Underactive bladder, Fowler's syndrome are potentially curable by uterosacral ligament repair.

Underactive bladder (UAB) is essentially an inability of the bladder to properly empty. UAB symptoms, when they co-occur with posterior fornix syndrome (PFS) symptoms (urge, frequency, nocturia, chronic pelvic pain), can be cured/improved, surgically by uterosacral ligament (USL) repair, non-surgically, by devices which give mechanical support of the USLs or strengthening pelvic muscle and ligaments with squatting-based exercises. The pathogenic pathway from weak USLs to UAB (and PFS) is that, when the muscles which externally open the posterior wall of the urethra contract against lax USLs, their contractile force weakens, and they cannot open the urethra adequately. The detrusor then contracts against a relatively unopened urethra to cause obstructive symptoms (i.e., UAB) such as slow stream, intermittent stream (stopping and starting), hesitancy (difficulty starting), feeling of incomplete emptying, and post-micturition dribble. Co-occurrence of PFS symptoms indicates that UAB may be part of the PFS, with USL causation, which can be tested by a tampon or probe in the posterior fornix. If the emptying (and other) PFS symptoms improve, it is a sign that UAB, and Fowler's syndrome (FS) can potentially be cured or improved by USL repair. Following USL repair, many studies have recorded very significant improvement in emptying symptoms, and objective tests, for example, postvoid residual (PVR), decreased natural bladder volume, and decreased emptying time. FS and UAB are most likely a part of the PFS and, therefore, potentially curable by USL repair.

A brief physiology and pathophysiology of the bladder.

The remit of this review is confined to experimental works and publications relevant to the integral theory of female urinary incontinence (IT). Since its first publication in 1990, the IT has challenged the general view that the pathogenesis of overactive bladder (OAB) (urge, frequency, nocturia) is unknown and there is no cure. According to the IT, normal function bladder control is binary, either closed or open. Control is cortical via a peripheral feedback component: oppositely acting reflex striated pelvic muscles contract against suspensory ligaments to close the urethra for continence, open it prior to evacuation, and stretch the vagina like a trampoline to prevent excess impulses from the urothelial stretch receptors which may cause unwanted urgency at low bladder volumes (OAB). The pathogenesis of female urinary incontinence is from outside the bladder, mainly weak ligaments or vagina, due to collagen deficiency. Damage in childbirth (collagen depolymerization) and age (collagen loss) make ligaments vulnerable to damage. With weak ligaments, muscles contracting against them weaken: the muscles cannot close the urethra (manifested as stress incontinence), open it (manifested as emptying problems or retention) or stretch the vagina to prevent the urothelial stretch receptors firing off prematurely (manifested as urge incontinence). Weak pubourethral ligaments can cause stress urinary incontinence (SUI), or SUI plus urge (mixed incontinence). Weak uterosacral ligaments (USLs) can cause urge, frequency, nocturia and emptying difficulties. Treatment consisting of surgical/non-surgical strengthening of ligaments can cure or improve SUI, OAB, and emptying dysfunctions. In summary, bladder control is from outside the bladder, binary, with cortical and peripheral components. A small change in definition, from "overactive" to "overactivated" is consistent with this concept, retains the acronym "OAB", and opens the door to probability of cure and a massive increase in research endeavours.

Development of a physiologically based pharmacokinetic model of fostemsavir and its pivotal application to support dosing in pregnancy.

It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi-drug-resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate-release and extended-release tablets) in healthy volunteers. Predicted TMR concentration-time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L/h). Predicted versus observed TMR AUC0-inf (ng.h/mL) in healthy volunteers following FTR administration of the extended-release tablet were 9542 (66) versus 7339 (33). The validated TMR PBPK model was then applied to predict TMR PK in a population of pregnant individuals during each trimester. Simulations showed TMR AUC in pregnant individuals receiving FTR 600 mg twice daily was decreased by 25% and 38% in the second and third trimesters, respectively. However, TMR exposure remained within the range observed in nonpregnant adults with no need for dose adjustment. The current PBPK model can also be applied for the prediction of local tissue concentrations and drug-drug interactions in pregnancy.

The Evolution of Agrarian Landscapes in the Tropical Andes.

