounds are required to reach the target, but this also reduces the need to restart MDA later in the program. For 80% coverage, the lower threshold is cost-effective across all baseline prevalences for India, Tanzania, and Haiti. For 65% MDA coverage, the lower threshold is not cost-effective due to additional MDA rounds, although it increases the probability of local elimination. Valuing the benefits of elimination to align with the GPELF goals, we find that a willingness to pay per capita government expenditure of approximately $1000-$4000 for 1% increase in the probability of local elimination would be required to make a lower threshold cost-effective. CONCLUSIONS: Lower Ag thresholds for stopping MDAs generally mean a higher probability of local elimination, reducing long-term costs and health impacts. However, they may also lead to an increased number of MDA rounds required to reach the lower threshold and, therefore, increased short-term costs. Collectively, our analyses highlight that lower target Ag thresholds have the potential to assist programs in achieving lymphatic filariasis goals.

How Does the Proportion of Never Treatment Influence the Success of Mass Drug Administration Programs for the Elimination of Lymphatic Filariasis?

BACKGROUND: Mass drug administration (MDA) is the cornerstone for the elimination of lymphatic filariasis (LF). The proportion of the population that is never treated (NT) is a crucial determinant of whether this goal is achieved within reasonable time frames. METHODS: Using 2 individual-based stochastic LF transmission models, we assess the maximum permissible level of NT for which the 1% microfilaremia (mf) prevalence threshold can be achieved (with 90% probability) within 10 years under different scenarios of annual MDA coverage, drug combination and transmission setting. RESULTS: For Anopheles-transmission settings, we find that treating 80% of the eligible population annually with ivermectin + albendazole (IA) can achieve the 1% mf prevalence threshold within 10 years of annual treatment when baseline mf prevalence is 10%, as long as NT <10%. Higher proportions of NT are acceptable when more efficacious treatment regimens are used. For Culex-transmission settings with a low (5%) baseline mf prevalence and diethylcarbamazine + albendazole (DA) or ivermectin + diethylcarbamazine + albendazole (IDA) treatment, elimination can be reached if treatment coverage among eligibles is 80% or higher. For 10% baseline mf prevalence, the target can be achieved when the annual coverage is 80% and NT ≤15%. Higher infection prevalence or levels of NT would make achieving the target more difficult. CONCLUSIONS: The proportion of people never treated in MDA programmes for LF can strongly influence the achievement of elimination and the impact of NT is greater in high transmission areas. This study provides a starting point for further development of criteria for the evaluation of NT.

Harmonizing the forensic nomenclature for STR loci D6S474 and DYS612.

The autosomal STR D6S474 and the Y-chromosomal STR DYS612 have been reported in multiple ways in the forensic literature, with differences in both the bracketed repeat structures and counting of numerical length-based capillary electrophoresis (CE) alleles. These issues often come to light when STR loci are introduced in commercial assays and results compared with historical publications of allele frequency data, or multiple assays are characterized with reference materials. We review the forensic literature and other relevant information, and provide suggestions for the future treatment of each STR.

A complete pipeline enables haplotyping and phasing macrohaplotype in long sequencing reads for polyploidy samples and a multi-source DNA mixture.

Macrohaplotype combines multiple types of phased DNA variants, increasing forensic discrimination power. High-quality long-sequencing reads, for example, PacBio HiFi reads, provide data to detect macrohaplotypes in multiploidy and DNA mixtures. However, the bioinformatics tools for detecting macrohaplotypes are lacking. In this study, we developed a bioinformatics software, MacroHapCaller, in which targeted loci (i.e., short TRs [STRs], single nucleotide polymorphisms, and insertion and deletions) are genotyped and combined with novel algorithms to call macrohaplotypes from long reads. MacroHapCaller uses physical phasing (i.e., read-backed phasing) to identify macrohaplotypes, and thus it can detect multi-allelic macrohaplotypes for a given sample. MacroHapCaller was validated with data generated from our designed targeted PacBio HiFi sequencing pipeline, which sequenced ∼8-kb amplicon regions harboring 20 core forensic STR loci in human benchmark samples HG002 and HG003. MacroHapCaller also was validated in whole-genome long-read sequencing data. Robust and accurate genotyping and phased macrohaplotypes were obtained with MacroHapCaller compared with the known ground truth. MacroHapCaller achieved a higher or consistent genotyping accuracy and faster speed than existing tools HipSTR and DeepVar. MacroHapCaller enables efficient macrohaplotype analysis from high-throughput sequencing data and supports applications using discriminating macrohaplotypes.

