Management of the diabetic foot.

The increasing prevalence of diabatic foot ulcers (DFUs) is not only costly, but carries a large mortality burden. In this article, we discuss important traditional concepts in the management of DFUs and elaborate on how new technologies have expanded our ability to treat DFUs effectively. New supplies and wound care products have been developed to target the following traditional areas of focus: tissue, infection/inflammation, moisture, and edge. Offloading strategies have grown from standard orthotics or insoles to total contact casting and three-dimensional-printed orthotics to produce the optimum material stiffness for each patient. The concepts of pressure and temperature monitoring have led to the development of multiple devices that transmit continuous monitoring in real time, giving a dynamic picture of plantar stress and training patients in new walking strategies for self-offloading. Surgical approaches have also evolved from the classic surgical debridement and correcting deformities that cause friction to creation of acellular and bio-printed cellular skin substitutes that can be used for grafting. Surveillance and long-term follow-up with a multidisciplinary team have also changed in the face of smartphones and watches that allow patients to monitor themselves in real time with daily prompts and reminders to shape desired behaviors in between clinic visits. Modern technology is changing management of DFUs by expanding on traditional concepts and improving standard therapies.

Orthologs of human circulating miRNAs associated with hepatocellular carcinoma are elevated in mouse plasma months before tumour detection.

Research examining the potential for circulating miRNA to serve as markers for preneoplastic lesions or early-stage hepatocellular carcinoma (HCC) is hindered by the difficulties of obtaining samples from asymptomatic individuals. As a surrogate for human samples, we identified hub miRNAs in gene co-expression networks using HCC-bearing C3H mice. We confirmed 38 hub miRNAs as associated with HCC in F2 hybrid mice derived from radiogenic HCC susceptible and resistant founders. When compared to a panel of 12 circulating miRNAs associated with human HCC, two had no mouse ortholog and 7 of the remaining 10 miRNAs overlapped with the 38 mouse HCC hub miRNAs. Using small RNA sequencing data generated from serially collected plasma samples in F2 mice, we examined the temporal levels of these 7 circulating miRNAs and found that the levels of 4 human circulating markers, miR-122-5p, miR-100-5p, miR-34a-5p and miR-365-3p increased linearly as the time approaching HCC detection neared, suggesting a correlation of miRNA levels with oncogenic progression. Estimation of change points in the kinetics of the 4 circulating miRNAs suggested the changes started 17.5 to 6.8 months prior to HCC detection. These data establish these 4 circulating miRNAs as potential sentinels for preneoplastic lesions or early-stage HCC.

Range-wide indicators of African great ape density distribution.

Species distributions are influenced by processes occurring at multiple spatial scales. It is therefore insufficient to model species distribution at a single geographic scale, as this does not provide the necessary understanding of determining factors. Instead, multiple approaches are needed, each differing in spatial extent, grain, and research objective. Here, we present the first attempt to model continent-wide great ape density distribution. We used site-level estimates of African great ape abundance to (1) identify socioeconomic and environmental factors that drive densities at the continental scale, and (2) predict range-wide great ape density. We collated great ape abundance estimates from 156 sites and defined 134 pseudo-absence sites to represent additional absence locations. The latter were based on locations of unsuitable environmental conditions for great apes, and on existing literature. We compiled seven socioeconomic and environmental covariate layers and fitted a generalized linear model to investigate their influence on great ape abundance. We used an Akaike-weighted average of full and subset models to predict the range-wide density distribution of African great apes for the year 2015. Great ape densities were lowest where there were high Human Footprint and Gross Domestic Product values; the highest predicted densities were in Central Africa, and the lowest in West Africa. Only 10.7% of the total predicted population was found in the International Union for Conservation of Nature Category I and II protected areas. For 16 out of 20 countries, our estimated abundances were largely in line with those from previous studies. For four countries, Central African Republic, Democratic Republic of the Congo, Liberia, and South Sudan, the estimated populations were excessively high. We propose further improvements to the model to overcome survey and predictor data limitations, which would enable a temporally dynamic approach for monitoring great apes across their range based on key indicators.

Quantitative estimates of glacial refugia for chimpanzees (Pan troglodytes) since the Last Interglacial (120,000 BP).

