Synthetically derived BiAux modulates auxin co-receptor activity to stimulate lateral root formation.

The root system plays an essential role in plant growth and adaptation to the surrounding environment. The root clock periodically specifies lateral root prebranch sites (PBS), where a group of pericycle founder cells (FC) is primed to become lateral root founder cells and eventually give rise to lateral root primordia or lateral roots (LRs). This clock-driven organ formation process is tightly controlled by modulation of auxin content and signaling. Auxin perception entails the physical interaction of TRANSPORT INHIBITOR RESPONSE 1 (TIR1) or AUXIN SIGNALING F-BOX (AFBs) proteins with AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) repressors to form a co-receptor system. Despite the apparent simplicity, the understanding of how specific auxin co-receptors are assembled remains unclear. We identified the compound bis-methyl auxin conjugated with N-glucoside, or BiAux, in Arabidopsis (Arabidopsis thaliana) that specifically induces the formation of PBS and the emergence of LR, with a slight effect on root elongation. Docking analyses indicated that BiAux binds to F-box proteins, and we showed that BiAux function depends on TIR1 and AFB2 F-box proteins and AUXIN RESPONSE FACTOR 7 activity, which is involved in FC specification and LR formation. Finally, using a yeast (Saccharomyces cerevisiae) heterologous expression system, we showed that BiAux favors the assemblage of specific co-receptors subunits involved in LR formation and enhances AUXIN/INDOLE-3-ACETIC ACID 28 protein degradation. These results indicate that BiAux acts as an allosteric modulator of specific auxin co-receptors. Therefore, BiAux exerts a fine-tune regulation of auxin signaling aimed to the specific formation of LR among the many development processes regulated by auxin.

PTSD moderates the association between subjective cognitive decline and Alzheimer's disease biomarkers in older veterans.

OBJECTIVES: Post-traumatic stress disorder (PTSD) and subjective cognitive decline (SCD) are independent risk factors for Alzheimer's disease (AD) and dementia, but the association of their interaction on AD biomarkers have yet to be characterized. This study aimed to examine the impact of PTSD on the association between SCD and tau and amyloid positron emission tomography (PET) as well as global cognition in older Veterans. METHOD: This study included 87 Vietnam-Era Veterans without dementia (42 with PTSD; 45 without PTSD) from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative. All participants had both tau and amyloid PET imaging as well as cognitive testing. SCD was measured using the Everyday Cognition questionnaire. RESULTS: While SCD was associated with tau PET, amyloid PET, and global cognition, PTSD moderated these associations for tau and amyloid PET levels. Specifically, Veterans without PTSD had a stronger positive relationship between SCD and AD biomarkers when compared to those with PTSD. CONCLUSION: Higher SCD was associated with greater tau and amyloid burden and worse cognitive performance across the sample, though the tau and amyloid associations were stronger for Veterans without PTSD. Results highlight the potential benefit of comprehensive clinical assessments including consideration of mental health among older Veterans with SCD to understand the underlying cause of the cognitive concerns. Additionally, more work is needed to understand alternative mechanisms driving SCD in older Veterans with PTSD.

Short-term stress responses and recovery of giant kelp (Macrocystis pyrifera, Laminariales, Phaeophyceae) juvenile sporophytes to a simulated marine heatwave and nitrate scarcity1.

The frequency of marine heatwaves (MHWs) is increasing due to climate change. Although seaweeds are resilient to environmental changes, an increasing body of evidence shows that rising sea surface temperatures have deleterious effects on temperate kelp species. However, information on the vulnerability of juvenile kelp to these stressors and their population stability is limited. This study summarizes findings on the ability of juvenile sporophytes of Macrocystis pyrifera to survive and recover from simulated MHW conditions (22°C, 5 d) in combination with nitrate limitation (<1 µM) by evaluating photosynthetic capacity, nitrate uptake, tissue composition, bio-optical properties, and oxidative stress of single-blade juvenile sporophytes (<20 cm). Temperature, nitrate availability, and their interaction had significant effects on the physiological status of juvenile sporophytes after the exposure and recovery periods. Overall, as expected, the photosynthetic capacity of juvenile sporophytes decreased with increased temperature and lower nitrate availability. Short-term exposure to simulated MHWs resulted in oxidative damage and reduced growth. The termination of the experimental warming allowed partial recovery to control values, indicating high physiological resilience. However, the interaction of both high temperature and nitrate scarcity induced irreversible damage to their photosynthetic capacity, with an increase in compensation irradiance, highlighting potential limitations in the carbon balance of juvenile sporophytes.

