Symptoms and Treatment Needs of People with Dementia-Related Psychosis: A Mixed-Methods Study of the Patient Experience.

OBJECTIVES: This study describes the person-centered experience and impact of symptoms and the treatment needs of dementia-related psychosis (DRP) from a patient and care partner perspective. METHODS: Qualitative interviews and a quantitative survey were used to collect patient experience data from persons with DRP or their care partners. RESULTS: Sixteen participants (1 person with DRP, 15 care partners) completed the qualitative interview; 212 participants (26 persons with DRP, 186 care partners) completed the quantitative survey. The most commonly reported symptoms were visual hallucinations, auditory hallucinations, persecutory delusions, and distortion of senses. The most common impacts were difficulty differentiating what is real from what is not real, increased anxiety, and effects on personal relationships. Current treatments were less than moderately helpful, and the ability to distinguish what is real from what is not real and overall symptom improvement were described as the most important benefits of an ideal treatment. CONCLUSIONS: Patient experience data provide insights into urgent therapeutic needs of patients by describing the nature, frequency, and severity of symptoms and the impacts they have on individuals' lives. CLINICAL IMPLICATIONS: Patient experience data demonstrate an unmet need for treatments to reduce the symptoms and impacts of DRP.

Contrasting responses of functional diversity to major losses in taxonomic diversity.

Taxonomic diversity of benthic marine invertebrate shelf species declines at present by nearly an order of magnitude from the tropics to the poles in each hemisphere along the latitudinal diversity gradient (LDG), most steeply along the western Pacific where shallow-sea diversity is at its tropical maximum. In the Bivalvia, a model system for macroevolution and macroecology, this taxonomic trend is accompanied by a decline in the number of functional groups and an increase in the evenness of taxa distributed among those groups, with maximum functional evenness (FE) in polar waters of both hemispheres. In contrast, analyses of this model system across the two era-defining events of the Phanerozoic, the Permian-Triassic and Cretaceous-Paleogene mass extinctions, show only minor declines in functional richness despite high extinction intensities, resulting in a rise in FE owing to the persistence of functional groups. We hypothesize that the spatial decline of taxonomic diversity and increase in FE along the present-day LDG primarily reflect diversity-dependent factors, whereas retention of almost all functional groups through the two mass extinctions suggests the operation of diversity-independent factors. Comparative analyses of different aspects of biodiversity thus reveal strongly contrasting biological consequences of similarly severe declines in taxonomic diversity and can help predict the consequences for functional diversity among different drivers of past, present, and future biodiversity loss.

Convergence, divergence, and parallelism in marine biodiversity trends: Integrating present-day and fossil data.

Paleontological data provide essential insights into the processes shaping the spatial distribution of present-day biodiversity. Here, we combine biogeographic data with the fossil record to investigate the roles of parallelism (similar diversities reached via changes from similar starting points), convergence (similar diversities reached from different starting points), and divergence in shaping the present-day latitudinal diversity gradients of marine bivalves along the two North American coasts. Although both faunas show the expected overall poleward decline in species richness, the trends differ between the coasts, and the discrepancies are not explained simply by present-day temperature differences. Instead, the fossil record indicates that both coasts have declined in overall diversity over the past 3 My, but the western Atlantic fauna suffered more severe Pliocene-Pleistocene extinction than did the eastern Pacific. Tropical western Atlantic diversity remains lower than the eastern Pacific, but warm temperate western Atlantic diversity recovered to exceed that of the temperate eastern Pacific, either through immigration or in situ origination. At the clade level, bivalve families shared by the two coasts followed a variety of paths toward today's diversities. The drivers of these lineage-level differences remain unclear, but species with broad geographic ranges during the Pliocene were more likely than geographically restricted species to persist in the temperate zone, suggesting that past differences in geographic range sizes among clades may underlie between-coast contrasts. More detailed comparative work on regional extinction intensities and selectivities, and subsequent recoveries (by in situ speciation or immigration), is needed to better understand present-day diversity patterns and model future changes.

Shaping the Latitudinal Diversity Gradient: New Perspectives from a Synthesis of Paleobiology and Biogeography.