Paleoclimate reconstructions have enhanced our understanding of how past climates have shaped present-day biodiversity. We hypothesize that the geographic extent of Pleistocene forest refugia and suitable habitat fluctuated significantly in time during the late Quaternary for chimpanzees (Pan troglodytes). Using bioclimatic variables representing monthly temperature and precipitation estimates, past human population density data, and an extensive database of georeferenced presence points, we built a model of changing habitat suitability for chimpanzees at fine spatio-temporal scales dating back to the Last Interglacial (120,000 BP). Our models cover a spatial resolution of 0.0467° (approximately 5.19 km2 grid cells) and a temporal resolution of between 1000 and 4000 years. Using our model, we mapped habitat stability over time using three approaches, comparing our modeled stability estimates to existing knowledge of Afrotropical refugia, as well as contemporary patterns of major keystone tropical food resources used by chimpanzees, figs (Moraceae), and palms (Arecacae). Results show habitat stability congruent with known glacial refugia across Africa, suggesting their extents may have been underestimated for chimpanzees, with potentially up to approximately 60,000 km2 of previously unrecognized glacial refugia. The refugia we highlight coincide with higher species richness for figs and palms. Our results provide spatio-temporally explicit insights into the role of refugia across the chimpanzee range, forming the empirical foundation for developing and testing hypotheses about behavioral, ecological, and genetic diversity with additional data. This methodology can be applied to other species and geographic areas when sufficient data are available.

Transcriptomic analysis links hepatocellular carcinoma (HCC) in HZE ion irradiated mice to a human HCC subtype with favorable outcomes.

High-charge, high-energy ion particle (HZE) radiations are extraterrestrial in origin and characterized by high linear energy transfer (high-LET), which causes more severe cell damage than low-LET radiations like γ-rays or photons. High-LET radiation poses potential cancer risks for astronauts on deep space missions, but the studies of its carcinogenic effects have relied heavily on animal models. It remains uncertain whether such data are applicable to human disease. Here, we used genomics approaches to directly compare high-LET radiation-induced, low-LET radiation-induced and spontaneous hepatocellular carcinoma (HCC) in mice with a human HCC cohort from The Cancer Genome Atlas (TCGA). We identified common molecular pathways between mouse and human HCC and discovered a subset of orthologous genes (mR-HCC) that associated high-LET radiation-induced mouse HCC with a subgroup (mrHCC2) of the TCGA cohort. The mrHCC2 TCGA cohort was more enriched with tumor-suppressing immune cells and showed a better prognostic outcome than other patient subgroups.

Structure of Chimpanzee Gut Microbiomes across Tropical Africa.

Understanding variation in host-associated microbial communities is important given the relevance of microbiomes to host physiology and health. Using 560 fecal samples collected from wild chimpanzees (Pan troglodytes) across their range, we assessed how geography, genetics, climate, vegetation, and diet relate to gut microbial community structure (prokaryotes, eukaryotic parasites) at multiple spatial scales. We observed a high degree of regional specificity in the microbiome composition, which was associated with host genetics, available plant foods, and potentially with cultural differences in tool use, which affect diet. Genetic differences drove community composition at large scales, while vegetation and potentially tool use drove within-region differences, likely due to their influence on diet. Unlike industrialized human populations in the United States, where regional differences in the gut microbiome are undetectable, chimpanzee gut microbiomes are far more variable across space, suggesting that technological developments have decoupled humans from their local environments, obscuring regional differences that could have been important during human evolution. IMPORTANCE Gut microbial communities are drivers of primate physiology and health, but the factors that influence the gut microbiome in wild primate populations remain largely undetermined. We report data from a continent-wide survey of wild chimpanzee gut microbiota and highlight the effects of genetics, vegetation, and potentially even tool use at different spatial scales on the chimpanzee gut microbiome, including bacteria, archaea, and eukaryotic parasites. Microbial community dissimilarity was strongly correlated with chimpanzee population genetic dissimilarity, and vegetation composition and consumption of algae, honey, nuts, and termites were potentially associated with additional divergence in microbial communities between sampling sites. Our results suggest that host genetics, geography, and climate play a far stronger role in structuring the gut microbiome in chimpanzees than in humans.