Effect of meloxicam or robenacoxib administration timing on renal function and postoperative analgesia in cats undergoing ovariohysterectomy: A randomized, blinded, controlled clinical trial.

We evaluated the effect of administration timing of meloxicam and robenacoxib on renal function, platelet cyclo-oxygenase and perioperative analgesia in 60 cats undergoing ovariohysterectomy, in a prospective randomized blinded controlled study. Twelve cats were randomly allocated to one subcutaneous treatment group: meloxicam (0.2 mg/kg) or robenacoxib (2 mg/kg) at admission (MA, RA), at induction (MI, RI) and robenacoxib at the end of surgery (RE). All cats received the same anaesthesia protocol. Plasma renin activity (PRA), plasma creatinine, drug concentrations and serum thromboxane (TxB2) were measured sequentially. Anaesthesia significantly increased PRA, as activity at end of the surgery was higher than 2 h later (mean ± SD: 26.6 ± 2.8 versus 10.0 ± 3.9 ng/mL/h). PRA remained higher at 2 h post-surgery in admission groups compared to induction groups (p = .01). Serum TxB2 was lower with meloxicam than robenacoxib (p = .001), and was lower in the MA than each robenacoxib group at catheter placement. Admission groups (16/24 from RA and MA groups) received earlier rescue analgesia than other groups (p = .033). In conclusion, the renin-angiotensin system was activated during anaesthesia despite cyclo-oxygenase inhibition, possibly due to hypotension or surgical stimulation. There was no effect of drug or timing on the markers of renal function but one cat receiving meloxicam at induction had suspected IRIS grade II acute kidney injury.

Identifying distant relatives using benchtop-scale sequencing.

The genetic component of forensic genetic genealogy (FGG) is an estimate of kinship, often conducted at genome scales between a great number of individuals. The promise of FGG is substantial: in concert with genealogical records and other nongenetic information, it can indirectly identify a person of interest. A downside of FGG is cost, as it is currently expensive and requires chemistries uncommon to forensic genetic laboratories (microarrays and high throughput sequencing). The more common benchtop sequencers can be coupled with a targeted PCR assay to conduct FGG, though such approaches have limited resolution for kinship. This study evaluates low-pass sequencing, an alternative strategy that is accessible to benchtop sequencers and can produce resolutions comparable to high-pass sequencing. Samples from a three-generation pedigree were augmented to include up to 7th degree relatives (using whole genome pedigree simulations) and the ability to recover the true kinship coefficient was assessed using algorithms qualitatively similar to those found in GEDmatch. We show that up to 7th degree relatives can be reliably inferred from 1 × whole genome sequencing obtainable from desktop sequencers.

A pilot study to evaluate clinical factors associated with iron and ferritin elevations during pediatric extracorporeal membrane oxygenation.

