Fully Integrated Artificial Pancreas in Type 1 Diabetes: Modular Closed-Loop Glucose Control Maintains Near Normoglycemia

Integrated closed-loop control (CLC), combining continuous glucose monitoring (CGM) with insulin pump (continuous subcutaneous insulin infusion [CSII]), known as artificial pancreas, can help optimize glycemic control in diabetes. We present a fundamental modular concept for CLC design, illustrated by clinical studies involving 11 adolescents and 27 adults at the Universities of Virginia, Padova, and Montpellier. We tested two modular CLC constructs: standard control to range (sCTR), designed to augment pump plus CGM by preventing extreme glucose excursions; and enhanced control to range (eCTR), designed to truly optimize control within near normoglycemia of 3.9-10 mmol/L. The CLC system was fully integrated using automated data transfer CGM→algorithm→CSII. All studies used randomized crossover design comparing CSII versus CLC during identical 22-h hospitalizations including meals, overnight rest, and 30-min exercise. sCTR increased significantly the time in near normoglycemia from 61 to 74%, simultaneously reducing hypoglycemia 2.7-fold. eCTR improved mean blood glucose from 7.73 to 6.68 mmol/L without increasing hypoglycemia, achieved 97% in near normoglycemia and 77% in tight glycemic control, and reduced variability overnight. In conclusion, sCTR and eCTR represent sequential steps toward automated CLC, preventing extremes (sCTR) and further optimizing control (eCTR). This approach inspires compelling new concepts: modular assembly, sequential deployment, testing, and clinical acceptance of custom-built CLC systems tailored to individual patient needs.     

The Constipation Severity Instrument: A Validated Measure

Purpose This study was designed to develop and test the validity and reliability of the Constipation Severity Instrument. Methods Scale development was conducted in two stages: 1) 74 items were generated through a literature review and focus groups of constipated patients and medical providers; and 2) a preliminary instrument was administered to 191 constipated patients and 103 healthy volunteers. Test-retest reliability of the constipated group was assessed (N = 90). Content, convergent, divergent, and discriminant validity were evaluated by using other validated measures by performing one-way analysis of variance and Pearson correlations. Results Exploratory and confirmatory factor analysis revealed three subscales: obstructive defecation, colonic inertia, and pain. Internal consistency (α = 0.88–0.91) and test-retest reliability (intraclass correlation coefficients = 0.84–0.91) were high for all subscales. Constipated patients were grouped by Rome II criteria: functional constipation (22 percent), pelvic floor dyssynergia (15 percent), constipation predominant irritable bowel syndrome (23 percent), and no specific criteria (40 percent). Those with constipation predominant irritable bowel syndrome or pelvic floor dyssynergia scored higher on the Obstructive Defecation and Colonic Inertia subscales than those with functional constipation or no specific criteria (P = 0.001–0.058). Subjects with functional constipation had much lower scores on the pain subscale than constipation predominant irritable bowel syndrome, functional constipation, or no specific criteria (P < 0.009).The Constipation Severity Instrument subscale and total score correlated very highly with the subscales and total score of the Patient Assessment of Constipation Symptom measure. The Constipation Severity Instrument subscales discriminated well between constipated patients and healthy volunteers (P < 0.001) and demonstrated excellent divergent validity. Higher Constipation Severity Instrument scores inversely correlated with general quality of life. Conclusions The Constipation Severity Instrument is a reliable and valid instrument for assessing constipated patients. Administration of the Constipation Severity Instrument to other constipated patients will further validate its use. Supported by the University of California San Francisco Hellman Family Award for Early Career Faculty. Read at the meeting of The American Society of Colon and Rectal Surgeons, St. Louis, Missouri, June 2 to 6, 2007. Reprints are not available.     