Recent genetic connectivity and clinal variation in chimpanzees.

Much like humans, chimpanzees occupy diverse habitats and exhibit extensive behavioural variability. However, chimpanzees are recognized as a discontinuous species, with four subspecies separated by historical geographic barriers. Nevertheless, their range-wide degree of genetic connectivity remains poorly resolved, mainly due to sampling limitations. By analyzing a geographically comprehensive sample set amplified at microsatellite markers that inform recent population history, we found that isolation by distance explains most of the range-wide genetic structure of chimpanzees. Furthermore, we did not identify spatial discontinuities corresponding with the recognized subspecies, suggesting that some of the subspecies-delineating geographic barriers were recently permeable to gene flow. Substantial range-wide genetic connectivity is consistent with the hypothesis that behavioural flexibility is a salient driver of chimpanzee responses to changing environmental conditions. Finally, our observation of strong local differentiation associated with recent anthropogenic pressures portends future loss of critical genetic diversity if habitat fragmentation and population isolation continue unabated.

Chimpanzee identification and social network construction through an online citizen science platform.

Citizen science has grown rapidly in popularity in recent years due to its potential to educate and engage the public while providing a means to address a myriad of scientific questions. However, the rise in popularity of citizen science has also been accompanied by concerns about the quality of data emerging from citizen science research projects. We assessed data quality in the online citizen scientist platform Chimp&See, which hosts camera trap videos of chimpanzees (Pan troglodytes) and other species across Equatorial Africa. In particular, we compared detection and identification of individual chimpanzees by citizen scientists with that of experts with years of experience studying those chimpanzees. We found that citizen scientists typically detected the same number of individual chimpanzees as experts, but assigned far fewer identifications (IDs) to those individuals. Those IDs assigned, however, were nearly always in agreement with the IDs provided by experts. We applied the data sets of citizen scientists and experts by constructing social networks from each. We found that both social networks were relatively robust and shared a similar structure, as well as having positively correlated individual network positions. Our findings demonstrate that, although citizen scientists produced a smaller data set based on fewer confirmed IDs, the data strongly reflect expert classifications and can be used for meaningful assessments of group structure and dynamics. This approach expands opportunities for social research and conservation monitoring in great apes and many other individually identifiable species.

Atypically High Reproductive Skew in a Small Wild Chimpanzee Community in a Human-Dominated Landscape.

Social rank is positively correlated with reproductive success in numerous species, albeit demographic factors often influence those patterns. In multimale primate species, reproductive skew tends to decrease with increasing numbers of males and sexually receptive females. Alpha male chimpanzees (Pan troglodytes) often sire a disproportionate, though somewhat variable, percentage of offspring compared to other males. In a small community of eastern chimpanzees inhabiting a human-dominated landscape in Bulindi, Uganda, we found extraordinarily high levels of alpha male reproductive success over a 5-year period (7/8 offspring = 88%), despite the presence of multiple subordinate males. The skew exceeds that reported in other studies of chimpanzees as well as closely related bonobos (Pan paniscus). Our findings underscore the role of demographic and social factors in male reproductive success and also suggest that conclusions about species differences may be premature. The interaction of small community size, dispersal limitations, and male reproductive strategies like those found here may decrease genetic diversity and increase the risk of concomitant inbreeding in chimpanzee communities under strong anthropogenic pressure.

Infant carrying by a wild chimpanzee father at Bulindi, Uganda.

Although infanticide by wild adult male chimpanzees has been reported from multiple sites, affiliative infant carrying by males is rare. We observed infant carrying by an alpha male chimpanzee at Bulindi (Uganda) on two consecutive mornings and collected faecal samples from the newborn infant female, her mother and all candidate fathers to determine whether the alpha male was the infant's father using a likelihood-based method of paternity assignment. In contrast to previous observations of male care of orphans, in this case the mother was present during observations. Further, unlike reports of male aggression towards infants, the infant was reunited with her mother on the third morning, and survived. Neither mother nor infant presented visible injuries. The alpha male never directed aggression towards the infant. Rather, he displayed attentive behaviours, for example by holding the infant to his chest, supporting her while moving, grooming her, and 'cuddling' and 'rocking' her. Paternity results revealed with a high degree of certainty that the alpha male was the infant's father. There are several alternative explanations for the male's behaviour, but this unusual case also highlights the need for further studies to determine under what circumstances adult male chimpanzees can recognise their own offspring.

