Changes in End-of-Life Symptom Management Prescribing among Long-Term Care Residents during COVID-19.

OBJECTIVE: To examine changes in the prescribing of end-of-life symptom management medications in long-term care (LTC) homes during the COVID-19 pandemic. DESIGN: Retrospective cohort study using routinely collected health administrative data in Ontario, Canada. SETTING AND PARTICIPANTS: We included all individuals who died in LTC homes between January 1, 2017, and March 31, 2021. We separated the study into 2 periods: before COVID-19 (January 1, 2017, to March 17, 2020) and during COVID-19 (March 18, 2020, to March 31, 2021). METHODS: For each LTC home, we measured the percentage of residents who died before and during COVID-19 who had a subcutaneous symptom management medication prescription in their last 14 days of life. We grouped LTC homes into quintiles based on their mean prescribing rates before COVID-19, and examined changes in prescribing during COVID-19 and COVID-19 outcomes across quintiles. RESULTS: We captured 75,438 LTC residents who died in Ontario's 626 LTC homes during the entire study period, with 19,522 (25.9%) dying during COVID-19. The mean prescribing rate during COVID-19 ranged from 46.9% to 79.4% between the lowest and highest prescribing quintiles. During COVID-19, the mean prescribing rate in the lowest prescribing quintile increased by 9.6% compared to before COVID-19. Compared to LTC homes in the highest prescribing quintile, homes in the lowest prescribing quintile experienced the highest proportion of COVID-19 outbreaks (73.4% vs 50.0%), the largest mean outbreak intensity (0.27 vs 0.09 cases/bed), the highest mean total days with a COVID-19 outbreak (72.7 vs 24.2 days), and the greatest proportion of decedents who were transferred and died outside of LTC (22.1% vs 8.6%). CONCLUSIONS AND IMPLICATIONS: LTC homes in Ontario had wide variations in the prescribing rates of end-of-life symptom management medications before and during COVID-19. Homes in the lower prescribing quintiles had more COVID-19 cases per bed and days spent in an outbreak.

Palliative End-of-Life Medication Prescribing Rates in Long-Term Care: A Retrospective Cohort Study.

BACKGROUND: Medications are often needed to manage distressing end-of-life symptoms (eg, pain, agitation). OBJECTIVES: In this study, we describe the variation in prescribing rates of symptom relief medications at the end of life among long-term care (LTC) decedents. We evaluate the extent these medications are prescribed in LTC homes and whether prescribing rates of end-of-life symptom management can be used as an indicator of quality end-of-life care. DESIGN: Retrospective cohort study using administrative health data. SETTING AND PARTICIPANTS: LTC decedents in all 626 publicly funded LTC homes in Ontario, Canada, between January 1, 2017, and March 17, 2020. METHODS: For each LTC home, we measured the percent of decedents who received 1+ prescription(s) for a subcutaneous end-of-life symptom management medication ("end-of-life medication") in their last 14 days of life. We then ranked LTC homes into quintiles based on prescribing rates. RESULTS: We identified 55,916 LTC residents who died in LTC. On average, two-thirds of decedents (64.7%) in LTC homes were prescribed at least 1 subcutaneous end-of-life medication in the last 2 weeks of life. Opioids were the most common prescribed medication (overall average prescribing rate of 62.7%). LTC homes in the lowest prescribing quintile had a mean of 37.3% of decedents prescribed an end-of-life medication, and the highest quintile mean was 82.5%. In addition, across these quintiles, the lowest prescribing quintile had a high average (30.3%) of LTC residents transferred out of LTC in the 14 days compared with the highest prescribing quintile (12.7%). CONCLUSIONS AND IMPLICATIONS: Across Ontario's LTC homes, there are large differences in prescribing rates for subcutaneous end-of-life symptom relief medications. Although future work may elucidate why the variability exists, this study provides evidence that administrative data can provide valuable insight into the systemic delivery of end-of-life care.

[François Gros: a leading figure, a secretive man]. / François Gros : Une personnalité de premier plan, un homme secret.

I joined François Gros' laboratory in 1975, to study mechanisms of gene expression in eukaryotes. Despite the lack of powerful tools, that would be brought later by genetic engineering, I obtained publishable results and was allowed to defend a third cycle thesis. Thereafter, I joined Margaret Buckingham's group, which was empowering within François' laboratory. I maintained regular meetings with François, a leading figure but a secretive man, who did not readily open up. It was my privilege, over the more than 45 years I have been around him, to have glimpses over what had been really significant to him. This has been a rich and very precious experience.

J'ai rejoint le laboratoire de François Gros en 1975, pour étudier les mécanismes de l'expression génétique chez les eucaryotes. Malgré la carence en outils performants, qu'allait apporter le génie génétique, j'ai obtenu des résultats publiables et pu soutenir une thèse de 3 e cycle. Après cela, j'ai rejoint le groupe de Margaret Buckingham, qui s'autonomisait dans le laboratoire de François. J'ai continué à avoir des rencontres régulières avec François, personnalité de premier plan mais homme secret, qui ne se livrait pas volontiers. J'ai eu le privilège, au cours des 45 ans et plus où je l'ai côtoyé, d'avoir quelques aperçus de ce qui l'avait marqué, l'avait formé, lui importait vraiment. Ça été une expérience riche et très précieuse.

