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BackgroundPathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma–paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.MethodsThree independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes.ResultsTruncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (pSDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (pConclusionsSDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.

We test one of the main predictions of the financial flexibility paradigm, that expectations about future firm-specific investment shocks affect the firm's leverage. We extract the expectations of small and large future shocks from the market prices of equity options. We find that leverage decreases when expectations for any one of the two types of future shocks increase and the relation is statistically significant even when we control for standard determinants of leverage and the firm's probability of default. Expectations for future shocks explain a greater fraction of leverage variation than most standard determinants of leverage do and they affect more the small and financially constrained firms. Our results are not subject to an endogeneity bias and they confirm DeAngelo et al. (2011) model's predictions and the evidence that managers seek for financial flexibility.

Background A recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting. Methods In this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application. Results 111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88–99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59–91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation. Conclusions PuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery.

Endoscopic imaging is the mainstay of gastrointestinal endoscopy and has experienced remarkable improvements in recent decades. Further endoscopic innovations stemming from major technological advances such as artificial intelligence and deep learning are at advanced stages of development and will be increasingly deployed in routine clinical practice. These will improve the detection and enable real-time optical diagnosis of pathologies in the gastrointestinal tract. Furthermore, the utilization of endoscopic robots may result in higher diagnostic yield and greater patient comfort. This chapter covers the most recent developments around computer-assisted diagnosis, hypoxia and three-dimensional imaging, robotic-assisted endoscopy, and eye-tracking technology in the field of gastrointestinal endoscopy highlighting devices that have received regulatory approval and systems that are at earlier developmental stages but that have the potential to strongly impact clinical practice in the future.

We derive mixing properties for a broad class of Poisson count time series satisfying a certain contraction condition. Using specific coupling techniques, we prove absolute regularity at a geometric rate not only for stationary Poisson-GARCH processes but also for models with an explosive trend. We provide easily verifiable sufficient conditions for absolute regularity for a variety of models including classical (log-)linear models. Finally, we illustrate the practical use of our results for hypothesis testing., 24 pages, 2 figures

Over the past two decades advances in genomic technologies have transformed knowledge of the genetic basis of phaeochromocytoma and paraganglioma (PPGL). Though traditional teaching suggested that inherited cases accounted for only 10% of all phaeochromocytoma diagnosis, current estimates are at least three times this proportion. Inherited PPGL is a highly genetically heterogeneous disorder but the most frequently results from inactivating variants in genes encoding subunits of succinate dehydrogenase. Expanding knowledge of the genetics of PPGL has been translated into clinical practice by the provision of widespread testing for inherited PPGL. In this review, we explore how the molecular stratification of PPGL is being utilized to enable more personalized strategies for investigation, surveillance and management of affected individuals and their families. Translating recent genetic research advances into clinical service can not only bring benefits through more accurate diagnosis and risk prediction but also challenges when there is a suboptimal evidence base for the clinical consequences or significance of rare genotypes. In such cases, clinical, biochemical, pathological and functional imaging assessments can all contribute to more accurate interpretation and clinical management.

The scientific contributions of E.M. van Zinderen Bakker (1907–2002) included the introduction of pollen analysis to Quaternary studies in South Africa. His palaeoecological theories evolved while performing palynological research in Southern Africa (the Maluti Mountains, Florisbad, Aliwal North, the Namib Desert), East Africa (Kalambo Falls, Mount Kenya, Cherangani Hills) and on the subantarctic islands (Marion and Prince Edward Islands). He was involved in the first radiocarbon dating from South Africa at Florisbad. Due to quantitative palynological studies he abandoned Wayland's (1929) Pluvial Theory that was generally accepted in the 1960s. He correlated observations of climate changes in Africa to data from marine borehole-cores and climatic fluctuations in the Northern Hemisphere. His observations led to the proposal that global temperature fluctuations are the primary cause of palaeoenvironmental changes. His studies culminated in a conceptual paleoecological model for the Last Glacial Maximum (LGM). Initially he based the model on symmetrical contraction of climatic belts about the equator that shifted the mid-latitude westerly wind system northward to increase the area receiving winter rainfall but later adjusted this by proposing a mechanism of westerly wind system intensification. He suggested that at this time grasslands had spread over wider areas in Southern Africa and that the tropical rain forests in the equatorial region fragmented. For interglacial periods he suggested that a southward shift of the Intertropical Convergence Zone (ITCZ) resulted in widespread humidity in the Congo Basin while large areas of the interior of Southern Africa became arid. Some of his ideas, especially his conceptual models of Quaternary vegetation and climate, are still relevant to the explanation of recent discoveries.