Comparison of the Quantra QPlus System With Thromboelastography in Cardiac Surgery.

OBJECTIVES: Use of viscoelastic testing, such as thromboelastography (TEG), is recommended in cardiac surgery to monitor coagulation and to guide the transfusion of blood products. The Quantra QPlus System is a novel point-of-care platform that uses ultrasonic pulses to characterize dynamic changes in viscoelastic properties of a blood sample during coagulation. Despite the ability to assess similar aspects of clot formation, limited studies addressing the interchangeability of viscoelastic testing parameters exist. The primary aim of the present study was to assess the correlation and agreement between Quantra and TEG5000 results using blood samples from cardiac surgery patients. DESIGN: Tertiary care, academic medical center. SETTING: Prospective observational study. PARTICIPANTS: Twenty-eight patients undergoing elective cardiac surgery undergoing cardiopulmonary bypass were evaluated. MEASUREMENTS AND MAIN RESULTS: Perioperative blood samples were collected and assessed using Quantra, and results were compared with TEG and conventional coagulation testing. Method comparison analysis demonstrated that Quantra parameters (Quantra clot time, clot stiffness, and fibrinogen contribution to clot stiffness) significantly correlated with TEG R and TEG G after induction of anesthesia, during cardiopulmonary bypass, and after rewarming (rs = 0.83, rs = 0.84, and rs = 0.73, respectively). However, Quantra parameters demonstrated poor agreement compared with equivalent TEG5000 parameters. CONCLUSIONS: The Quantra QPlus System significantly correlated with TEG5000, suggesting that this test may be used in a similar clinical context. Despite the strength of correlation between Quantra and TEG parameters, measurements are not interchangeable.

PYL8 mediates ABA perception in the root through non-cell-autonomous and ligand-stabilization-based mechanisms.

The phytohormone abscisic acid (ABA) plays a key role regulating root growth, root system architecture, and root adaptive responses, such as hydrotropism. The molecular and cellular mechanisms that regulate the action of core ABA signaling components in roots are not fully understood. ABA is perceived through receptors from the PYR/PYL/RCAR family and PP2C coreceptors. PYL8/RCAR3 plays a nonredundant role in regulating primary and lateral root growth. Here we demonstrate that ABA specifically stabilizes PYL8 compared with other ABA receptors and induces accumulation of PYL8 in root nuclei. This requires ABA perception by PYL8 and leads to diminished ubiquitination of PYL8 in roots. The ABA agonist quinabactin, which promotes root ABA signaling through dimeric receptors, fails to stabilize the monomeric receptor PYL8. Moreover, a PYL8 mutant unable to bind ABA and inhibit PP2C is not stabilized by the ligand, whereas a PYL85KR mutant is more stable than PYL8 at endogenous ABA concentrations. The PYL8 transcript was detected in the epidermis and stele of the root meristem; however, the PYL8 protein was also detected in adjacent tissues. Expression of PYL8 driven by tissue-specific promoters revealed movement to adjacent tissues. Hence both inter- and intracellular trafficking of PYL8 appears to occur in the root apical meristem. Our findings reveal a non-cell-autonomous mechanism for hormone receptors and help explain the nonredundant role of PYL8-mediated root ABA signaling.

The polyadenylation factor FIP1 is important for plant development and root responses to abiotic stresses.