Molecular analysis of black coatings and anointing fluids from ancient Egyptian coffins,mummy cases,and funerary objects

Black organic coatings and ritual deposits on ancient Egyptian coffins and cartonnage cases are important and understudied sources of evidence about the rituals of funerary practice. Sometimes, the coatings were applied extensively over the surface of the coffin, resembling paint; in other cases, they were poured over the mummy case or wrapped body, presumably as part of a funerary ritual. For this study, multiple samples of black coatings and ritual liquids were taken from 20 Egyptian funerary items dating to a specific time period (c. 943 to 716 BC). Multiple sampling from each object enabled several comparisons to be made: the variability of the black coating within one application, the variability between two applications on one object, and the variability from object to object. All samples were analyzed for lipids using gas chromatography–mass spectrometry (GC-MS), and 51 samples from across the 20 items were further analyzed for the presence of bitumen using solid phase separation followed by selected ion monitoring GC-MS. The majority of the black substances were found to comprise a complex mixture of organic materials, including bitumen from the Dead Sea, conifer resin, and Pistacia resin, providing evidence for a continuation in international trade between Egypt and the eastern Mediterranean after the Late Bronze Age. Both the coating and the anointing liquid are very similar to mummification balms, pointing to parallels with Egyptian embalming rituals and raising questions about the practical aspects of Egyptian funerary practice.

To the ancient Egyptians, black symbolized the underworld and Osiris (often shown with black skin) and also night, especially when used in contrast with yellow and gold (for the sun) and the rich black soil of fertility and regeneration (1–3). The practice of using black coatings on Egyptian coffins is first attested in the Middle Kingdom (e.g., the cartonnage cases of Nepthys and Hapiankhtifi, Metropolitan Museum of Art 11.150.15 and 12.183.11c.1-0.2) and occurs in the New Kingdom, when black coatings are also used on funerary objects such as divine figures, shabtis, and shabti boxes (3–5). A secondary application of a black anointing liquid in a funerary context is known from at least as early as the burial of Tjuyu (18th Dynasty, c. 1375 BC), whose gilded funerary mask was anointed with black fluid (6).The application of black substances as coatings and anointing liquids on coffins and mummy cases also occurs in the Third Intermediate Period c. 1086 to 664 BC. This period in Egypt was a time of decentralized rule. In its first phase (21st Dynasty c. 1086 to 943 BC), kings based in the eastern Delta ruled the northern part of Egypt, sharing power with a line of generals, who also acted as high priests of Amun at Thebes, and controlled the southern stretch of the Nile valley. A return to centralized administration in the early 22nd Dynasty (c. 943 to 716 BC) was followed by a gradual fragmentation of the country into smaller political units, some of which were ruled by individuals claiming kingly status, while others were controlled by rulers of Libyan chiefdoms (7), thus Dynasties 22 to 24 and the early 25th Dynasty overlap. The end of the Bronze Age had seen catastrophic events across the eastern Mediterranean, with the Mycenaean and Hittite states collapsing (8, 9). Egypt itself saw incursions and lost control of land in Syria Palestine. Evidence from Egypt and the Levant during this time suggests fluctuating levels of contact and influence (10).During this period, burial practices were changing; instead of a decorated tomb and a wide array of tomb goods, the focus turned toward the body and the coffin (11, 12). The elite continued to lavish expenditure on their burials, but due to high levels of tomb raiding and tomb and coffin appropriation, emphasis was no longer placed on the funerary goods placed in the tomb, as was common in the New Kingdom (13). Instead, the expenditure was concentrated on the body and the coffin, which could be moved to a more secure location if necessary. The 21st Dynasty saw developments in mummification that indicate an increase in the resources allocated for those procedures (14). In the 22nd Dynasty, further changes in the treatment of the body were introduced, most notably the introduction of the cartonnage case, into which the mummy was tightly laced (3). Cartonnage is made with layers of linen, plaster, and glue, similar to papier maché, which can be molded to shape and which dries to make a hard case. These cases were valuable in terms of a vehicle for display as they could be highly decorated and gilded (14), and cartonnage is much more difficult to repurpose than other funerary goods because the body of the deceased is sewn inside. Concentrating resources into the preparation of the body, mummy case, and coffin allowed the elite to display their wealth and power while at the same time securing their investment.Black substances painted on the inside and/or outside of coffins and other funerary items or poured over cartonnage as part of the funerary ritual are a material source of evidence for examining the resourcing of funerary activities during this time of political upheaval. A research project on the 22nd-Dynasty coffins, cartonnage mummy cases, shabti boxes, and Osiris figures in the collection of the British Museum offered the opportunity to address this subject. Using analytical chemistry to examine the complex molecular composition of the black ritual substances, the study aimed to identify the materials used and their likely sources. Determination of chemical composition also offered a means to investigate how the materials were processed and applied as well as patterns of use within the funerary context.Previous research on similar materials has been limited and varied in terms of analytical techniques, covering multiple time periods and considering ritual applications alongside mummification balms (15, 16) or considering a small subset of samples (5, 17–19).^* By focusing on burial goods of the 22nd Dynasty, this research is a more targeted examination of funerary ritual residues than has been previously undertaken.     