An investigation of the vegetation and climate from the Middle Pleistocene until the end of the Late Pleistocene reveals a plethora of terrestrial and marine biological, geological and archaeological evidence for marked and complex climate cycles of change, which reflect on past circulation patterns. While acknowledging the usefulness of diverse proxies for detecting these changes, an efficient way to summarize past events is to focus on one of them, viz. fossil pollen, which, although providing scattered and incomplete records, gives fairly direct reflections of past climates and vegetation growth. The findings are structured according to six subregions and reveal distinct changes in temperature and moisture patterns, e.g. during the Last Glacial Maximum (LGM) and the Younger Dryas. The data suggest an environmental background against which cultural evolution took place, e.g., the appearance of Fauresmith, Still Bay, Howiesons Poort and Later Stone Age lithic industries. The pollen archives can be associated with global climate changes, as recorded in isotopes in marine sequences (Marine Isotope Stages or MISs). The observations show differences between regions, which can serve as a base for improving palaeo-data to eventually simulate past and future climates and to better understand the role of past global climates in relation to human and animal occupation in Southern Africa.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Probe-based confocal laser endomicroscopy (pCLE) is a subcellular in vivo imaging technique capable of producing images that enable diagnosis of malign structural modifications in epithelial tissue. Images acquired with pCLE are, however, often tainted by significant artifacts that impair diagnosis. This is especially detrimental for automated image analysis, which is why said images are often excluded from recognition pipelines. We present an approach for the automatic detection of motion artifacts in pCLE images and apply this methodology to a data set of 15 thousand images of epithelial tissue acquired in the oral cavity and the vocal folds. The approach is based on transfer learning from intermediate endpoints within a pre-trained Inception v3 network with tailored preprocessing. For detection within the non-rectangular pCLE images, we perform pooling within the activation maps of the network and evaluate this at different network depths. We achieved area under the ROC curve values of 0.92 with the proposed method, compared to 0.80 for the best feature-based machine learning approach. Our overall accuracy with the presented approach is 94.8%. Over traditional machine learning approaches with state-of-the-art features, we achieved significantly improved overall performance.

The local dynamics of dendritic sidearms during coarsening are studied by combining in-situ radiography observations with numerical and analytical models. A flat sample of a Ga-In alloy is partially solidified and then held isothermally in a vertical temperature gradient. The evolving dendritic microstructure is visualized using synchrotron X-ray imaging at the BM20 (ROBL) beamline at ESRF, France. During the coarsening stage, the temporal evolution of the geometrical features of sidebranches is captured by automated image processing. This data is then used to quantify the dynamics of two basic evolution mechanisms for sidebranches: retraction and pinch-off. The universal dynamics of sidearm necks during pinch-off are exploited to determine the product of liquid diffusivity and capillarity length D d 0 , as a parameter that is crucial in the calibration of quantitative models. By employing an idealized phase-field model for the evolution of a single sidebranch, the behavior of selected sidebranches is reproduced from the experiments in a consistent way.