Root development and its response to environmental changes is crucial for whole plant adaptation. These responses include changes in transcript levels. Here, we show that the alternative polyadenylation (APA) of mRNA is important for root development and responses. Mutations in FIP1, a component of polyadenylation machinery, affects plant development, cell division and elongation, and response to different abiotic stresses. Salt treatment increases the amount of poly(A) site usage within the coding region and 5' untranslated regions (5'-UTRs), and the lack of FIP1 activity reduces the poly(A) site usage within these non-canonical sites. Gene ontology analyses of transcripts displaying APA in response to salt show an enrichment in ABA signaling, and in the response to stresses such as salt or cadmium (Cd), among others. Root growth assays show that fip1-2 is more tolerant to salt but is hypersensitive to ABA or Cd. Our data indicate that FIP1-mediated alternative polyadenylation is important for plant development and stress responses.

RIMA-Dependent Nuclear Accumulation of IYO Triggers Auxin-Irreversible Cell Differentiation in Arabidopsis.

The transcriptional regulator MINIYO (IYO) is essential and rate-limiting for initiating cell differentiation in Arabidopsis thaliana Moreover, IYO moves from the cytosol into the nucleus in cells at the meristem periphery, possibly triggering their differentiation. However, the genetic mechanisms controlling IYO nuclear accumulation were unknown, and the evidence that increased nuclear IYO levels trigger differentiation remained correlative. Searching for IYO interactors, we identified RPAP2 IYO Mate (RIMA), a homolog of yeast and human proteins linked to nuclear import of selective cargo. Knockdown of RIMA causes delayed onset of cell differentiation, phenocopying the effects of IYO knockdown at the transcriptomic and developmental levels. Moreover, differentiation is completely blocked when IYO and RIMA activities are simultaneously reduced and is synergistically accelerated when IYO and RIMA are concurrently overexpressed, confirming their functional interaction. Indeed, RIMA knockdown reduces the nuclear levels of IYO and prevents its prodifferentiation activity, supporting the conclusion that RIMA-dependent nuclear IYO accumulation triggers cell differentiation in Arabidopsis. Importantly, by analyzing the effect of the IYO/RIMA pathway on xylem pole pericycle cells, we provide compelling evidence reinforcing the view that the capacity for de novo organogenesis and regeneration from mature plant tissues can reside in stem cell reservoirs.

Achieving Safe, Effective, and Compassionate Quarantine or Isolation of Older Adults With Dementia in Nursing Homes.

Nursing homes are facing the rapid spread of COVID-19 among residents and staff and are at the centre of the public health emergency due to the COVID-19 pandemic. As policy changes and interventions designed to support nursing homes are put into place, there are barriers to implementing a fundamental, highly effective element of infection control, namely the isolation of suspected or confirmed cases. Many nursing home residents have dementia, associated with impairments in memory, language, insight, and judgment that impact their ability to understand and appreciate the necessity of isolation and to voluntarily comply with isolation procedures. While there is a clear ethical and legal basis for the involuntary confinement of people with dementia, the potential for unintended harm with these interventions is high, and there is little guidance for nursing homes on how to isolate safely, while maintaining the human dignity and personhood of the individual with dementia. In this commentary, we discuss strategies for effective, safe, and compassionate isolation care planning, and present a case vignette of a person with dementia who is placed in quarantine on a dementia unit.

Photoacclimation and Photoprotection of Juvenile Sporophytes of Macrocystis pyrifera (Laminariales, Phaeophyceae) Under High-light Conditions During Short-term Shallow-water Cultivation1.