An impediment to understanding the origin and dynamics of the latitudinal diversity gradient (LDG)-the most pervasive large-scale biotic pattern on Earth-has been the tendency to focus narrowly on a single causal factor when a more synthetic, integrative approach is needed. Using marine bivalves as a model system and drawing on other systems where possible, we review paleobiologic and biogeographic support for two supposedly opposing views, that the LDG is shaped primarily by (a) local environmental factors that determine the number of species and higher taxa at a given latitude (in situ hypotheses) or (b) the entry of lineages arising elsewhere into a focal region (spatial dynamics hypotheses). Support for in situ hypotheses includes the fit of present-day diversity trends in many clades to such environmental factors as temperature and the correlation of extinction intensities in Pliocene bivalve faunas with net regional temperature changes. Support for spatial dynamics hypotheses includes the age-frequency distribution of bivalve genera across latitudes, which is consistent with an out-of-the-tropics dynamic, as are the higher species diversities in temperate southeastern Australia and southeastern Japan than in the tropical Caribbean. Thus, both in situ and spatial dynamics processes must shape the bivalve LDG and are likely to operate in other groups as well. The relative strengths of the two processes may differ among groups showing similar LDGs, but dissecting their effects will require improved methods of integrating fossil data with molecular phylogenies. We highlight several potential research directions and argue that many of the most dramatic biotic patterns, past and present, are likely to have been generated by diverse, mutually reinforcing drivers.

Superior mesenteric artery outcomes after fenestrated endovascular aortic aneurysm repair.

OBJECTIVE: The Zenith (Cook Medical, Bloomington, Ind) fenestrated endovascular graft may be designed with single-wide scallops or large fenestrations to address the superior mesenteric artery (SMA). Misalignment of the SMA with an unstented scallop or a large fenestration is possible. This study assessed SMA outcomes after fenestrated endovascular aortic aneurysm repair (FEVAR). METHODS: During an 18-month period, 47 FEVARs were performed at a single institution. For analysis, patients were grouped according to unstented (n = 23) vs stented (n = 24) SMA scallops/fenestrations. The Institutional Review Board approved this single-institution observational study. Because this was a retrospective review of the data, patient consent was unnecessary for the study. RESULTS: Technical success for FEVAR was 100%. The median follow-up period was 7.7 months (range, 1-16 months). Nine of 21 patients (43%) in the unstented group had some degree of misalignment of the SMA (range, 9%-71%). Among these, four patients (44%) developed complications: three SMA stenoses and one occlusion. The mean peak systolic velocity in patients with and without SMA misalignment was 317.8 cm/s vs 188.4 cm/s (P < .08), respectively. No misalignment occurred in the stented group, and only one of 19 patients (5%) developed an SMA stenosis that required angioplasty. Overall, patients with unstented SMAs had significantly more adverse events directly attributable to SMA misalignment than the stented group (44% vs 5%, respectively; P < .05). CONCLUSIONS: Misalignment of the SMA with the use of unstented unreinforced scallops or fenestrations occurs frequently. Routine stenting of single-wide and large fenestrations, when feasible, may be a safer option for patients undergoing FEVAR.

Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors.

The central role of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter with important cognitive and behavioral functions is well known. However, 5-HT produced in the brain only accounts for approximately 5% of the total amount of 5-HT generated in the body. At the onset of our work, it appeared that substituted phenylalanine derivatives or related aryl amino acids were required to produce potent inhibitors of TPH1, as significant losses of inhibitory activity were noted in the absence of this structural element. We disclose herein the discovery of a new class of TPH1 inhibitors that significantly lower peripherally 5-HT.

Out of the tropics, but how? Fossils, bridge species, and thermal ranges in the dynamics of the marine latitudinal diversity gradient.

Latitudinal diversity gradients are underlain by complex combinations of origination, extinction, and shifts in geographic distribution and therefore are best analyzed by integrating paleontological and neontological data. The fossil record of marine bivalves shows, in three successive late Cenozoic time slices, that most clades (operationally here, genera) tend to originate in the tropics and then expand out of the tropics (OTT) to higher latitudes while retaining their tropical presence. This OTT pattern is robust both to assumptions on the preservation potential of taxa and to taxonomic revisions of extant and fossil species. Range expansion of clades may occur via "bridge species," which violate climate-niche conservatism to bridge the tropical-temperate boundary in most OTT genera. Substantial time lags (∼5 Myr) between the origins of tropical clades and their entry into the temperate zone suggest that OTT events are rare on a per-clade basis. Clades with higher diversification rates within the tropics are the most likely to expand OTT and the most likely to produce multiple bridge species, suggesting that high speciation rates promote the OTT dynamic. Although expansion of thermal tolerances is key to the OTT dynamic, most latitudinally widespread species instead achieve their broad ranges by tracking widespread, spatially-uniform temperatures within the tropics (yielding, via the nonlinear relation between temperature and latitude, a pattern opposite to Rapoport's rule). This decoupling of range size and temperature tolerance may also explain the differing roles of species and clade ranges in buffering species from background and mass extinctions.