Changes in land-use practices have been a central element of human adaptation to Holocene climate change. Many practices that result in the short-term stabilization of socio-natural systems, however, have longer-term, unanticipated consequences that present cascading challenges for human subsistence strategies and opportunities for subsequent adaptations. Investigating complex sequences of interaction between climate change and human land-use in the past-rather than short-term causes and effects-is therefore essential for understanding processes of adaptation and change, but this approach has been stymied by a lack of suitably-scaled paleoecological data. Through a high-resolution paleoecological analysis, we provide a 7000-year history of changing climate and land management around Lake Acopia in the Andes of southern Peru. We identify evidence of the onset of pastoralism, maize cultivation, and possibly cultivation of quinoa and potatoes to form a complex agrarian landscape by c. 4300 years ago. Cumulative interactive climate-cultivation effects resulting in erosion ended abruptly c. 2300 years ago. After this time, reduced sedimentation rates are attributed to the construction and use of agricultural terraces within the catchment of the lake. These results provide new insights into the role of humans in the manufacture of Andean landscapes and the incremental, adaptive processes through which land-use practices take shape.

Phytolith assemblages reflect variability in human land use and the modern environment.

Phytoliths preserved in soils and sediments can be used to provide unique insights into past vegetation dynamics in response to human and climate change. Phytoliths can reconstruct local vegetation in terrestrial soils where pollen grains typically decay, providing a range of markers (or lack thereof) that document past human activities. The ca. 6 million km2 of Amazonian forests have relatively few baseline datasets documenting changes in phytolith representation across gradients of human disturbances. Here we show that phytolith assemblages vary on local scales across a gradient of (modern) human disturbance in tropical rainforests of Suriname. Detrended correspondence analysis showed that the phytolith assemblages found in managed landscapes (shifting cultivation and a garden), unmanaged forests, and abandoned reforesting sites were clearly distinguishable from intact forests and from each other. Our results highlight the sensitivity and potential of phytoliths to be used in reconstructing successional trajectories after site usage and abandonment. Percentages of specific phytolith morphotypes were also positively correlated with local palm abundances derived from UAV data, and with biomass estimated from MODIS satellite imagery. This baseline dataset provides an index of likely changes that can be observed at other sites that indicate past human activities and long-term forest recovery in Amazonia. Supplementary Information: The online version contains supplementary material available at 10.1007/s00334-023-00932-2.

Effects of the HIV-1 maturation inhibitor GSK3640254 on QT interval in healthy participants.

GSK3640254 (GSK'254) is a novel HIV-1 maturation inhibitor with pharmacokinetics supporting once-daily (QD) therapy for HIV-1 treatment. This thorough QT/corrected QT (QTc) study evaluated the effect of GSK'254 on cardiac repolarization. In this two-part, randomized study, healthy participants received GSK'254 or placebo QD for 7 days (part 1) to determine safety and pharmacokinetics of a 500-mg supratherapeutic dose. Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400-mg moxifloxacin dose on Day 7 (all with a moderate-fat meal). Concentration-QTc analyses modeled the relationship between GSK'254 plasma concentrations and placebo-adjusted change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF). Of 50 participants enrolled, 48 completed the study (part 1, 8/8; part 2, 40/42). Least-squares (LS) mean change from baseline in QTcF for GSK'254 100 mg followed the placebo pattern across time points (maximum LS mean ΔΔQTcF, 1.7 ms); the upper bound of the 90% CI remained <10 ms. Maximum LS mean ΔΔQTcF for GSK'254 500 mg exceeded the 10-ms threshold: 10.6 ms (90% CI 7.75-13.38). Neither GSK'254 dose had clinically relevant effects on heart rate or cardiac conduction. By concentration-QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL-1 . No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100-mg dose.

Warming, drought, and disturbances lead to shifts in functional composition: A millennial-scale analysis for Amazonian and Andean sites.

Tropical forests are changing in composition and productivity, probably in response to changes in climate and disturbances. The responses to these multiple environmental drivers, and the mechanisms underlying the changes, remain largely unknown. Here, we use a functional trait approach on timescales of 10,000 years to assess how climate and disturbances influence the community-mean adult height, leaf area, seed mass, and wood density for eight lowland and highland forest landscapes. To do so, we combine data of eight fossil pollen records with functional traits and proxies for climate (temperature, precipitation, and El Niño frequency) and disturbances (fire and general disturbances). We found that temperature and disturbances were the most important drivers of changes in functional composition. Increased water availability (high precipitation and low El Niño frequency) generally led to more acquisitive trait composition (large leaves and soft wood). In lowland forests, warmer climates decreased community-mean height probably because of increased water stress, whereas in highland forests warmer climates increased height probably because of upslope migration of taller species. Disturbance increased the abundance of acquisitive, disturbance-adapted taxa with small seeds for quick colonization of disturbed sites, large leaves for light capture, and soft wood to attain fast height growth. Fire had weak effects on lowland forests but led to more stress-adapted taxa that are tall with fast life cycles and small seeds that can quickly colonize burned sites. Site-specific analyses were largely in line with cross-site analyses, except for varying site-level effects of El Niño frequency and fire activity, possibly because regional patterns in El Niño are not a good predictor of local changes, and charcoal abundances do not reflect fire intensity or severity. With future global changes, tropical Amazonian and Andean forests may transition toward shorter, drought- and disturbance-adapted forests in the lowlands but taller forests in the highlands.