This study was designed to understand better if and how juvenile sporophytes of Macrocystis pyrifera can photoacclimate to high-light conditions when transplanted from 10 to 3 meters over 7 d. Acclimation of adult sporophytes to light regimes in the bathymetric gradient has been extensively documented. It primarily depends on photoacclimation and translocation of resources among blades. Among other physiological differences, juvenile sporophytes of M. pyrifera lack the structural complexity shown by adults. As such, juveniles may primarily depend on their photoacclimation capacities to maintain productivity and even avoid mortality under changing light regimes. However, little is known about how these mechanisms operate in young individuals. The capacity of sporophytes to photoacclimate was assessed by examining changes in their photosynthetic performance, pigment content, and bio-optical properties of the blade. Sporophytes nutritional status and oxidative damage were also determined. Results showed that juvenile sporophytes transplanted to shallow water were able to regulate light harvesting by reducing pigment concentration, and thus, absorptance and photosynthetic efficiency. Also, shallow-water sporophytes notably enhanced the dissipation of light energy as heat (NPQ) as a photoprotective mechanism. Generally, these adjustments allowed sporophytes to manage the absorption and utilization of light energy, hence reducing the potential for photo-oxidative damage. Furthermore, no substantial changes were found in the internal reserves (i.e., soluble carbohydrates and nitrogen) of these sporophytes. To our knowledge, these results are the first to provide robust evidence of photoprotective and photoacclimation strategies in juveniles of M. pyrifera, allowing them to restrict or avoid photodamage during shallow-water cultivation.

Field Performance and Diagnostic Accuracy of a Low-Cost Instrument-Free Point-of-Care CD4 Test (Visitect CD4) Performed by Different Health Worker Cadres among Pregnant Women.

Measuring CD4 counts remains an important component of HIV care. The Visitect CD4 is the first instrument-free low-cost point-of-care CD4 test with results interpreted visually after 40 min, providing a result of ≥350 CD4 cells/mm3 The field performance and diagnostic accuracy of the test was assessed among HIV-infected pregnant women in South Africa. A nurse performed testing at the point-of-care using both venous and finger-prick blood, and a counselor and laboratory staff tested venous blood in the clinic laboratory (four Visitect CD4 tests/participant). Performance was compared to the mean CD4 count from duplicate flow cytometry tests on venous blood (FACSCalibur Trucount). In 2017, 156 patients were enrolled, providing a total of 624 Visitect CD4 tests (468 venous and 156 finger-prick samples). Of 624 tests, 28 (4.5%) were inconclusive. Generalized linear mixed modeling showed better performance of the test on venous blood (sensitivity = 81.7%; 95% confidence interval [CI] = 72.3 to 91.1]; specificity = 82.6%, 95% CI = 77.1 to 88.1) than on finger-prick specimens (sensitivity = 60.7%; 95% CI = 45.0 to 76.3; specificity = 89.5%, 95% CI = 83.2 to 95.8; P = 0.001). No difference in performance was detected by cadre of health worker (P = 0.113) or between point-of-care versus laboratory-based testing (P = 0.108). Adequate performance of Visitect CD4 with different operators and at the point of care, with no need of electricity or instrument, shows the potential utility of this device, especially for facilitating decentralization of CD4 testing services in rural areas.

Performance of a Novel Low-Cost, Instrument-Free Plasma Separation Device for HIV Viral Load Quantification and Determination of Treatment Failure in People Living with HIV in Malaysia: a Diagnostic Accuracy Study.

