Search

Background The majority of cases of Dent’s disease are caused by pathogenic variants in the CLCN5 gene, which encodes a voltage-gated chloride ion channel (ClC-5), resulting in proximal tubular dysfunction. We present three members of the same family and one unrelated paediatric patient with the same insertion-deletion CLCN5 variant. The identification of these patients and positive familial segregation led to the re-classification of this variant from one of unknown significance to one of likely pathogenicity. Case presentation A 41 year old male presented with end stage kidney failure, proteinuria and haematuria. Whole genome sequencing identified an insertion-deletion variant in CLCN5, resulting in a missense change (c.1744_1745delinsAA p.(Ala582Lys)). His brother and nephew, who both exhibited renal impairment, haematuria, proteinuria, glycosuria and nephrocalcinosis, were found to have the same variant. In addition, genetic testing of an un-related paediatric patient who presented with proteinuria and hypercalciuria, demonstrated the same variant. Conclusions The identification of this novel variant in four individuals with features of Dent’s disease, has led to the re-classification of the variant to one of likely pathogenicity.

Strangulating hair mats in dogs are characterized as soft tissue injury secondary to chronically matted hair, which can encircle the extremities and constrict lymphatic tissue and local vasculature. As the tissue swells, the hair constriction tightens and may result in tissue necrosis and osseous changes secondary to ischemic necrosis. The objectives of this retrospective case series were to describe the radiographic characteristics of persistent hair mat strangulation in dogs, to identify clinical features that would distinguish between dogs with soft tissue lesions only and dogs with osseous changes and to describe the clinical outcome in these dogs. All dogs with clinically identified strangulating hair matting had radiographically identified soft tissues defects and over half of the limbs evaluated had osseous lesions including focal periostitis, bone remodeling, bone atrophy, lysis of bone, and occasionally subluxation of joints. Chronically matted hair and strangulating hair mats in dogs are recognized by veterinarians as a medical finding in animal neglect. The osseous features of strangulating hair mats have not been described in the veterinary medical literature. This study describes the clinical features and radiographic characteristics of strangulating hair mats.

The COVID-19 pandemic is affecting lives around the world in many ways. Governments have temporarily closed schools in an attempt to contain the spread of the virus. Here, an elementary school teac...

Many older patients with myeloid neoplasms experience treatment-related toxicities. We previously demonstrated that a home-based, progressive aerobic walking and resistance exercise program (EXCAP) improved physical and psychological outcomes in patients with cancer. However, older patients have more difficulty adhering to exercise than younger patients. Reasons may include low motivation, difficulty with transportation, and limited access to exercise professionals. To improve exercise adherence, we integrated a mobile app with EXCAP (GO-EXCAP) and assessed its feasibility and usability in a single-arm pilot study among older patients with myeloid neoplasms undergoing outpatient chemotherapy. GO-EXCAP intervention lasts for 2 cycles of treatment, and the primary feasibility metric was data reporting on the app. Usability was evaluated via the system usability scale (SUS). Patients were interviewed at mid and postintervention to elicit their feedback, and deductive thematic analysis was applied to the transcripts. Twenty-five patients (mean age, 72 years) were recruited. Recruitment and retention rates were 64% and 88%, respectively. Eighty-two percent (18/22) of patients entered some exercise data on the app at least half of the study days, excluding hospitalization (a priori, we considered 70% as feasible). Averaged daily steps were 2848 and 3184 at baseline and after intervention, respectively. Patients also performed resistance exercises 26.2 minutes per day, 2.9 days per week at low intensity (rate of perceived exertion 3.8/10). Usability was above average (SUS, 70.3). In qualitative analyses, 3 themes were identified, including positive experience with the intervention, social interactions, and flexibility. The GO-EXCAP intervention is feasible and usable for older patients with myeloid neoplasms undergoing outpatient chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT04035499.

Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

Background CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin ɑ3β1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease. Methods Next-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9. Results We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence. Conclusions Our results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

Summary Isolated Growth Hormone Deficiency (IGHD) is a rare cause of short stature, treated with the standard regimen of subcutaneous synthetic growth hormone (GH). Patients typically achieve a maximum height velocity in the first year of treatment, which then tapers shortly after treatment is stopped. We report a case of a 9-year-old male who presented with short stature (95th percentile for age and race. In conclusion, this is a case of primary hypopituitarism with differential diagnosis of IGHD vs Idiopathic Short Stature vs Constitutional Growth Delay. This case supports two objectives: Firstly, it highlights the importance of confirmatory genetic testing in patients with suspected, though diagnostically uncertain, IGHD. Secondly, it demonstrates a novel secondary growth pattern with implications for better understanding the tremendous variability of GH treatment response. Learning points: GHD is a common cause of growth retardation, and IGHD is a specific subtype of GHD in which patients present solely with short stature. The standard treatment for IGHD is subcutaneous synthetic GH until mid-parental height is reached, with peak height velocity attained in the 1st year of treatment in the vast majority of patients. Genetic testing should be strongly considered in cases of diagnostic uncertainty prior to initiating treatment. Future investigations of GH treatment response that stratify by gene and specific mutation will help guide treatment decisions. Response to treatment in patients with IGHD is variable, with some patients demonstrating little to no response, while others are ‘super-responders.’

A community structure analysis compared cross-national coverage of genetically modified organisms (GMOs) with variations in national-level demographics from 19 newspapers worldwide, yielding combined article “prominence” and “direction” “Media Vector” newspaper scores emphasizing either “favorable” (42%) or “unfavorable” (58%) coverage of GMOs. Regression analysis revealed “poverty level” (24.2% of variance) and “percent of agricultural land” (4.7%) totaled 28.9% of the variance, confirming that “vulnerability” indicators are associated with favorable media coverage of GMOs. Contrary to conventional “guard dog” assumptions that media mirror elite interests, systematic research on demographics and GMO coverage reveals that media can mirror the interests of society’s most “vulnerable.”

Imaging studies are often of evidentiary value in medicolegal investigations involving animals and the role of the veterinary radiologist is to interpret those images for courts as an expert or opinion witness. With progressing interest in prosecuting animal crimes and strengthening of penalties for crimes against animals, the participation of veterinary radiologists in medicolegal investigations is expected to increase. Veterinary radiologists who are aware of radiographic and imaging signs that result in animal suffering, abuse, or neglect; knowledgeable in ways radiology and imaging may support cause of death determinations; conversant in postmortem imaging; comfortable discussing mechanisms and timing of blunt or sharp force and projectile trauma in imaging; and prepared to identify mimics of abuse can assist court participants in understanding imaging evidence. The goal of this commentary review is to familiarize veterinary radiologists with the forensic radiology and imaging literature and with the advantages and disadvantages of various imaging modalities utilized in forensic investigations. Another goal is to provide background information for future research studies in veterinary forensic radiology and imaging.

In this dissertation, new results on stochastic geometric models in high dimensional space are presented. We first concentrate on a particular class of repulsive point processes called determinantal point processes (DPPs). We establish a coupling of a DPP and its reduced Palm version showing the repulsive effect of a point of the point process. This is used for discussing the degree of repulsiveness in DPPs, including Ginibre point processes and other specific parametric models for DPPs. We then study this repulsion for stationary DPPs in high dimensional Euclidean space. It is shown that for many families of DPPs, a typical point has no repulsive effect with high probability for large space dimension n. It is also proved that for some DPPs there exists an R* such that the repulsive effect occurs at a distance of [square root] nR* with high probability for large n. This R* is interpreted as the asymptotic reach of repulsion of the DPP. Examples of DPPs exhibiting this behavior are presented and an application to high dimensional Boolean models is given. The second half of this dissertation examines zero cells of stationary Poisson tessellations. First, a stationary stochastic geometric model is proposed for analyzing one-bit data compression. The data is assumed to be an unconstrained stationary set, and each data point is compressed using one bit with respect to each hyperplane in a stationary and isotropic Poisson hyperplane tessellation. Size metrics of the zero cell of the tessellation are studied to determine how the intensity of hyperplanes must scale with dimension to ensure sufficient separation of different data by the hyperplanes or sufficient proximity of the data compressed together. The results have direct implications in compressive sensing and source coding. We then study the concentration of the norm of a random vector Y uniformly sampled in the centered zero cell of a stationary random tessellation in high dimensions. It is shown that for a stationary and isotropic Poisson-Voronoi tessellation, [mathematical equation] approaches one as the dimension approaches infinity. For a stationary and isotropic Poisson hyperplane tessellation, we prove that [mathematical equation] will be within a fixed range (R [subscript ℓ], R [subscript u]) with probability approaching one as dimension n tends to infinity.