Introduction: Elevations in serum ferritin and serum iron occur during pediatric extracorporeal membrane oxygenation (ECMO). Previous reports attribute the elevation to frequent red blood cell transfusions and/or hemolysis. Chronic transfusion can cause iron deposition in tissues leading to multisystem organ dysfunction. This study aims identify clinical factors associated with elevated ferritin and iron in pediatric ECMO patients, along with post-decannulation magnetic resonance imaging (MRI) assessment of iron deposition in liver and brain.Methods: Prospective, pilot study, using descriptive statistics to investigate potential associations between patient characteristics, serum ferritin and iron levels, and post-decannulation hepatic and basal ganglia iron deposition.Results: In this study, nine patients (100%) had elevated serum ferritin levels during ECMO. High ferritin levels were more common with veno-arterial than with veno-venous cannulation (p = 0.026) and were also associated with high plasma free hemoglobin levels (p < 0.001). Five patients presented with elevated serum iron levels. High serum iron levels were associated with higher daily (p = 0.016) and cumulative transfusion volumes (p = 0.013) as well ECMO duration beyond 7 days. MRI scans were performed on three patients with no evidence of abnormal iron deposition detected in the liver or brain.Conclusions: This pilot study shows that during pediatric ECMO, elevations in serum ferritin and serum iron occur and those elevations may be related to the cannulation modality, ECMO duration, amount of hemolysis, and volume of red blood cell transfusions. Further investigation is warranted to fully understand the implications of elevated serum iron and ferritin in pediatric ECMO.

Mixture detection with Demixtify.

The de facto genetic markers of forensics are short tandem repeats (STRs). There are many analytical tools designed to work with STRs, including techniques for analyzing and assessing DNA mixtures. In contrast, the nascent field of forensic genetic genealogy often relies on biallelic single nucleotide polymorphisms (SNPs). Tools designed for the forensic assessment of SNPs are somewhat lacking, especially for DNA mixtures. In this paper we introduce Demixtify, a program that detects DNA mixtures using biallelic SNPs. Demixtify is quite powerful; highly imbalanced mixtures can be detected (≤1:99, considering in silico and in vitro mixtures) when coverage is ample. Demixtify can also detect mixtures in low coverage (∼1×) samples (when the mixture is relatively balanced). Demixtify includes an empirical estimator of sequence error that is specific to the markers assayed, making it especially relevant to the forensic community. Orthogonal techniques are also developed to characterize in vitro mixtures, as well as samples thought to be single source, and the results of these approaches serve to validate the techniques presented.

Interpreting forces as deep learning gradients improves quality of predicted protein structures.

Protein structure predictions from deep learning models like AlphaFold2, despite their remarkable accuracy, are likely insufficient for direct use in downstream tasks like molecular docking. The functionality of such models could be improved with a combination of increased accuracy and physical intuition. We propose a new method to train deep learning protein structure prediction models using molecular dynamics force fields to work toward these goals. Our custom PyTorch loss function, OpenMM-Loss, represents the potential energy of a predicted structure. OpenMM-Loss can be applied to any all-atom representation of a protein structure capable of mapping into our software package, SidechainNet. We demonstrate our method's efficacy by finetuning OpenFold. We show that subsequently predicted protein structures, both before and after a relaxation procedure, exhibit comparable accuracy while displaying lower potential energy and improved structural quality as assessed by MolProbity metrics.

Clinical Performance of hrHPV Primary Screening Using Vaginal versus Cervical Samples to Detect High-grade Intraepithelial Lesions.