HIV viral load (VL) testing is the recommended method for monitoring the response of people living with HIV and receiving antiretroviral therapy (ART). The availability of standard plasma VL testing in low- and middle-income countries (LMICs), and access to this testing, are limited by the need to use fresh plasma. Good specimen collection methods for HIV VL testing that are applicable to resource-constrained settings are needed. We assessed the diagnostic performance of the filtered dried plasma spot (FDPS), created using the newly developed, instrument-free VLPlasma device, in identifying treatment failure at a VL threshold of 1,000 copies/ml in fresh plasma. Performance was compared with that of the conventional dried blood spot (DBS). Venous blood samples from 201 people living with HIV and attending an infectious disease clinic in Malaysia were collected, and HIV VL was quantified using fresh plasma (the reference standard), FDPS, and DBS specimens. VL testing was done using the Roche Cobas AmpliPrep/Cobas TaqMan v2.0 assay. At a threshold of 1,000 copies/ml, the diagnostic performance of the FDPS was superior (sensitivity, 100% [95% confidence interval {CI}, 89.1 to 100%]; specificity, 100% [95% CI, 97.8 to 100%]) to that of the DBS (sensitivity, 100% [95% CI, 89.4 to 100%]; specificity, 36.8% [95% CI, 29.4 to 44.7%]) (P < 0.001). A stronger correlation was observed between the FDPS VL and the plasma VL (r = 0.94; P < 0.001) than between the DBS VL and the plasma VL (r = 0.85; P < 0.001). The mean difference in VL measures between the FDPS and plasma (plasma VL minus FDPS VL) was 0.127 log10 copies/ml (standard deviation [SD], 0.32), in contrast to -0.95 log10 copies/ml (SD, 0.84) between the DBS and plasma. HIV VL measurement using the FDPS outperformed that with the DBS in identifying treatment failure at a threshold of 1,000 copies/ml and compared well with the quantification of VL in plasma. The FDPS can be an attractive alternative to fresh plasma for improving access to HIV VL monitoring among people living with HIV on ART in LMICs.

A Sizer model for cell differentiation in Arabidopsis thaliana root growth.

Plant roots grow due to cell division in the meristem and subsequent cell elongation and differentiation, a tightly coordinated process that ensures growth and adaptation to the changing environment. How the newly formed cells decide to stop elongating becoming fully differentiated is not yet understood. To address this question, we established a novel approach that combines the quantitative phenotypic variability of wild-type Arabidopsis roots with computational data from mathematical models. Our analyses reveal that primary root growth is consistent with a Sizer mechanism, in which cells sense their length and stop elongating when reaching a threshold value. The local expression of brassinosteroid receptors only in the meristem is sufficient to set this value. Analysis of roots insensitive to BR signaling and of roots with gibberellin biosynthesis inhibited suggests distinct roles of these hormones on cell expansion termination. Overall, our study underscores the value of using computational modeling together with quantitative data to understand root growth.

Living Outside the Gender Box in Mexico: Testimony of Transgender Mexican Asylum Seekers.

OBJECTIVES: To explore preimmigration experiences of violence and postimmigration health status in male-to-female transgender individuals (n = 45) from Mexico applying for asylum in the United States. METHODS: We used a document review process to examine asylum declarations and psychological evaluations of transgender Mexican asylum seekers in the United States from 2012. We coded documents in 2013 and 2014 using NVivo, a multidisciplinary team reviewed them, and then we analyzed them for themes. RESULTS: Mexican transgender asylum applicants experienced pervasive verbal, physical, and sexual abuse from multiple sources, including family, school, community, and police. Applicants also experienced discrimination in school and in the workplace. Applicants immigrated to the United States to escape persistent assaults and threats to their life. Applicants suffered health and psychological effects from their experiences in Mexico that affected opportunities in the United States for employment, education, and social inclusion. CONCLUSIONS: Additional social protections for transgender individuals and antidiscrimination measures in Mexican schools and workplaces are warranted as are increased mental health assessment and treatment, job training, and education services for asylum seekers in the United States.

Brassinosteroids control meristem size by promoting cell cycle progression in Arabidopsis roots.

Brassinosteroids (BRs) play crucial roles in plant growth and development. Previous studies have shown that BRs promote cell elongation in vegetative organs in several plant species, but their contribution to meristem homeostasis remains unexplored. Our analyses report that both loss- and gain-of-function BR-related mutants in Arabidopsis thaliana have reduced meristem size, indicating that balanced BR signalling is needed for the optimal root growth. In the BR-insensitive bri1-116 mutant, the expression pattern of the cell division markers CYCB1;1, ICK2/KRP2 and KNOLLE revealed that a decreased mitotic activity accounts for the reduced meristem size; accordingly, this defect could be overcome by the overexpression of CYCD3;1. The activity of the quiescent centre (QC) was low in the short roots of bri1-116, as reported by cell type-specific markers and differentiation phenotypes of distal stem cells. Conversely, plants treated with the most active BR, brassinolide, or mutants with enhanced BR signalling, such as bes1-D, show a premature cell cycle exit that results in early differentiation of meristematic cells, which also negatively influence meristem size and overall root growth. In the stem cell niche, BRs promote the QC renewal and differentiation of distal stem cells. Together, our results provide evidence that BRs play a regulatory role in the control of cell-cycle progression and differentiation in the Arabidopsis root meristem.