An ongoing re-investigation of the early Miocene Saldanha Bay (South Africa) palynoflora, using combined light and scanning electron microscopy (single grain method), is revealing several pollen types new to the African fossil record. One of the elements identified is Loranthaceae pollen. These grains represent the first and only fossil record of Loranthaceae in Africa. The fossil pollen grains resemble those produced by the core Lorantheae and are comparable to recent Asian as well as some African taxa/lineages. Molecular and fossil signals indicate that Loranthaceae dispersed into Africa via Asia sometime during the Eocene. The present host range of African Loranthaceae and the composition of the palynoflora suggest that the fossil had a range of potential host taxa to parasitise during the early Miocene in the Saldanha Bay region.

We propose a modification of local polynomial estimation which improves the efficiency of the conventional method when the observation errors are correlated. The procedure is based on a pre-transformation of the data as a generalization of the pre-whitening procedure introduced by Xiao et al. [(2003), ‘More Efficient Local Polynomial Estimation in Nonparametric Regression with Autocorrelated Errors’, Journal of the American Statistical Association, 98, 980–992]. While these authors assumed a linear process representation for the error process, we avoid any structural assumption. We further allow the regressors and the errors to be dependent. More importantly, we show that the inclusion of both leading and lagged variables in the approximation of the error terms outperforms the best approximation based on lagged variables only. Establishing its asymptotic distribution, we show that the proposed estimator is more efficient than the standard local polynomial estimator. As a by-product we prove a suit...

The specific area of the solid-liquid interface of an assembly of dendrites is an important integral measure of the morphology of the microstructure forming during alloy solidification. It represents the inverse of a characteristic length scale and is needed for the prediction of solidification defects and material properties. In the present study, the evolution of the interfacial area of dendrites is analysed using 3D phase-field simulations. A general evolution equation is developed for the specific interface area as a function of time and solid volume fraction that accounts for the effects of growth, curvature-driven coarsening and interface coalescence. The relation is validated using data from previously performed synchrotron X-ray tomography and isothermal coarsening experiments. It is found to be valid for arbitrary and even varying cooling rates and for a wide range of binary alloys. The rate constant in the evolution equation is successfully related to alloy properties.

Objective Hyperglucagonemia is present in many forms of diabetes and contributes to hyperglycemia, and glucagon suppression can ameliorate diabetes in mice. Leptin, a glucagon suppressor, can also reverse diabetes in rodents. Lipid nanoparticle (LNP) delivery of small interfering RNA (siRNA) effectively targets the liver and is in clinical trials for the treatment of various diseases. We compared the effectiveness of glucagon receptor (Gcgr)-siRNA delivered via LNPs to leptin in two mouse models of diabetes. Methods Gcgr siRNA encapsulated into LNPs or leptin was administered to mice with diabetes due to injection of the β-cell toxin streptozotocin (STZ) alone or combined with high fat diet (HFD/STZ). Results In STZ-diabetic mice, a single injection of Gcgr siRNA lowered blood glucose levels for 3 weeks, improved glucose tolerance, and normalized plasma ketones levels, while leptin therapy normalized blood glucose levels, oral glucose tolerance, and plasma ketones, and suppressed lipid metabolism. In contrast, in HFD/STZ-diabetic mice, Gcgr siRNA lowered blood glucose levels for 2 months, improved oral glucose tolerance, and reduced HbA1c, while leptin had no beneficial effects. Conclusions While leptin may be more effective than Gcgr siRNA at normalizing both glucose and lipid metabolism in STZ diabetes, Gcgr siRNA is more effective at reducing blood glucose levels in HFD/STZ diabetes., Highlights • Gcgr siRNA improves glucose metabolism but not lipid metabolism in STZ diabetic mice. • Leptin improves both glucose and lipid metabolism in STZ diabetic mice. • Gcgr siRNA improves glucose metabolism in HFD/STZ diabetic mice. • Leptin does not improve glucose metabolism in HFD/STZ diabetic mice.