Novelty Response of Wild African Apes to Camera Traps.

Temperament and personality research in humans and nonhuman animals measures behavioral variation in individual, population, or species-specific traits with implications for survival and fitness, such as social status, foraging, and mating success [1-5]. Curiosity and risk-taking tendencies have been studied extensively across taxa by measuring boldness and exploration responses to experimental novelty exposure [3, 4, 6-15]. Here, we conduct a natural field experiment using wildlife monitoring technology to test variation in the reaction of wild great apes (43 groups of naive chimpanzees, bonobos, and western gorillas across 14 field sites in Africa) to a novel object, the camera trap. Bonobo and gorilla groups demonstrated a stronger looking impulse toward the camera trap device compared to chimpanzees, suggesting higher visual attention and curiosity. Bonobos were also more likely to show alarm and other fearful behaviors, although such neophobic (and conversely, neophilic) responses were generally rare. Among all three species, individuals looked at cameras longer when they were young, were associating with fewer individuals, and did not live near a long-term research site. Overall, these findings partially validate results from great ape novelty paradigms in captivity [7, 8]. We further suggest that species-typical leadership styles [16] and social and environmental effects, including familiarity with humans, best explain novelty responses of wild great apes. In sum, this study illustrates the feasibility of large-scale field experiments and the importance of both intrinsic and extrinsic factors in shaping animal curiosity. VIDEO ABSTRACT.

An assessment of the efficacy of camera traps for studying demographic composition and variation in chimpanzees (Pan troglodytes).

Demographic factors can strongly influence patterns of behavioral variation in animal societies. Traditionally, these factors are measured using longitudinal observation of habituated social groups, particularly in social animals like primates. Alternatively, noninvasive biomonitoring methods such as camera trapping can allow researchers to assess species occupancy, estimate population abundance, and study rare behaviors. However, measures of fine-scale demographic variation, such as those related to age and sex structure or subgrouping patterns, pose a greater challenge. Here, we compare demographic data collected from a community of habituated chimpanzees (Pan troglodytes verus) in the Taï Forest using two methods: camera trap videos and observational data from long-term records. By matching data on party size, seasonal variation in party size, measures of demographic composition, and changes over the study period from both sources, we compared the accuracy of camera trap records and long-term data to assess whether camera trap data could be used to assess such variables in populations of unhabituated chimpanzees. When compared to observational data, camera trap data tended to underestimate measures of party size, but revealed similar patterns of seasonal variation as well as similar community demographic composition (age/sex proportions) and dynamics (particularly emigration and deaths) during the study period. Our findings highlight the potential and limitations of camera trap surveys for estimating fine-scale demographic composition and variation in primates. Continuing development of field and statistical methods will further improve the usability of camera traps for demographic studies.

Nocturnal activity in wild chimpanzees (Pan troglodytes): Evidence for flexible sleeping patterns and insights into human evolution.

OBJECTIVES: We investigated occurrences and patterns of terrestrial nocturnal activity in wild chimpanzees (Pan troglodytes) and modelled the influence of various ecological predictors on nocturnal activity. METHODS: Data were extracted from terrestrial camera-trap footage and ecological surveys from 22 chimpanzee study sites participating in the Pan African Programme: The Cultured Chimpanzee. We described videos demonstrating nocturnal activity, and we tested the effects of the percentage of forest, abundance of predators (lions, leopards and hyenas), abundance of large mammals (buffalos and elephants), average daily temperature, rainfall, human activity, and percent illumination on the probability of nocturnal activity. RESULTS: We found terrestrial nocturnal activity to occur at 18 of the 22 study sites, at an overall average proportion of 1.80% of total chimpanzee activity, and to occur during all hours of the night, but more frequently during twilight hours. We found a higher probability of nocturnal activity with lower levels of human activity, higher average daily temperature, and at sites with a larger percentage of forest. We found no effect of the abundance of predators and large mammals, rainfall, or moon illumination. DISCUSSION: Chimpanzee terrestrial nocturnal activity appears widespread yet infrequent, which suggests a consolidated sleeping pattern. Nocturnal activity may be driven by the stress of high daily temperatures and may be enabled at low levels of human activity. Human activity may exert a relatively greater influence on chimpanzee nocturnal behavior than predator presence. We suggest that chimpanzee nocturnal activity is flexible, enabling them to respond to changing environmental factors.