The context dependence of beneficiary feedback effects on benefactors in plant facilitation.

Facilitative effects of some species on others are a major driver of biodiversity. These positive effects of a benefactor on its beneficiary can result in negative feedback effects of the beneficiary on the benefactor and reduced fitness of the benefactor. However, in contrast to the wealth of studies on facilitative effects in different environments, we know little about whether the feedback effects show predictable patterns of context dependence. We reanalyzed a global data set on alpine cushion plants, previously used to assess their positive effects on biodiversity and the nature of the beneficiary feedback effects, to specifically assess the context dependence of how small- and large-scale drivers alter the feedback effects of cushion-associated (beneficiary) species on their cushion benefactors using structural equation modelling. The effect of beneficiaries on cushions became negative when beneficiary diversity increased and facilitation was more intense. Local-scale biotic and climatic conditions mediated these community-scale processes, having indirect effects on the feedback effect. High-productivity sites demonstrated weaker negative feedback effects of beneficiaries on the benefactor. Our results indicate a limited impact of the beneficiary feedback effects on benefactor cushions, but strong context dependence. This context dependence may help to explain the ecological and evolutionary persistence of this widespread facilitative system.

A global analysis of bidirectional interactions in alpine plant communities shows facilitators experiencing strong reciprocal fitness costs.

Facilitative interactions are defined as positive effects of one species on another, but bidirectional feedbacks may be positive, neutral, or negative. Understanding the bidirectional nature of these interactions is a fundamental prerequisite for the assessment of the potential evolutionary consequences of facilitation. In a global study combining observational and experimental approaches, we quantified the impact of the cover and richness of species associated with alpine cushion plants on reproductive traits of the benefactor cushions. We found a decline in cushion seed production with increasing cover of cushion-associated species, indicating that being a benefactor came at an overall cost. The effect of cushion-associated species was negative for flower density and seed set of cushions, but not for fruit set and seed quality. Richness of cushion-associated species had positive effects on seed density and modulated the effects of their abundance on flower density and fruit set, indicating that the costs and benefits of harboring associated species depend on the composition of the plant assemblage. Our study demonstrates 'parasitic' interactions among plants over a wide range of species and environments in alpine systems, and we consider their implications for the possible selective effects of interactions between benefactor and beneficiary species.

Antihyperalgesic effects of an aqueous stem bark extract of Mangifera indica L.: role of mangiferin isolated from the extract.

This study aimed to assess the effects of a Mangifera indica stem bark extract (MSBE) and mangiferin (MG) on pain-related acute behaviors in the formalin 5% test. Rats received repeated oral MSBE (125-500 mg/kg) once daily for 7 days before formalin injection. Other four groups with the same treatments were performed in order to study the effect of MSBE on the formalin-induced long-term secondary mechano-hyperalgesia at 7 days after the injury by means of the pin-prick method. Additional groups received a single oral MSBE dose (250 mg/kg) plus ascorbic acid (1 mg/kg, i.p.). Also, repeated oral MG doses (12.5-50 mg/kg) during 7 days were administered. MSBE decreased licking/biting and flinching behaviors only in phase II and reduced the long-term formalin injury-induced secondary chronic mechano-hyperalgesia. The combination of MSBE plus ascorbic acid produced a reinforcement of this effect for flinching behavior, advising that antioxidant mechanisms are involved, at least in part, in these actions. Chronic administration of MG reproduced the effects of MSBE. For the first time, the antihyperalgesic effects of MSBE and MG in formalin 5% test, a recommended concentration for studying the antinociceptive activity of nitric oxide-related and N-methyl-d-aspartate-related compounds, were reported. These results could represent an important contribution to explain the analgesic ethnobotanical effects recognized to M. indica and other species containing MG.