First descriptions of diseases attract tremendous interest because they reveal scientific insight even in retrospect. Max Schottelius, the pathologist contributing the first histological description of pheochromocytoma, remains anonymous. We reviewed the description by Schottelius and weighed the report in modern context. Schottelius described the classical diagnostic elements of pheochromocytoma, including the brown appearance after exposure to chromate-containing Mueller’s fixative. This color change, known as chromaffin reaction, results from oxidation of catecholamines and is reflected in the name pheochromocytoma, meaning dusky-colored chromate-positive tumor. Thus Schottelius performed the first known histochemical contribution to diagnosis, which is today standard with immunohistochemistry for chromogranin., Max Schottelius, the first to describe the histology of pheochromocytoma in 1886, is introduced. He applied histochemistry for diagnosis of the chromaffin tumors, a cornerstone until now.

A multi-proxy study of an offshore core in Saldanha Bay (South Africa) provides new insights into fluvial deposition, ecosystems, phytogeography and sea-level history during the late Paleogene-early Neogene. Offshore seismic data reveal bedrock topography, and provide evidence of relative sea levels as low as − 100 m during the Oligocene. 3D landscape reconstruction reveals hills, plains and an anastomosing river system. A Chattian or early Miocene age for the sediments is inferred from dinoflagellate taxa Distatodinium craterum, Chiropteridium lobospinosum, Homotryblium plectilum and Impagidinium paradoxum. The subtropical forest revealed by palynology includes lianas and vines, evergreen trees, palms and ferns, implying higher water availability than today, probably reduced seasonal drought and stronger summer rainfall. From topography, sedimentology and palynology we reconstruct Podocarpaceae-dominated forests, Proto-Fynbos, and swamp/riparian forests with palms and other angiosperms. Rhizophoraceae present the first South African evidence of Palaeogene/Neogene mangroves. Subtropical woodland-thicket with Combretaceae and Brachystegia (Peregrinipollis nigericus) probably developed on coastal plains. Some of the last remaining Gondwana elements on the sub-continent, e.g., Araucariaceae, are recorded. Charred particles signal fires prior to the onset of summer dry climate at the Cape. Marine and terrestrial palynomorphs, together with organic and inorganic geochemical proxy data, suggest a gradual glacio-eustatic transgression. The data shed light on Southern Hemisphere biogeography and regional climatic conditions at the Palaeogene-Neogene transition. The proliferation of the vegetation is partly ascribed to changes in South Atlantic oceanographic circulation, linked to the closure of the Central American Seaway and the onset of the Benguela Current ~ 14 Ma.

Background Under the EU chemicals regulation REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals EC 1907/2006), registrants are not obliged to provide information related to intrinsic substance properties for substances that pose a threat to the drinking water resources. In 2019, perfluorobutane sulfonic acid (PFBS) and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoic acid (HFPO-DA trade name GenX) were demonstrated to have an equivalent level of concern (ELoC) to persistent, bioaccumulative and toxic or very persistent and very bioaccumulative (PBT/vPvB) substances owing to their persistent, mobile and toxic (PMT) substance properties and very persistent and very mobile (vPvM) substance properties, respectively. They were both subsequently identified as substances of very high concern (SVHC) applying Article 57(f) in REACH. This work follows up on this regulatory decision by presenting a science based, conceptual level comparison that all PMT/vPvM substances pose an ELoC to PBT/vPvB substances. Using the two cases named above, as well as 1,4-dioxane, 16 categories were developed to evaluate a) serious effects on human health, b) serious effects on the environment and c) additional effects. 1,4-dioxane has recently been proposed to be classified as Carcinogenic 1B by the Committee for Risk Assessment (RAC). The aim was to enable an objective and scientifically justified conclusion that these classes of substances have an equivalent level of concern for the environment and human health. Results In all of the categories related to human health, the environment and other effects, the PMT/vPvM case study substances exhibited comparable effects to PBT/vPvB substances. A difference in the human and environmental exposure pathways of PMT/vPvM and PBT/vPvB substances exists as they vary temporally and spatially. However, effects and impacts are similar, with PMT/vPvM substances potentially accumulating in (semi-)closed drinking water cycles and pristine aquatic environments, and PBT/vPvB substances accumulating in humans and the food chain. Both PMT/vPvM and PBT/vPvB substances share the common difficulty that long term and long-range transport and risk of exposure is very difficult to determine in advance and with sufficient accuracy. Conclusion The registration process of substances under REACH should reflect that PMT/vPvM substances pose an equivalent level of concern to PBT/vPvB substances.