Adult bone marrow-derived stem cells use R-cadherin to target sites of neovascularization in the developing retina.

Adult bone marrow contains a population of hematopoietic stem cells (HSCs) that can give rise to cells capable of targeting sites of neovascularization in the peripheral or retinal vasculature. However, relatively little is known about the mechanism of targeting of these cells to sites of neovascularization. We have analyzed subpopulations of HSCs for the expression of a variety of cell surface adhesion molecules and found that R-cadherin, a calcium-dependent cell-cell adhesion molecule important for normal retinal endothelial cell guidance, was preferentially expressed by functionally targeting HSCs. Preincubation of HSCs with function-blocking anti-R-cadherin antibodies or novel R-cadherin-specific peptide antagonists effectively prevented targeting of bone marrow-derived cells to the developing retinal vasculature in vivo. Whereas control-injected HSCs targeted to all 3 normal developing retinal vascular layers, blocking R-cadherin-mediated adhesion resulted in mistargeting of the HSCs to the normally avascular outer retina. Our results suggest that vascular targeting of bone marrow-derived HSCs is dependent on mechanisms similar to those used by endogenous retinal vascular endothelial cells. Thus, R-cadherin antagonists may be useful in the treatment of neovascular diseases in which circulating HSCs contribute to abnormal angiogenesis.     

A videotape-based training method for improving the detection of depression in residents of long-term care facilities

PURPOSE: This article reviews the effectiveness of a new training program for improving nursing staffs' detection of depression within long-term care facilities. The course was designed to increase recognition of the Minimal Data Set (MDS) Mood Trigger items, to be brief, and to rely on images rather than didactics. DESIGN AND METHODS: This study used a delayed intervention design. Twenty nurses from two facilities participated in all four sessions of the study. RESULTS: Staff exposed to the intervention (Site 1) improved significantly in their ability to detect mood symptoms in videotaped patients after completing the training course compared with those exposed to the delayed intervention (Site 2). Improvement in detection skills at Site 2 following the training confirmed the intervention's utility. The improvement was demonstrated across levels of staff (licensed and unlicensed). Maintenance of skills was demonstrated at the 4-month follow-up. IMPLICATIONS: Staff successfully improved knowledge and skill of MDS mood triggers. This method may lend itself to other MDS domains.     

Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.     

Restoration of Serotonin Neuronal Firing Following Long-Term Administration of Bupropion but Not Paroxetine in Olfactory Bulbectomized Rats

Background:

Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine.

Methods:

Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats.

Results:

Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin_1A receptors; paroxetine (10mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin_1A receptors.

Conclusions:

The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin_1A receptors in hippocampus.     

From the Cover: Bumblebees perceive the spatial layout of their environment in relation to their body size and form to minimize inflight collisions

Animals that move through complex habitats must frequently contend with obstacles in their path. Humans and other highly cognitive vertebrates avoid collisions by perceiving the relationship between the layout of their surroundings and the properties of their own body profile and action capacity. It is unknown whether insects, which have much smaller brains, possess such abilities. We used bumblebees, which vary widely in body size and regularly forage in dense vegetation, to investigate whether flying insects consider their own size when interacting with their surroundings. Bumblebees trained to fly in a tunnel were sporadically presented with an obstructing wall containing a gap that varied in width. Bees successfully flew through narrow gaps, even those that were much smaller than their wingspans, by first performing lateral scanning (side-to-side flights) to visually assess the aperture. Bees then reoriented their in-flight posture (i.e., yaw or heading angle) while passing through, minimizing their projected frontal width and mitigating collisions; in extreme cases, bees flew entirely sideways through the gap. Both the time that bees spent scanning during their approach and the extent to which they reoriented themselves to pass through the gap were determined not by the absolute size of the gap, but by the size of the gap relative to each bee’s own wingspan. Our findings suggest that, similar to humans and other vertebrates, flying bumblebees perceive the affordance of their surroundings relative their body size and form to navigate safely through complex environments.