Human-induced ecological cascades: Extinction, restoration, and rewilding in the Galápagos highlands.

Oceanic islands support unique biotas but often lack ecological redundancy, so that the removal of a species can have a large effect on the ecosystem. The larger islands of the Galápagos Archipelago once had one or two species of giant tortoise that were the dominant herbivore. Using paleoecological techniques, we investigate the ecological cascade on highland ecosystems that resulted from whalers removing many thousands of tortoises from the lowlands. We hypothesize that the seasonal migration of a now-extinct tortoise species to the highlands was curtailed by decreased intraspecific competition. We find the trajectory of plant community dynamics changed within a decade of the first whaling vessels visiting the islands. Novel communities established, with a previously uncommon shrub, Miconia, replacing other shrubs of the genera Alternanthera and Acalypha. It was, however, the introduction of cattle and horses that caused the local extirpation of plant species, with the most extreme impacts being evident after c. 1930. This modified ecology is considered the natural state of the islands and has shaped subsequent conservation policy and practice. Restoration of El Junco Crater should emphasize exclusion of livestock, rewilding with tortoises, and expanding the ongoing plantings of Miconia to also include Acalypha and Alternanthera.

Early to mid-Holocene human activity exerted gradual influences on Amazonian forest vegetation.

Humans have been present in Amazonia throughout the Holocene, with the earliest archaeological sites dating to 12 000 years ago. The earliest inhabitants began managing landscapes through fire and plant domestication, but the total extent of vegetation modification remains relatively unknown. Here, we compile palaeoecological records from lake sediments containing charcoal and from pollen analyses to understand how human land-use affected vegetation during the early to mid-Holocene, and place our results in the context of previous archaeological work. We identified gradual, rather than abrupt changes in forest openness, disturbance and enrichment, with useful species at almost all sites. Early human occupations occurred in peripheral sites of Amazonia, where natural fires are part of the vegetation dynamics, so human-made fires did not exert a novel form of disturbance. Synchronicity between evidence of the onset of human occupation in lake records and archaeological sites was found for eastern Amazonia. For southwestern and western Amazonia and the Guiana Shield, the timing of the onset of human occupation differed by thousands of years between lake records and archaeological sites. Plant cultivation showed a different spatio-temporal pattern, appearing ca 2000 years earlier in western Amazonia than in other regions. Our findings highlight the spatial-temporal heterogeneity of Amazonia and indicate that the region cannot be treated as one entity when assessing ecological or cultural history. This article is part of the theme issue 'Tropical forests in the deep human past'.

Potential distributions of pre-Columbian people in Tropical Andean landscapes.

Much has yet to be learned of the spatial patterning of pre-Columbian people across the Tropical Andes. Using compiled archaeological data and a suite of environmental variables, we generate an ensemble species distribution model (SDM) that incorporates general additive models, random forest models and Maxent models to reconstruct spatial patterns of pre-Columbian people that inhabited the Tropical Andes east of the continental divide, within the modern countries of Bolivia, Peru and Ecuador. Within this region, here referred to as the eastern Andean flank, elevation, mean annual cloud frequency, distance to rivers and precipitation of the driest quarter are the environmental variables most closely related to human occupancy. Our model indicates that 11.04% of our study area (65 368 km2) was likely occupied by pre-Columbian people. Our model shows that 30 of 351 forest inventory plots, which are used to generate ecological understanding of Andean ecosystems, were likely occupied in the pre-Columbian period. In previously occupied sites, successional trajectories may still be shaping forest dynamics, and those forests may still be recovering from the ecological legacy of pre-Columbian impacts. Our ensemble SDM links palaeo- and neo-ecology and can also be used to guide both future archaeological and ecological studies. This article is part of the theme issue 'Tropical forests in the deep human past'.

How deregulation, drought and increasing fire impact Amazonian biodiversity.