The prediction and final survival rate of gastrointestinal cancers are dependent on the stage of disease. The ideal would be to detect those gastrointestinal lesions at early stage or even premalignant forms which are difficult to detect by conventional endoscopy with white light optical imaging as they show minimum or no changes in morphological characteristics and are thus left untreated. The introduction of molecular imaging has greatly changed the pattern for detecting gastrointestinal lesions from purely macroscopic structural imaging to the molecular level. It allows microscopic examination of the gastrointestinal mucosa with endoscopy after the topical or systemic application of molecular probes. In recent years, major advancements in endoscopic instruments and specific molecular probes have been achieved. This review focuses on the current status of endoscopic imaging and highlights the application of molecular imaging in gastrointestinal and hepatic disease in the context of diagnosis and therapy based on recently published literature in this field. We also discuss the challenges of molecular endoscopic imaging, its future directions and potential that could have a tremendous impact on endoscopic research and clinical practice in future.

Pheochromocytoma and Paraganglioma Pheochromocytoma and paraganglioma are related tumors that differ mainly in location; pheochromocytomas are adrenal, and paragangliomas can be anywhere else. The ...

Background: Unrecognized or newly diagnosed pheochromocytoma (PHEO) or paraganglioma (PGL) during pregnancy may lead to adverse maternal and fetal outcomes. Recommendations for the management of women with PHEO or PGL (PPGL) during pregnancy are limited by the scarcity of published literature. Objective: To describe the presentation, management and outcomes of women with active PPGL during pregnancy and to identify predictors of unfavorable maternal and fetal outcomes. Methods: international retrospective multi-center study, 1968-2018. Results: Seventy-nine women with active PPGL had 89 pregnancies at a median age of 28 yrs (range, 16-46). At the time of pregnancy, 37 (42%) women had unilateral PHEO, 11 (12%) bilateral PHEO, 26 (29%) PGL, 8 (9)% multifocal disease and 7 (8%) metastatic PPGL. Of 51 patients evaluated for a predisposing mutation, 38 were positive (12 SDHB, 11 VHL, 8 RET, 7 other). Median tumor size was 6 cm (range, 1.9-29). Of 74 patients with available data on function, 65 (88%) had functioning PPGL. Of 89 pregnancies, only 13 (15%) patients had a known PPGL prior to pregnancy (8 with known metastases), while in 42 (47%) pregnancies, PPGL was diagnosed during pregnancy at a median gestation of 16 weeks (range, 2-38) and during 34 (38%) pregnancies, PPGL remained unrecognized until postpartum, diagnosed at a median of 9 weeks (range, 0-78) after delivery. PPGL surgery was performed in 72 women: 14 intrapartum at median gestation week 16 (range, 13-26) and 58 postpartum at a median of 36 weeks (range, 0-270) after pregnancy. Of 41 pregnancies with antepartum diagnosis of PHEO not treated with surgery, 25 (61%) were managed with medical therapy and 15 (39%) were closely monitored. Delivery was by C-section in 39 (44%) pregnancies (38 healthy babies, one death delivered at 22 weeks) and vaginal in 35 (39%) with no adverse maternal or fetal outcomes. Elective abortion was pursued in 5 (6%) pregnancies. Intrauterine fetal demise occurred in 6 (7%) pregnancies at a median of 21 weeks gestation (range, 11-28), all in women with unrecognized functioning PPGL. Adverse maternal outcomes occurred in 3 (3%) pregnancies, all in unrecognized functioning PPGL resulting in 1 death (at gestation week 38) and 2 severe cardiovascular complications (immediately postpartum). The most significant predictor of an unfavorable pregnancy outcome was postpartum diagnosis of PHEO, with an odds ratio of 16.6 (95% CI, 2-140, P=0.001), but not maternal age, tumor size, presence of metastases, antepartum surgery for PHEO, or known PHEO syndrome. Conclusion: The majority of pregnancies in women with active PPGL had excellent outcomes, even in women with metastatic or functional disease, especially when PPGL was diagnosed before or during pregnancy, allowing for appropriate management. However, unrecognized and untreated PPGL was associated with 16-fold higher risk of either maternal or fetal complications.