Avoiding collisions with obstacles is a requirement for successful locomotion through most natural habitats, where the physical environment is often cluttered and complex. At the most elemental level, animals moving through their environments need to identify gaps between obstacles and assess their passability. In this context, whether a gap between obstacles “affords” passing is determined by the fit between the spatial layout of the environment and the properties of the organism’s form and action system, as described in classical theses on affordances (1–3). In humans and other highly cognitive vertebrates, the perception of affordances for performing visually guided actions such as grasping, passing through apertures, and climbing is actively shaped throughout ontogeny, as body size, configuration, and experience change (2, 4–7). However, the strategies used by animals with much smaller brains, such as insects, to contend with the challenges of navigating environmental clutter and spatial heterogeneity are unclear.We used bumblebees to investigate whether flying insects take into account their own size during interactions with their surroundings. Bumblebees and other volant insects that travel long distances (8) and frequently encounter regions of dense clutter can be expected to exhibit strategies to avoid collisions, because damage to sensitive structures such as the wings is irreparable and adversely impacts flight performance and lifespan (9, 10). For an animal attempting to navigate through tight spaces, perceiving the relationship between the layout of the environment and its own size can help inform the animal of its potential for collision-free passage. Bumblebee workers naturally display large variation in body size within a given colony (11, 12), and thus are particularly suitable models for testing the effects of insect body size on aerial navigation and for determining whether insects perceive the external environment in relation to their own spatial dimensions.To elicit repeatable flight behavior, we trained foraging bumblebees to fly within a 1.6 × 0.3 × 0.3 m (l × w × h) flight tunnel that separated the hive from a foraging arena (Materials and Methods, SI Appendix, Fig. S1, and Movie S1). After bees were habituated to the setup and began foraging normally, we placed an unexpected obstacle within the tunnel, consisting of a thin vertical wall (5-mm thickness) spanning the tunnel’s width and height. The obstructing wall contained a rectangular gap starting midway up and extending to the top of the wall (Materials and Methods, SI Appendix, Fig. S1, and Movie S1). The width of the gap was varied between 20 and 60 mm over different trials, with the presenting order of gap sizes chosen randomly. A high-speed camera placed above the tunnel was used to record bees’ instantaneous positions, heading/yaw orientations (Fig. 1A), and trajectories as they approached the obstructing wall and passed through the gap. To prevent bees from becoming familiar with the experimental paradigm, the obstructing wall was removed after each flight recording. In total, we recorded and analyzed over 400 flights of bees of varying body sizes flying through seven different gap sizes (SI Appendix, Table S1). For the population of bees recorded, wingspan was the longest dimension of the body and it varied linearly by a factor of 1.9 compared to their longitudinal body length while in flight (SI Appendix, Fig. S2A).Open in a separate windowFig. 1.Bumblebees can safely fly through gaps that are smaller than their wingspan. (A and B) Illustrations indicating the wingspan of bees (Ws), the size of the gap (Gs), and the positive and negative yaw (heading) angles for bees flying in the tunnel, respectively. (C) Schematic illustration of the flight of a bee flying through a gap that is much wider than its wingspan. (D) The instantaneous yaw angle of bee shown in C. (E) Schematic illustrationof the flightofabeeflying through a gap that is smaller than its wingspan. (F) The instantaneous yaw angle of bee shown in E. Flights, in both cases (C and E), consisted of approach, lateral peering, and—for the smaller gap size (E)—body reorientation (an increase in yaw angle) while passing through the gap. The differences in reorientation behavior can be noted at x = 0 (location of the gap), whereas in F the bee displays a large increase in yaw angle that reorients its body to pass through the small gap, and body reorientation in D is minimal. For the flight shown in C and D, Ws = 27.5 mm and Gs = 50 mm, while for the flight shown in E and F, Ws = 27 mm and Gs = 25 mm.