Genetic analysis suggests dispersal among chimpanzees in a fragmented forest landscape in Uganda.

Habitat fragmentation is a leading threat to global biodiversity. Dispersal plays a key role in gene flow and population viability, but the impact of fragmentation on dispersal patterns remains poorly understood. Among chimpanzees, males typically remain in their natal communities while females often disperse. However, habitat loss and fragmentation may cause severe ecological disruptions, potentially resulting in decreased fitness benefits of male philopatry and limited female dispersal ability. To investigate this issue, we genotyped nearly 900 non-invasively collected chimpanzee fecal samples across a fragmented forest habitat that may function as a corridor between two large continuous forests in Uganda, and used the spatial associations among co-sampled genotypes to attribute a total of 229 individuals to 10 distinct communities, including 9 communities in the corridor habitat and 1 in continuous forest. We then used parentage analyses to infer instances of between-community dispersal. Of the 115 parent-offspring dyads detected with confidence, members of 39% (N = 26) of mother-daughter dyads were found in different communities, while members of 10% (N = 5) of father-son dyads were found in different communities. We also found direct evidence for one dispersal event that occurred during the study period, as a female's sample found first in one community was found multiple times in another community 19 months later. These findings suggest that even in fragmented habitats, chimpanzee males remain in their natal communities while females tend to disperse. Corridor enhancement in unprotected forest fragments could help maintain gene flow in chimpanzees and other species amid anthropogenic pressures.

Symptom Distress Among Diverse Patients Referred for Community-Based Palliative Care: Sociodemographic and Medical Correlates.

CONTEXT: Community-based palliative care programs are appearing in the U.S. Many of these programs, particularly those in large cities, serve highly diverse populations. Information about the sources of variation in the conditions that drive illness burden, like symptom distress, may be useful in program planning. OBJECTIVES: To characterize variation in symptom distress among highly diverse patients referred for palliative care in an urban setting. METHODS: This is a retrospective cross-sectional survey of data obtained from patients at the time of enrollment in a community-based palliative care program. Symptom distress was measured using the Condensed Memorial Symptom Assessment Scale. Severe distress was defined as reporting either "quite a bit"/"very much" or "frequently"/"almost constantly" for one or more symptoms. Multivariate analysis evaluated the associations between symptom distress and sources of patient variability. RESULTS: Patients (n = 1532) were aged 72.2 years on average; 60.0% were women, 56.4% were African-American or Hispanic, and 30.8% were non-English speaking. Most had cancer or congestive heart failure (68.6%); 90.2% had a Karnofsky Performance Status score of 40-70. The most prevalent symptoms were fatigue (71.8%), pain (47.3%), and sadness (41.6%); the most distressing symptoms were fatigue (58.5%), worrying (54.8%), and weight loss (52.1%). In multivariate analyses, Caucasian race, non-Asian language, low Karnofsky Performance Status scores, and cancer diagnosis predicted severe symptom distress. CONCLUSION: In a diverse urban population receiving community-based palliative care, symptoms were highly prevalent and distressing, and both sociodemographic and medical factors predicted severe distress. Program planning should consider the needs of subpopulations at risk for high symptom burden.

Chimpanzees (Pan troglodytes) Flexibly Use Introduced Species for Nesting and Bark Feeding in a Human-Dominated Habitat.