Discovery of spirocyclic-diamine inhibitors of mammalian acetyl CoA-carboxylase.

A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 µM.

Global environmental predictors of benthic marine biogeographic structure.

Analyses of how environmental factors influence the biogeographic structure of biotas are essential for understanding the processes underlying global diversity patterns and for predicting large-scale biotic responses to global change. Here we show that the large-scale geographic structure of shallow-marine benthic faunas, defined by existing biogeographic schemes, can be predicted with 89-100% accuracy by a few readily available oceanographic variables; temperature alone can predict 53-99% of the present-day structure along coastlines. The same set of variables is also strongly correlated with spatial changes in species compositions of bivalves, a major component of the benthic marine biota, at the 1° grid-cell resolution. These analyses demonstrate the central role of coastal oceanography in structuring benthic marine biogeography and suggest that a few environmental variables may be sufficient to model the response of marine biogeographic structure to past and future changes in climate.

Discovery and synthesis of novel 4-aminopyrrolopyrimidine Tie-2 kinase inhibitors for the treatment of solid tumors.

The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.

Ontogenetic Changes in Nutrients and Stoichiometry in the Invasive Mosquito, Aedes albopictus (Diptera: Culicidae).

A variety of physiological, morphological, and behavioral changes occur throughout the life cycle of mosquitoes, which can be correlated with a shift from the aquatic to terrestrial environment. Aedes albopictus Skuse is an abundant invasive species from Asia that was introduced into the Americas in the 1980's and is responsible for transmitting several important human disease-causing pathogens. How physiological and anatomical changes within each instar and throughout the developmental stages are related to changes in carbon (C) and nitrogen (N) levels are an unexplored area of mosquito ecology. We hypothesized that these changes as well as stoichiometry (C:N) would vary with instar stage and larval diet. Cohorts of larvae were grown in three different diets: animal only (crickets), plant only (red maple leaves), and a mixture containing both types. Larval instars (1st-4th), pupae, and adults were raised in each diet and were separately analyzed for nutrient content (%C, %N) and stoichiometry (C:N). Significant changes in nutrient values occurred across the life cycle, with C:N values being lower in early instars versus adults or pupae, especially in animal only or mixed diets; few differences were detected in %C or %N across ontogeny. This knowledge may lead to a better understanding of mosquito ecology and pathogen transmission.

Toward patient-centered treatment goals for duchenne muscular dystrophy: insights from the "Your Voice" study.

BACKGROUND: Patient-centered research has emerged as critically important for understanding the impact of treatments on key stakeholders. The subjective experience of quality of life (QOL) is increasingly recognized as fundamental to delineating treatment goals. The present study utilized content analysis of qualitative data and quantitative analysis to highlight important domains of disease burden and underlying reasons for their importance, and to characterize goals for new treatments for Duchenne Muscular Dystrophy (DMD). RESULTS: The study sample reflected the perspectives of DMD patients and caregivers representing ambulatory, transitional, and non-ambulatory stages of disability progression (n = 20 per category). Open-ended interviews were content-analyzed and non-parametric statistical tests were used to compare ambulation groups. As patients progressed in disability, the noted DMD burdens reflected some differences in functional areas. While daily functioning and sports/recreation remained the most important priority areas across ambulation groups, "health" became less prominent as the disability progressed from ambulatory to transitional to non-ambulatory phases of disability; whereas relationships became more prominent as one progressed to the non-ambulatory phase from the ambulatory or transitional phases (Kruskall Wallis H = 12.24 and 5.28, p = 0.002 and 0.02, respectively). When asked why their burdens were important to them and how it impacted their or their child's life, self-esteem/confidence was most important for ambulatory patients, and became less prominent for patients in the transitional and non-ambulatory phases of disability (Kruskall Wallis H = 9.46, p = 0.009). In contrast, independence was less important for ambulatory patients, and became increasing prominent for patients in the transitional and non-ambulatory phases of disability (Kruskall Wallis H = 7.35, p = 0.025). Emotional functioning was most prominent for all ambulation groups on their best and worst days. Goals for new DMD treatments focused on functional goals, general QOL goals, and concerns about safety, ease of use, and effectiveness. CONCLUSION: This study provides useful information about treatment goals for DMD from the perspective of patients and their caregivers. It highlights some consistent values across the disability trajectory, as well as introducing an evolution of priorities as the person with DMD becomes more disabled. Results provide a roadmap for patient-centered DMD drug development.