High-risk human papillomavirus (hrHPV) testing is now the most recommended primary method for cervical cancer screening worldwide. Clinician-collected cervical sampling continues to be the main sampling method, but hrHPV vaginal self-sampling is an appealing alternative because of its greater acceptability and potentially higher cost-effectiveness. This study aimed to determine whether hrHPV vaginal self-sampling is comparable with clinician-collected cervical sampling for detecting histologically confirmed high-grade cervical intraepithelial neoplasia (CIN2/3) as part of a cervical cancer screening program in Mexico. We analyzed data from 5,856 women screened during a hrHPV-based screening study. Clinical performance and diagnostic efficiency metrics were estimated for the two sampling methods for the CIN3 and CIN2+ endpoints, using three triage strategies: HPV16/18 genotyping, HPV16/18/33/58 extended genotyping, and HPV16/18/31/33/58 extended genotyping. hrHPV-positivity was found in 801 (13.7%) cervical and 897 (15.3%) vaginal samples. All women with hrHPV-positive samples were referred to colposcopy, which detected 17 total CIN3 cases before considering retrospective triage strategies. Using the HPV16/18/31/33/58 extended genotyping strategy, 245 women had hrHPV-positive cervical samples and 269 had hrHPV-positive vaginal samples. Ten CIN3 cases were detected each among women with hrHPV-positive cervical samples and among those with hrHPV-positive vaginal samples when using this strategy, with no significant differences in sensitivity and specificity observed. We observe that self- and clinician-collected sampling methods are comparable for detecting CIN3 and CIN2+ regardless of the triage strategy used. These findings can help public health officials to develop more cost-effective cervical cancer screening programs that maximize participation. PREVENTION RELEVANCE: We found that hrHPV vaginal self-sampling is comparable with hrHPV clinician cervical sampling when using any triage strategy to refer women to colposcopy, so self-sampling is a viable cervical screening method. Therefore, policymakers should consider incorporating self-sampling into cervical screening programs to increase screening coverage and reduce cervical cancer burden. See related Spotlight, p. 649.

Bioinspired Switchable Passive Daytime Radiative Cooling Coatings.

Passive daytime radiative cooling (PDRC) relies on simultaneous reflection of sunlight and radiation toward cold outer space. Current designs of PDRC coatings have demonstrated potential as eco-friendly alternatives to traditional electrical air conditioning (AC). While many features of PDRC have been individually optimized in different studies, for practical impact, it is essential for a system to demonstrate excellence in all essential aspects, like the materials that nature has created. We propose a bioinspired PDRC structure templated by bicontinuous interfacially jammed emulsion gels (bijels) that possesses excellent cooling, thinness, tunability, scalability, and mechanical robustness. The unique bicontinuous disordered structure captures key features of Cyphochilus beetle scales, enabling a thin (130 µm) bijel PDRC coating to achieve high solar reflectance (≳0.97) and high longwave-infrared (LWIR) emissivity (≳0.93), resulting in a subambient temperature drop of ∼5.6 °C under direct sunlight. We further demonstrate switchable cooling inspired by the exoskeleton of the Hercules beetle and mechanical robustness in analogy to spongy bone structures.

Towards NHS Zero: greener gastroenterology and the impact of virtual clinics on carbon emissions and patient outcomes. A multisite, observational, cross-sectional study.

Objective: The National Health Service (NHS) produces more carbon emissions than any public sector organisation in England. In 2020, it became the first health service worldwide to commit to becoming carbon net zero, the same year as the COVID-19 pandemic forced healthcare systems globally to rapidly adapt service delivery. As part of this, outpatient appointments became largely remote. Although the environmental benefit of this change may seem intuitive the impact on patient outcomes must remain a priority. Previous studies have evaluated the impact of telemedicine on emission reduction and patient outcomes but never before in the gastroenterology outpatient setting. Method: 2140 appointments from general gastroenterology clinics across 11 Trusts were retrospectively analysed prior to and during the pandemic. 100 consecutive appointments during two periods of time, from 1 June 2019 (prepandemic) to 1 June 2020 (during the pandemic), were used. Patients were telephoned to confirm the mode of transport used to attend their appointment and electronic patient records reviewed to assess did-not-attend (DNA) rates, 90-day admission rates and 90-day mortality rates. Results: Remote consultations greatly reduced the carbon emissions associated with each appointment. Although more patients DNA their remote consultations and doctors more frequently requested follow-up blood tests when reviewing patients face-to-face, there was no significant difference in patient 90-day admissions or mortality when consultations were remote. Conclusion: Teleconsultations can provide patients with a flexible and safe means of being reviewed in outpatient clinics while simultaneously having a major impact on the reduction of carbon emissions created by the NHS.

Learning Curves in Establishing a New Minimally Invasive Pancreas Program.