Biodiversity contributes to the ecological and climatic stability of the Amazon Basin1,2, but is increasingly threatened by deforestation and fire3,4. Here we quantify these impacts over the past two decades using remote-sensing estimates of fire and deforestation and comprehensive range estimates of 11,514 plant species and 3,079 vertebrate species in the Amazon. Deforestation has led to large amounts of habitat loss, and fires further exacerbate this already substantial impact on Amazonian biodiversity. Since 2001, 103,079-189,755 km2 of Amazon rainforest has been impacted by fires, potentially impacting the ranges of 77.3-85.2% of species that are listed as threatened in this region5. The impacts of fire on the ranges of species in Amazonia could be as high as 64%, and greater impacts are typically associated with species that have restricted ranges. We find close associations between forest policy, fire-impacted forest area and their potential impacts on biodiversity. In Brazil, forest policies that were initiated in the mid-2000s corresponded to reduced rates of burning. However, relaxed enforcement of these policies in 2019 has seemingly begun to reverse this trend: approximately 4,253-10,343 km2 of forest has been impacted by fire, leading to some of the most severe potential impacts on biodiversity since 2009. These results highlight the critical role of policy enforcement in the preservation of biodiversity in the Amazon.

Population Pharmacokinetic Modeling and Simulations to Evaluate a Potential Dose Regimen of Testosterone Undecanoate in Hypogonadal Males.

Intramuscular testosterone undecanoate is indicated as testosterone replacement in adult males with a deficiency in or absence of endogenous testosterone (hypogonadism). Intramuscular testosterone undecanoate 750 mg is approved to be administered at initiation and at 4 weeks, followed by a maintenance dose every 10 weeks. However, a more frequent maintenance regimen may improve symptom management of low testosterone at the end of each dosing interval. The current objective was to develop a population pharmacokinetic (PK) model for intramuscular testosterone undecanoate 750 mg and to perform PK simulations to assess the impact of an 8-week maintenance regimen on testosterone exposure. A 1-compartment model with first-order absorption and first-order elimination best described the PK of testosterone undecanoate. The model included time-dependent suppression and gradual recovery of endogenous testosterone production during testosterone undecanoate administration. Significant covariates included body weight and sex hormone-binding globulin level. With the final PK model, simulations were performed to evaluate the impact of an 8-week vs a 10-week maintenance regimen on testosterone exposure. The 8-week testosterone undecanoate regimen had a predicted 11% increase in average concentration and last observed concentration during a dosing interval before a subsequent dose and a 5% increase in maximum concentration. This translated into an ≈10% increase in the percentage of patients predicted to have a last observed concentration during a dosing interval before a subsequent dose >300 ng/dL, minimal change in the percentage of patients with average concentration in the normal range, and a low likelihood of maximum concentration >2500 ng/dL. These simulations suggest that more frequent administration of intramuscular testosterone undecanoate may be beneficial in some patients. Further clinical evaluation of an 8-week dose regimen is warranted.

The Non-Steroidal Mineralocorticoid Receptor Antagonist KBP-5074 Limits Albuminuria and has Improved Therapeutic Index Compared With Eplerenone in a Rat Model With Mineralocorticoid-Induced Renal Injury.

The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.

Andean drought and glacial retreat tied to Greenland warming during the last glacial period.

Abrupt warming events recorded in Greenland ice cores known as Dansgaard-Oeschger (DO) interstadials are linked to changes in tropical circulation during the last glacial cycle. Corresponding variations in South American summer monsoon (SASM) strength are documented, most commonly, in isotopic records from speleothems, but less is known about how these changes affected precipitation and Andean glacier mass balance. Here we present a sediment record spanning the last ~50 ka from Lake Junín (Peru) in the tropical Andes that has sufficient chronologic precision to document abrupt climatic events on a centennial-millennial time scale. DO events involved the near-complete disappearance of glaciers below 4700 masl in the eastern Andean cordillera and major reductions in the level of Peru's second largest lake. Our results reveal the magnitude of the hydroclimatic disruptions in the highest reaches of the Amazon Basin that were caused by a weakening of the SASM during abrupt arctic warming. Accentuated warming in the Arctic could lead to significant reductions in the precipitation-evaporation balance of the southern tropical Andes with deleterious effects on this densely populated region of South America.

On the vital role of enamel prism interfaces and graded properties in human tooth survival.

Teeth of omnivores face a formidable evolutionary challenge: how to protect against fracture and abrasive wear caused by the wide variety of foods they process. It is hypothesized that this challenge is met in part by adaptations in enamel microstructure. The low-crowned teeth of humans and some other omnivorous mammals exhibit multiple fissures running longitudinally along the outer enamel walls, yet remain intact. It is proposed that inter-prism weakness and enamel property gradation act together to avert entry of these fissures into vulnerable inner tooth regions and, at the same time, confer wear resistance at the occlusal surface. A simple indentation experiment is employed to quantify crack paths and energetics in human enamel, and an extended-finite-element model to evaluate longitudinal crack growth histories. Consideration is given as to how tooth microstructure may have played a vital role in human evolution, and by extension to other omnivorous mammals.