Evaluation of a Pharmacy-Driven Calcitonin Protocol for Treating Hypercalcemia in Hospitalized Patients: A Multisite Study.

BACKGROUND: The dramatic increase in the acquisition cost of injectable calcitonin led to creating a pharmacy-driven calcitonin protocol to improve the appropriate use of calcitonin and other treatment modalities for hypercalcemia. OBJECTIVE: This study aimed to characterize the use of calcitonin before and after implementation of a pharmacy-driven calcitonin protocol. METHODS: This was a multi-center, retrospective study of the use of injectable calcitonin in adult hospitalized patients with hypercalcemia. The study included patients treated with calcitonin from October 2014 to September 2016 and from October 2017 to September 2019. The primary outcomes were percentage of patients with a complete response, partial response, and non-responders. The secondary outcomes were time to relapse, duration of partial response, number of doses, and associated costs of calcitonin. RESULTS: Of the 131 patients included in this study, 93 were included in a pre-protocol group and 38 were included in a post-protocol group. The primary outcome of complete response by 3 days was met in 28% of patients in the pre-protocol group and 53% of patients in the post-protocol group (P = 0.007). Calcitonin spending in dollars in the pre-protocol group was $818,956 compared to $224,320 in the post-protocol group; a difference of $594,636. CONCLUSION: Implementation of a pharmacy-driven calcitonin protocol effectively improved calcium levels, reduced inappropriate calcitonin use, and reduced calcitonin spending during a period of 2 fiscal years.

Comparison of surgical operative experience of trainees and practicing vascular surgeons: a report from the Vascular Surgery Board of the American Board of Surgery.

INTRODUCTION: The Vascular Surgery Board (VSB) of the American Board of Surgery sought to answer the following questions: what is the scope of contemporary vascular surgery practice? Do current vascular surgery residents obtain training that is appropriate for their future career expectations and for successful Board certification? How effectively do practicing vascular surgeons incorporate emerging technologies and procedures into practice? METHODS: We analyzed the operative logs submitted to the VSB by recent vascular surgery residents applying for the Vascular Surgery Qualifying Examination (QE; 2006-2009) or by practicing vascular surgeons applying for the Vascular Surgery Recertification Examination (RE; 1995-2009). The relationship between reported operative experience and performance of the QE and RE was examined. RESULTS: There has been a threefold increase in the mean number of primary cases reported by both RE and QE applicants over the past 15 years and the increase in case volume has been driven largely by an increase in the number of endovascular procedures. Endovascular procedures have been broadly incorporated into the practice of most vascular surgeons applying for recertification. The number of major open surgical cases reported by recent QE applicants has remained unchanged over the period of observation. For QE applicants, the number of endovascular aneurysm repairs (EVARs) has reached a plateau at approximately 50 cases, whereas the mean number of open infrarenal aneurysm repairs has decreased for both QE and RE applicants, reflecting national trends favoring EVAR. There was a significant association between case volume and performance on the QE but not on the RE. CONCLUSION: Over the past 15 years, there has been a significant increase in the total number of operative cases reported to the VSB by both QE and RE applicants. Contrary to popular belief, the volume of major open vascular surgery reported by recent vascular surgery residents has remained relatively stable since 1994. Over the same time period, endovascular procedures have been rapidly incorporated into clinical practice by the majority of vascular surgeons applying for recertification by the VSB. Current vascular surgery residents receive a rich operative experience in both open and endovascular procedures that is reflective of contemporary practice.

Genus age, provincial area and the taxonomic structure of marine faunas.