INTRODUCTION: Robotic pancreaticoduodenectomy (rPD) is a complex operation with a reported learning curve of 80 cases. Two recent graduates of a formal robotic complex general surgical oncology training program have been performing rPD at our institution since 2016, which had no previous institutional experience with rPD. OBJECTIVE: To evaluate the learning curve associated with developing a new robotic pancreaticoduodenectomy (rPD) program by fellowship trained surgeons with institutional support. METHODS: Sixty patients undergoing rPD from 2016 to 2022 were reviewed for and compared with proficiency benchmarks set by the University of Pittsburg experience. RESULTS: By 30 cases, operative time met the proficiency benchmark of 391 minutes. Additionally, the entire cohort had comparable rates of clinically relevant postoperative pancreatic fistula (6.7% vs 3%, P = .6), 30-day mortality (0% vs 3%, P = .18), major complications (Clavien >2; 23% vs 17%, P = .14), and length of stay (6 vs 7 days, P = .49) when compared to the benchmark. CONCLUSION: Perioperative outcomes were comparable to proficiency benchmarks from initiation of the new rPD program, and operative time reached proficiency benchmark by 30 cases. This data suggests that graduates of formal rPD training programs can safely establish new minimally invasive pancreas programs at sites with no previous institutional rPD experience.

A population-level application of a method for estimating the timing of HIV acquisition among migrants to Australia.

INTRODUCTION: Australia has set the goal for the virtual elimination of HIV transmission by the end of 2022, yet accurate information is lacking on the level of HIV transmission occurring among residents. We developed a method for estimating the timing of HIV acquisition among migrants, relative to their arrival in Australia. We then applied this method to surveillance data from the Australian National HIV Registry with the aim of ascertaining the level of HIV transmission among migrants to Australia occurring before and after migration, and to inform appropriate local public health interventions. METHODS: We developed an algorithm incorporating CD4+ T-cell decline back-projection and enhanced variables (clinical presentation, past HIV testing history and clinician estimate of the place of HIV acquisition) and compared it to a standard algorithm which uses CD4+ T-cell back-projection only. We applied both algorithms to all new HIV diagnoses among migrants to estimate whether HIV infection occurred before or after arrival in Australia. RESULTS: Between 1 January 2016 and 31 December 2020, 1909 migrants were newly diagnosed with HIV in Australia, 85% were men, and the median age was 33 years. Using the enhanced algorithm, 932 (49%) were estimated to have acquired HIV after arrival in Australia, 629 (33%) before arrival (from overseas), 250 (13%) close to arrival and 98 (5%) were unable to be classified. Using the standard algorithm, 622 (33%) were estimated to have acquired HIV in Australia, 472 (25%) before arrival, 321 (17%) close to arrival and 494 (26%) were unable to be classified. CONCLUSIONS: Using our algorithm, close to half of migrants diagnosed with HIV were estimated to have acquired HIV after arrival in Australia, highlighting the need for tailored culturally appropriate testing and prevention programmes to limit HIV transmission and achieve elimination targets. Our method reduced the proportion of HIV cases unable to be classified and can be adopted in other countries with similar HIV surveillance protocols, to inform epidemiology and elimination efforts.

Trends and variability in the Southern Annular Mode over the Common Era.

The Southern Annular Mode (SAM) is the leading mode of atmospheric variability in the extratropical Southern Hemisphere and has wide ranging effects on ecosystems and societies. Despite the SAM's importance, paleoclimate reconstructions disagree on its variability and trends over the Common Era, which may be linked to variability in SAM teleconnections and the influence of specific proxies. Here, we use data assimilation with a multi-model prior to reconstruct the SAM over the last 2000 years using temperature and drought-sensitive climate proxies. Our method does not assume a stationary relationship between the SAM and the proxy records and allows us to identify critical paleoclimate records and quantify reconstruction uncertainty through time. We find no evidence for a forced response in SAM variability prior to the 20th century. We do find the modern positive trend falls outside the 2σ range of the prior 2000 years at multidecadal time scales, supporting the inference that the SAM's positive trend over the last several decades is a response to anthropogenic climate change.