There is a need to develop novel breeding approaches to increase the rate of genetic gain for wheat yield due to rising demand and climate volatility. Genomic selection (GS) can increase genetic gain in quantitative traits, such as yield, principally through a shorter selection cycle. ‘Speed breeding’ (SB) could further accelerate the breeding cycle by using extended photoperiod in the glasshouse, enabling rapid generation advance. An integrated breeding approach could include fast inbred line development, phenotyping of yield secondary traits for multivariate GS and indirect phenotypic selection for important traits prior to field trials in a target environment. The objective of this thesis was to explore a comprehensive breeding strategy that combines the aforementioned tools, aimed at increasing the rate of genetic gain in wheat. Firstly, to investigate the potential for SB application across major crop species, a sample of wheat, barley, canola and chickpea cultivars were evaluated under either 22-hour light (SB) or natural, diurnal lighting in a temperature-controlled glasshouse to quantify and compare the effects on development. Wheat and barley were also grown at high densities to investigate potential single seed descent (SSD) programs. Time to anthesis was significantly reduced for all species relative to the natural photoperiod conditions. Coupled with harvesting seed two weeks post-anthesis, SB could enable up to six generations of wheat per year. Grain and spike number were similar between lighting treatments and germination percentage was higher in grain of SB-grown plants at two weeks after flowering. These findings indicated that SB had potential to be used at multiple stages of a breeding program. In order to identify traits that could be measured under SB (SB traits) that were correlated to field-based yield and could be used in multivariate GS, an explorative study was carried out on a 135-line, bi-parental (SeriM82 x Hartog, SxH) bread wheat population. Days to anthesis (SB-DTA), plant height (SB-height), spike length and flag leaf length were measured under SB and narrow-sense heritability and genetic correlation with field-based yield was determined from previously performed field trials in three environments that varied with respect to extent and timing of water deficit. Field-based traits were also measured, including DTA, plot height and two senescence indices. The heritability of most SB and field-based traits were higher than yield heritability and SB-DTA and SB-height showed strong genetic correlations with yield (up to -0.80 and -0.66 respectively) in the irrigated environment. Further investigation with a larger, more diverse population was carried out using a previously developed 256-line, multi-reference bread wheat population, and data from two previous rain-fed yield trials. Multivariate models incorporating the field-based senescence indices significantly increased yield prediction ability although the addition of SB traits did not improve prediction above that of univariate models. Yield heritability in these field trials was relatively high and using cross-validation meant a 20% reduction in training population (TP) size, which may have contributed to this result. To validate the proposed breeding strategy of combining GS and SB in a real breeding scenario, a new population of 350 selection candidates (SC) was created by inter-crossing 20 individuals from the SxH population, followed by five generations of selfing under SB. Development of this near-homozygous population was completed in 15 months. A 193-line subset of the SxH population with yield data from five field trials was used as the TP to predict yield of SC lines. These predictions were validated in three yield trials; one irrigated and two rain-fed trials performed across two locations. Four SB traits measured on both the TP and SC population were used to derive principal components (SB-PCs), which were incorporated into multivariate GS models. Predictive ability was significantly increased by multivariate GS with SB-PCs, in some cases being twice the ability of univariate GS, except when predicting yield at Warwick, a higher water-stress location. The genetic correlations between the SB-PCs and yield from the Warwick SC trial were lower than those with Gatton, a location that experienced higher rainfall, illustrating the impact of environmental differences between secondary traits and yield at the target location on prediction ability. In fact, the addition of SB-PCs appeared to have a negative impact on ability to predict yield in Warwick. These findings could be related to the difficulties of predicting into water deficit environments, such as Warwick, compared to environments with more water availability, such as in Gatton and SB conditions. An additional use for SB traits during population development, indirect phenotypic selection for important field-based traits, was explored. The genetic correlations of SB-DTA to field-based time to anthesis and SB-height to plot height indicated indirect phenotypic selection under SB, prior to field trials, could rapidly condition populations for a target environment. Lower selection accuracy, compared to field-based phenotypic selection, could be compensated for by high generation turnover and result in a higher rate of genetic gain. This strategy could benefit wheat breeding programs by increasing, and in some cases, doubling, the rate of genetic gain through rapid development of improved selections.