As habitat loss and fragmentation place growing pressure on endangered nonhuman primate populations, researchers find increasing evidence for novel responses in behavior. In western Uganda between the Budongo and Bugoma Forests, chimpanzees (Pan troglodytes schweinfurthii) inhabit a mosaic landscape comprising forest fragments, human settlements, and agricultural land. We recorded nests and feeding evidence of unhabituated chimpanzees in this region over a 12-mo period. We found extensive evidence of nesting in introduced tree species, including eucalyptus (Eucalyptus grandis), guava (Psidium guajava), cocoa (Theobroma cacao), and Caribbean pine (Pinus caribaea). In addition, we found instances of ground nesting, nest reuse, and composite nests constructed from branches of multiple trees. This evidence may indicate a lack of suitable nesting trees or attempts by chimpanzees to nest in areas of riparian forest that allow them to avoid human detection. We also found new evidence for eucalyptus bark feeding by chimpanzees. Such evidence suggests chimpanzees respond flexibly to mitigate anthropogenic pressures in human-dominated landscapes. The limits of such flexibility remain unknown. Further research is needed to examine systematically the factors influencing the use of such resources and to understand better the extent to which chimpanzees can persist while relying on them.

Treatment of Enterocutaneous Fistulas, Then and Now.

BACKGROUND: An enterocutaneous fistula (ECF) is an aberrant connection between the gastrointestinal tract and the skin or atmosphere (enteroatmospheric fistula [EAF]). Multimodal treatment includes surgical procedures, nutrition support, and wound care. We evaluated our practice and compared our outcomes with previous results published from our institution. MATERIALS AND METHODS: We performed a retrospective analysis of hospitalized ECF/EAF patients admitted between January 2011 and November 2015. Patients with internal fistulas; active inflammatory bowel disease; malignancy; radiation treatment; end-stage renal, hepatic, or cardiac disease; and active alcoholism were excluded. Data collected included demographics, fistula characteristics, nutrition therapy, treatment, operative success, and hospital mortality. Parametric and nonparametric tests for independent and paired groups were performed. RESULTS: Thirty-one patients were included in the analysis. The median (interquartile range) age was 60 (53-76) years, and 81% were female. Parenteral nutrition was initially prescribed in 80% of patients, but 61% received enteral nutrition (EN) at some point during their hospitalization. Two patients were fed by fistuloclysis. Eighty percent of the patients underwent surgical repair a median of 12 months after diagnosis with 92% operative success. Surgical repair had a modest correlation with home discharge (ρ = 0.517, P = .003). A large proportion of patients (77%) were discharged home. The in-hospital mortality at our institution decreased from 44% in 1960 to 21% in 1970 to 3% in the current study. CONCLUSIONS: Modern treatment of ECF/EAF, including EN and advanced local wound care, is associated with improvements in clinical outcomes such as hospital mortality.

Does Axillary Reverse Mapping Prevent Lymphedema After Lymphadenectomy?

BACKGROUND: We hypothesized that disconcerting lymphedema rates in both sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) may be because of unrecognized vunerable variations in arm lymphatic drainage within the axilla. Axillary reverse mapping (ARM) facilitates identification and avoidance of arm lymphatics within the axilla and its use may reduce lymphedema. METHODS: This institutional review board-approved study from June 2007 to December 2013 involved patients undergoing SLNB with or without ALND, or ALND alone. Technetium is injected subareolarly for localization of the breast SLN and isosulfan blue dye (5 mL) is injected in the ipsilateral upper arm for localization of nonbreast lymphatics. Data were collected on identification and preservation of arm lymphatics, crossover rates, blue node metastases, axillary recurrence, and lymphedema as measured by volume displacement. RESULTS: A total of 654 patients prospectively underwent 685 ARM procedures with a SLNB and/or ALND. Objective lymphedema rates for SLNB and ALND were 0.8% and 6.5% respectively, with 26-month median follow up. Blue lymphatics were identified in 29.2% (138/472) of SLNB and 71.8% (153/213) of ALND. Crossover was seen in 3.8% (18/472) of SLNB and 5.6% (12/213) of ALND. Blue node metastases rate was 4.5% (2/44). Axillary recurrence rate was 0.2% and 1.4% for SLNB and ALND, respectively. CONCLUSIONS: ARM allows frequent identification of arm lymphatics in the axilla, which would have been transected during routine surgery. Rates of metastases in noncrossover nodes and axillary recurrences are low. Lymphedema rates are dramatically reduced using ARM when compared with accepted standards.