Effect of Food Intake and Body Position on the Pharmacokinetics of Swallowed APT-1011, a Fluticasone Orally Disintegrating Tablet, in Healthy Adult Volunteers.

Eosinophilic esophagitis is a common atopic disease of the esophagus. APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate under development for the treatment of eosinophilic esophagitis. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of APT-1011 under fed or fasted conditions in the morning (am) or at bedtime (hs) in the supine position. The study was a randomized, single-dose, 3-way, crossover design in healthy adult volunteers. In each study period participants received 2 3-mg orally disintegrating APT-1011 tablets. Serial plasma samples were collected before dosing and up to 72 hours after each dose. Twenty-two participants completed the study. The fluticasone propionate peak concentration (Cmax ) ranged from 5.97 to 200 pg/mL. Compared with am-fasted dosing, am-fed dosing was associated with a modestly higher Cmax (∼21%) but lower net exposure (area under the concentration-time curve ∼56% difference) and shorter time to reach Cmax (Tmax ) (Tmax fasted = 10 hours, fed = 5 hours). Dosing at hs resulted in an 18% and 32% decrease in Cmax relative to am-fasted and am-fed conditions, respectively. Dosing at hs led to an exposure that was higher than am-fed but lower than am-fasted dosing. Tmax with hs dosing (14 hours) was later than that with am dosing (Tmax fasted = 10 hours, fed = 5 hours). Adverse events were mild. There is low systemic exposure of fluticasone propionate with APT-1011. The rate of absorption was increased with a high-fat meal but decreased with hs dosing, suggesting the potential for longer dwell times in the esophagus.

2,100 years of human adaptation to climate change in the High Andes.

Humid montane forests are challenging environments for human habitation. We used high-resolution fossil pollen, charcoal, diatom and sediment chemistry data from the iconic archaeological setting of Laguna de los Condores, Peru to reconstruct changing land uses and climates in a forested Andean valley. Forest clearance and maize cultivation were initiated during periods of drought, with periods of forest recovery occurring during wetter conditions. Between AD 800 and 1000 forest regrowth was evident, but this trend was reversed between AD 1000 and 1200 as drier conditions coincided with renewed land clearance, the establishment of a permanent village and the use of cliffs overlooking the lake as a burial site. By AD 1230 forests had regrown in the valley and maize cultivation was greatly reduced. An elevational transect investigating regional patterns showed a parallel, but earlier, history of reduced maize cultivation and forest regeneration at mid-elevation. However, a lowland site showed continuous maize agriculture until European conquest but very little subsequent change in forest cover. Divergent, climate-sensitive landscape histories do not support categorical assessments that forest regrowth and peak carbon sequestration coincided with European arrival.

Brazilian montane rainforest expansion induced by Heinrich Stadial 1 event.

The origin of modern disjunct plant distributions in the Brazilian Highlands with strong floristic affinities to distant montane rainforests of isolated mountaintops in the northeast and northern Amazonia and the Guyana Shield remains unknown. We tested the hypothesis that these unexplained biogeographical patterns reflect former ecosystem rearrangements sustained by widespread plant migrations possibly due to climatic patterns that are very dissimilar from present-day conditions. To address this issue, we mapped the presence of the montane arboreal taxa Araucaria, Podocarpus, Drimys, Hedyosmum, Ilex, Myrsine, Symplocos, and Weinmannia, and cool-adapted plants in the families Myrtaceae, Ericaceae, and Arecaceae (palms) in 29 palynological records during Heinrich Stadial 1 Event, encompassing a latitudinal range of 30°S to 0°S. In addition, Principal Component Analysis and Species Distribution Modelling were used to represent past and modern habitat suitability for Podocarpus and Araucaria. The data reveals two long-distance patterns of plant migration connecting south/southeast to northeastern Brazil and Amazonia with a third short route extending from one of them. Their paleofloristic compositions suggest a climatic scenario of abundant rainfall and relative lower continental surface temperatures, possibly intensified by the effects of polar air incursions forming cold fronts into the Brazilian Highlands. Although these taxa are sensitive to changes in temperature, the combined pollen and speleothems proxy data indicate that this montane rainforest expansion during Heinrich Stadial 1 Event was triggered mainly by a less seasonal rainfall regime from the subtropics to the equatorial region.