Species are unevenly distributed among genera within clades and regions, with most genera species-poor and few species-rich. At regional scales, this structure to taxonomic diversity is generated via speciation, extinction and geographical range dynamics. Here, we use a global database of extant marine bivalves to characterize the taxonomic structure of climate zones and provinces. Our analyses reveal a general, Zipf-Mandelbrot form to the distribution of species among genera, with faunas from similar climate zones exhibiting similar taxonomic structure. Provinces that contain older taxa and/or encompass larger areas are expected to be more species-rich. Although both median genus age and provincial area correlate with measures of taxonomic structure, these relationships are interdependent, nonlinear and driven primarily by contrasts between tropical and extra-tropical faunas. Provincial area and taxonomic structure are largely decoupled within climate zones. Counter to the expectation that genus age and species richness should positively covary, diverse and highly structured provincial faunas are dominated by young genera. The marked differences between tropical and temperate faunas suggest strong spatial variation in evolutionary rates and invasion frequencies. Such variation contradicts biogeographic models that scale taxonomic diversity to geographical area.

Escherichia coli expression, purification and characterization of functional full-length recombinant alpha2beta2gamma3 heterotrimeric complex of human AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) is an energy-sensing serine/threonine protein kinase that plays a central role in whole-body energy homeostasis. AMPK is a heterotrimeric enzyme with a catalytic (alpha) subunit and two regulatory (beta and gamma) subunits. The muscle-specific AMPK heterotrimeric complex (alpha2beta2gamma3) is involved in glucose and fat metabolism in skeletal muscle and therefore has emerged as an attractive target for drug development for diabetes and metabolic syndrome. To date, expression of recombinant full-length human AMPK alpha2beta2gamma3 has not been reported. Here we describe the expression, purification and biochemical characterization of functional full-length AMPK alpha2beta2gamma3 heterotrimeric complex using an Escherichia coli expression system. All three subunits of AMPK alpha2beta2gamma3 were transcribed as a single tricistronic transcript driven by the T7 RNA polymerase promoter, allowing spontaneous formation of the heterotrimeric complex in the bacterial cytosol. The self-assembled trimeric complex was purified from the cell lysate by nickel-ion chromatography using the hexahistidine tag fused exclusively at the N-terminus of the alpha 2 domain. The un-assembled beta 2 and gamma 3 domains were removed by extensive washing of the column. Further purification of the heterotrimer was performed using size exclusion chromatography. The final yield of the recombinant AMPK alpha2beta2gamma3 complex was 1.1mg/L culture in shaker flasks. The E. coli expressed enzyme was catalytically inactive after purification, but was activated in vitro by upstream kinases such as CaMKKbeta and LKB1. The kinase activity of activated AMPK alpha2beta2gamma3 complex was significantly enhanced by AMP (an allosteric activator) but not by thienopyridone A-769662, a known small molecule activator of AMPK. Mass spectrometric characterization of recombinant AMPK alpha2beta2gamma3 showed significant heterogeneity before and after activation that could potentially hamper crystallographic studies of this complex.

An octahydro-cyclopenta[c]pyrrole series of inhibitors of the type 1 glycine transporter.

We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.

Contrarian clade confirms the ubiquity of spatial origination patterns in the production of latitudinal diversity gradients.

The latitudinal diversity gradient (LDG), wherein the number of species and higher taxa peaks in the tropics and decreases toward the poles, is the best-documented large-scale diversity pattern on Earth, but hypotheses explaining the standard LDG must also account for rare "contrarian" taxa that show diversity maxima outside of the tropics. For marine bivalves, one of the few groups that provide spatially explicit temporal data on a global scale, we show that a major contrarian group, the Anomalodesmata, unexpectedly exhibits the same large-scale dynamics as related clades having normal LDGs in two key respects. First, maxima in standing genus diversity and genus origination rates coincide spatially. Second, the strength of a clade's present-day LDG is significantly related to the proportion of its living genera that originated in the tropics during the late Cenozoic, with the contrarian gradient strength at both species and genus level predicted quantitatively by the values for the other clades. Geologic age distributions indicate that the anomalous LDG results from origination that is damped in the tropics rather than heightened in the temperate zones. The pervasive role of spatial origination patterns in shaping LDGs, regardless of the position of their diversity maxima, corroborates hypotheses based on clades showing standard gradients and underscores the insights that contrarian groups can provide into general principles of diversity dynamics.

Therapies for rare diseases: therapeutic modalities, progress and challenges ahead.

Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.