Background: Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects.Methods: FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762.Findings: Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months.Interpretation: Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function.Funding: UK Stroke Association and NIHR Health Technology Assessment Programme.

Purpose To determine the clinical outcomes of patients who underwent image-guided drainage of peripancreatic fluid collections after simultaneous pancreas-kidney (SPK) transplantation. Materials and Methods A retrospective review of all patients who underwent peripancreatic fluid collection drainage after SPK, from January 2000 to August 2017, at a single institution was performed. Patient characteristics, surgical technique, medication regimen, microbial analysis, and clinical outcomes were reviewed. Thirty-one patients requiring a total of 41 drainages were included in this study. The median age was 44 years (range 30–58 years), and median time between SPK and drainage was 28 days (range 8 to 3,401 days). Fisher’s exact test, unpaired Student t -tests, and Pearson correlations were used for statistical analysis. Results Fever (51%) and abdominal pain (31%) were the most common presenting symptoms. The average amount of fluid drained at the time of drain placement was 97 mL (SD 240 mL). The average time spent with a drain in place was 33 days (SD 31 days). Microorganisms were isolated in the fluid of 22 of 41 drainages (54%), with mixed gastrointestinal flora being the most common. No further intervention was needed in 34 of 41 drainages (82%). However, drainage failed in 5 of 31 patients (16%), requiring surgical intervention with removal of the pancreas transplant. Conclusions Percutaneous drainage of peripancreatic fluid collections after SPK transplantation is a safe and effective treatment option.

Background. The Neuromuscular Recovery Scale (NRS) was developed by researchers and clinicians to functionally classify people with spinal cord injury (SCI) by measuring functionally relevant motor tasks without compensation. Previous studies established strong interrater and test-retest reliability and validity of the scale. Objective. To determine responsiveness of the NRS, a version including newly added upper-extremity items, in an outpatient rehabilitation setting. Methods. Assessments using the NRS and 6 other instruments were conducted at enrollment and discharge from a locomotor training program for 72 outpatients with SCI classified as American Spinal Injury Association Impairment Scale grades A to D (International Standards for Neurological Classification of Spinal Cord Injury). Mixed-model t statistics for instruments were calculated and adjusted for confounding factors (eg, sample size, demographic variables) for all patients and subgroups stratified by injury level and/or severity. The resulting adjusted response means (ARMs) and 95% confidence intervals (CIs) were used to determine responsiveness, and significant differences between instruments were identified with pairwise comparisons. Results. The NRS was significantly responsive for SCI outpatients (ARM = 1.05; CI = 0.75-1.35). Changes in motor function were detected across heterogeneous groups. Regardless of injury level or severity, the responsiveness of the NRS was equal to, and often significantly exceeded, the responsiveness of other instruments. Conclusions. The NRS is a responsive measure that detects change in motor function during outpatient neurorehabilitation for SCI. There is potential utility for its application in randomized controlled trials and as a measure of clinical recovery across diverse SCI populations.

Through collaborative consultation with school staff, school psychologists have increasingly helped schools add bullying prevention and intervention programming to their service delivery systems. As schools search for ways to lessen the impact of bullying on the social-emotional health and academic achievement of students, forgiveness education is an area that may offer another perspective to bullying prevention and intervention. In order to infuse forgiveness education into schools' current tiered-service delivery systems, school psychologists and their district partners can use the frameworks of collaborative strategic planning (CSP) and the concerns-based adoption model (CBAM) in tandem to guide the development and implementation of forgiveness-focused bullying interventions at the core, supplementary, and intensive levels of a multitiered system of service delivery.