Evolution of Telehealth-Its Impact on Palliative Care and Medication Management.

Palliative care plays a crucial role in enhancing the quality of life for individuals facing serious illnesses, aiming to alleviate suffering and provide holistic support. With the advent of telehealth, there is a growing interest in leveraging technology to extend the reach and effectiveness of palliative care services. This article provides a comprehensive review of the evolution of telehealth, the current state of telemedicine in palliative care, and the role of telepharmacy and medication management. Herein we highlight the potential benefits, challenges, and future directions of palliative telemedicine. As the field continues to advance, the article proposes key considerations for future research, policy development, and clinical implementation, aiming to maximize the advantages of telehealth in assisting individuals and their families throughout the palliative care journey. The comprehensive analysis presented herein contributes to a deeper understanding of the role of telehealth in palliative care and serves as a guide for shaping its future trajectory.

Rational Prescribing of Pancreatic Enzymes for Patients with Pancreatic Cancer.

Most patients with pancreatic cancer at some point present with symptoms related to exocrine pancreatic insufficiency (EPI). These include diarrhea, abdominal bloating, indigestion, steatorrhea, weight loss, and anorexia. Even though up to 80% of pancreatic cancer patients eventually present with symptoms related to exocrine pancreatic insufficiency, only 21% are prescribed pancreatic enzyme replacement therapy (PERT). Its effectiveness is also highly dependent on its proper timing of administration, and patients must be thoroughly educated about this. The impact of symptoms of EPI can lead to poorer overall well-being. Pharmacists play a crucial role in properly educating patients on the correct use of pancreatic enzyme replacement therapy. PERT is a key strategy in managing the symptoms of EPI and can improve quality of life, which is a central focus in palliative care. This treatment is profoundly underutilized in the palliative care of these patients. The objective of this review is to discuss the pharmacology, pharmacokinetics, side effects, available evidence of the effectiveness of pancreatic enzyme use for patients with pancreatic cancer, and challenges, along with proposed solutions regarding its use.

A Systematic Review of Naldemedine and Naloxegol for the Treatment of Opioid-Induced Constipation in Cancer Patients.

BACKGROUND: Opioid-induced constipation (OIC) is a pervasive and distressing side effect of chronic opioid therapy in patients with cancer pain, significantly impacting their quality of life. Peripherally acting µ-opioid receptor antagonists (PAMORAS) were developed for treatment-resistant OIC but most studies were conducted with non-cancer patients. OBJECTIVE: to discuss two oral formulations of PAMORAs, naldemedine and naloxegol, and to review available evidence of the effectiveness of these drugs for OIC in cancer patients. METHODS: a comprehensive search to identify primary literature for either naldemedine or naloxegol for OIC in cancer patients. RESULTS: Only three prospective randomized, double-blind, placebo-controlled clinical trials for naldemedine enrolling cancer patients were identified; the results of a subgroup analysis of two of those studies and two non-interventional post marketing surveillance studies of these trials are also reported here. For naloxegol, only two randomized controlled trials were identified; both were unsuccessful in enrolling sufficient patients. An additional four prospective non-interventional observational studies with naloxegol were found that enrolled cancer patients. There were significantly higher rates of responders in the PAMORA groups than in the placebo groups. The most common side effect for both PAMORAs was diarrhea. LIMITATIONS: All studies were industry-funded, and given that only three trials were randomized controlled studies, the overall quality of the studies was lacking. CONCLUSION: Naldemedine or naloxegol appeared safe and useful in the treatment of OIC in cancer patients and may improve their quality of life. Larger-scale randomized placebo-controlled studies of PAMORAs in cancer patients would strengthen existing evidence.