Mpondoland on the South African east coast is a particularly dynamic region in terms of climate change as it is influenced by both temperate and tropical circulation and climate systems. We present a sediment record that indicates regional climatic change and anthropogenic influence during the last ∼5500 yr. Catchment data allow an understanding of signal transmission from the catchment to the site of the marine core. Plant-wax isotope distributions and elemental composition, as well as palynological, burned phytolith and micro-charcoal data, are used to infer paleoclimatic shifts and reconstruct past human activity. Whereas previous studies have often disregarded early anthropogenic drivers of environmental change, our study provides palynological evidence of human impacts and geochemical evidence of increased erosion starting as early as ∼1500 years ago. Downcore proxy analysis suggests that particularly humid conditions persisted from ∼900 to ∼300 cal yr BP, encompassing both the Medieval Climate Anomaly and the Little Ice Age. We suggest that humidity during the Medieval Climate Anomaly was sourced from a poleward shift of the Southern Hemispheric Westerlies and the South African high-pressure cell, allowing for the southward expansion of the Southern Indian Ocean Convergence Zone. During the Little Ice Age, the equatorward movement of the Southern Hemispheric Westerlies probably brought increased rainfall to areas that are normally beyond the northern limit of the Southern Hemispheric Westerlies. Comparison of our record to available regional archives of centennial-scale late Holocene climate variability in South Africa demonstrates that Mpondoland is located at a transition zone of tropical and sub-tropical climatic influences.

Purpose During the COVID 19- pandemic, there is no consensus on management strategies for treating infected heart transplant patients. The outcomes of these patients vary by institution. We report our center experience and management strategies to date. Methods All patients who received heart transplantation, from January 4th 2018 to September 25th 2020 and were diagnosed with SARS-CoV-2 were included and full chart review was performed. Results There were 113 heart transplants at our institution by September 2020. A total of 13 (12%) patients were infected with SARS-CoV-2: 9 (69%) isolated heart, 3 heart -kidney (23%) and 1 heat- lung (8%). The median (IQR) time from transplant to diagnosis was 10 (5-16) months. The mean age was 57 years and 50% were male; 50% were of Hispanic ethnicity. The main presenting symptoms were fever (43%), cough (86%) and SOB (43%). Chest x-ray was abnormal in all patients. We evaluated all patients and 79% were hospitalized and 21% were closely monitored as outpatients. None of our patients were hospitalized at outside institutions. Two (14%) required intubation and none required V-V ECMO support. The immunotherapy was modified in all patients: MMF and prednisone were discontinued, tacrolimus dose was reduced. COVID19 treatment was: 71% received hydroxychloroquine, 50% azithromycin, 15% remdesevir, 7% convalescent plasma. All hospitalized patients received anticoagulation. One patient had 2R/3A rejection within 30 days prior to diagnosis. Graft function was maintained in all patients with median LVEF% 65 (59-65%) except one patient who had received thymoglobulin 2 weeks prior to COVID 19 infection (LVEF 30%). The patient had a prolonged intubation but ultimately recovered and was discharged from the hospital. The one death (7.1%) was a heart - kidney recipient who concomitantly presented with pseudomonas sepsis and severe neutropenia. The remaining patients have all been discharged home. Conclusion We present our single center experience in managing COVID 19 infected heart transplant patients. We implemented uniform management strategies by incorporating aggressive reduction of immunosuppression, frequent scheduled contacts with infected outpatients and making sure all infected patients requiring hospitalization were treated at a transplant center.