Pendimethalin is commonly applied for PRE weed control in container nursery production. Field and laboratory trials were conducted to determine herbicide effectiveness and leaching of two pendimethalin formulations in pine bark, the primary component used in the growing medium of container-grown plants in the South. The microencapsulated (ME) formulation of pendimethalin gave lower control of southern crabgrass and leached deeper than the emulsifiable concentrate (EC) formulation in pine bark. The EC formulation controlled southern crabgrass 93% compared with only 70% with the ME formulation at 4.48 kg ai ha−1. After applying 3.4 kg ai ha−1pendimethalin and 17.8 cm of irrigation water, the ME formulation showed greater leaching into the 3- to 6- and 6- to 9-cm depths than the EC formulation on the basis of a southern crabgrass bioassay. Using a microwave extraction method, only 0.91 mg kg−1pendimethalin was found in the 3- to 6-cm pine bark depth compared with 4.0 mg kg−1for the ME formulation. Below the 6-cm depth, no pendimethalin was detected when the EC formulation was applied, but 0.5 ppm was found for the ME formulation. No pendimethalin was detected in effluent collected from irrigation water for the EC; however, 3.0 mg kg−1was collected from leachate for the ME formulation. Pendimethalin ME is leaching much deeper than the EC formulation in the pine bark profile, which results in lower weed control. This extensive leaching of ME formulation may be due to capsule movement with the irrigation water, combined with a delayed release of pendimethalin, which then binds to the pine bark much lower in the container profile.

Objective: This study sought to develop and evaluate the psychometric properties of a tool designed to assess social work students’ knowledge of and perceptions and attitudes toward human trafficking. To achieve this aim, the Perceptions, Knowledge, and Attitudes toward Human Trafficking Questionnaire (PKA-HTQ) was developed and its psychometric properties were evaluated. Specifically, the factor structure and the internal consistency of the PKA-HTQ were evaluated. Methods: Exploratory factor analysis (EFA) and a replication EFA were conducted on two independent samples of university students, an initial validation ( n = 325), and cross-validation ( n = 212) sample. Findings: The EFA revealed a three-factor structure, that is, self-appraisal of knowledge/skills (α = .89), worldview (α =.78), and help-seeking behavior (α =.66); this three-factor structure was supported by replication EFA. Conclusion: The PKA-HTQ questionnaire shows promise as a meaningful, potentially reliable and valid measure.

East African landscapes today are the result of the cumulative effects of climate and land-use change over millennial timescales. In this review, we compile archaeological and palaeoenvironmental data from East Africa to document land-cover change, and environmental, subsistence and land-use transitions, over the past 6000?years. Throughout East Africa there have been a series of relatively rapid and high-magnitude environmental shifts characterised by changing hydrological budgets during the mid- to late Holocene. For example, pronounced environmental shifts that manifested as a marked change in the rainfall amount or seasonality and subsequent hydrological budget throughout East Africa occurred around 4000, 800 and 300 radiocarbon years before present (yr BP). The past 6000?years have also seen numerous shifts in human interactions with East African ecologies. From the mid-Holocene, land use has both diversified and increased exponentially, this has been associated with the arrival of new subsistence systems, crops, migrants and technologies, all giving rise to a sequence of significant phases of land-cover change. The first large-scale human influences began to occur around 4000?yr BP, associated with the introduction of domesticated livestock and the expansion of pastoral communities. The first widespread and intensive forest clearances were associated with the arrival of iron-using early farming communities around 2500?yr BP, particularly in productive and easily-cleared mid-altitudinal areas. Extensive and pervasive land-cover change has been associated with population growth, immigration and movement of people. The expansion of trading routes between the interior and the coast, starting around 1300?years ago and intensifying in the eighteenth and nineteenth centuries CE, was one such process. These caravan routes possibly acted as conduits for spreading New World crops such as maize (Zea mays), tobacco (Nicotiana spp.) and tomatoes (Solanum lycopersicum), although the processes and timings of their introductions remains poorly documented. The introduction of southeast Asian domesticates, especially banana (Musa spp.), rice (Oryza spp.), taro (Colocasia esculenta), and chicken (Gallus gallus), via transoceanic biological transfers around and across the Indian Ocean, from at least around 1300?yr BP, and potentially significantly earlier, also had profound social and ecological consequences across parts of the region.\ud \ud Through an interdisciplinary synthesis of information and metadatasets, we explore the different drivers and directions of changes in land-cover, and the associated environmental histories and interactions with various cultures, technologies, and subsistence strategies through time and across space in East Africa. This review suggests topics for targeted future research that focus on areas and/or time periods where our understanding of the interactions between people, the environment and land-cover change are most contentious and/or poorly resolved. The review also offers a perspective on how knowledge of regional land-use change can be used to inform and provide perspectives on contemporary issues such as climate and ecosystem change models, conservation strategies, and the achievement of nature-based solutions for development purposes.