What do primary care providers want to know when caring for patients living with frailty? An analysis of eConsult communications between primary care providers and specialists.

BACKGROUND: Frailty is a complex condition that primary care providers (PCPs) are managing in increasing numbers, yet there is no clear guidance or training for frailty care. OBJECTIVES: The present study examined eConsult questions PCPs asked specialists about patients with frailty, the specialists' responses, and the impact of eConsult on the care of these patients. DESIGN: Cross-sectional observational study. SETTING: ChamplainBASE™ eConsult located in Eastern Ontario, Canada. PARTICIPANTS: Sixty one eConsult cases closed by PCPs in 2019 that use the terms "frail" or "frailty" to describe patients 65 years of age or older. MEASUREMENTS: The Taxonomy of Generic Clinical Questions (TGCQ) was used to classify PCP questions and the International Classification for Primary Care 3 (ICPC-3) was used to classify the clinical content of each eConsult. The impact of eConsult on patient care was measured by PCP responses to a mandatory survey. RESULTS: PCPs most frequently directed their questions to cardiology (n = 7; 11%), gastroenterology (n = 7; 11%), and endocrinology (n = 6; 10%). Specialist answers most often pertained to medications (n = 63, 46%), recommendations for clinical investigation (n = 24, 17%), and diagnoses (n = 22, 16%). Specialist responses resulted in PCPs avoiding referral in 57% (n = 35) of cases whereas referrals were still required in 15% (n = 9) of cases. Specialists responded to eConsults in a median 1.11 days (IQR = 0.3-4.7), and 95% (n = 58) of cases received a response within 7 days. Specialists recorded a median of 15 min to respond (IQR = 10-20), with a median cost of $50.00 CAD (IQR = 33.33 - 66.66) per eConsult. CONCLUSIONS: Through the analysis of questions and responses submitted to eConsult, this study provides novel information on PCP knowledge gaps and approaches to care for patients living with frailty. Furthermore, these analyses provide evidence that eConsult is a feasible and valuable tool for improving care for patients with frailty in primary care settings.

Focusing on Provider Quality Measurement: Continued Consensus and Feasibility Testing of Practice-Based Quality Measures for Primary Care Providers in Long-Term Care.

Medical providers in long-term care (LTC) use a unique skillset in delivering comprehensive resident care. Publicly reported quality measures (QMs) do not directly emphasize medical provider competency and their role in care. The impact of providers is understudied and to a large extent, unknown. Our objective was to define, test, and validate QMs to pragmatically measure the practice-based quality of medical providers in a pilot study. We included 7 North American LTC homes with data from practicing medical providers for LTC residents. We engaged in a 4-phased approach. In phase 1, experts rated 95 candidate QMs using 5 pragmatic-focused criteria in a RAND-modified Delphi process. Phase 2 involved specifying 37 QMs for collection (4 QMs were dropped during pilot testing). We created an abstraction manual and data collection tool for all QMs. Phase 3 involved a retrospective chart review in 7 LTC homes on 33 QMs with trained data abstractors. Data were sufficient to analyze performance for 26 QMs. Lastly, in phase 4 results and psychometric properties were reviewed with an expert panel. They ranked the tested measures for validity and feasibility for use by a nonphysician auditor to evaluate medical provider performance based on medical record review. In total, we examined data from 343 resident charts from 7 LTC homes and 49 providers. Our process yielded 10 QMs as being specified for measurement, feasible to collect, and had good test performance. This is the only study to systematically identify a subset of QMs for feasible collection from the medical record by various data collectors. This pragmatic approach to measuring practice-based quality and quantifying select medical provider competencies allows for the evaluation of individual and facility-level performance and facilitates quality improvement initiatives. Future work should perform broader testing and validate and refine operationalized QMs.

The cost-effectiveness of a nursing home-based transitional care unit for increasing the potential for independent living in the community among hospitalized older adults.

OBJECTIVE: In Canada, a persistent barrier to achieving healthcare system efficiency has been patient days accumulated by individuals with an alternate level of care (ALC) designation. Transitional care units (TCUs) may address the capacity pressures associated with ALC. We sought to assess the cost-effectiveness of a nursing home (NH) based TCU leveraging existing infrastructure to support a hospitalized older adult's transition to independent living at home. METHODS: This case-control study included frail, older adults who received care within a function-focused TCU following a hospitalization between 1 March 2018 and 30 June 2019. TCU patients were propensity score matched to hospitalized ALC patients ("usual care"). The primary outcome was days without requiring institutional care six months following discharge, defined as institutional-free days. This was calculated by excluding all days in hospitals, rehabilitation facilities, complex continuing care facilities and NHs. Using the total direct cost of care up to discharge from TCU or hospital, the incremental cost-effectiveness ratio was calculated. RESULTS: TCU patients spent, on average, 162.0 days institution-free (95% CI: 156.3-167.6d) within six months days post-discharge, while usual care patients spent 140.6 days institution-free (95% CI: 132.3-148.8d). TCU recipients had a lower total cost of care, by CAN$1,106 (95% CI: $-6,129-$10,319), due to the reduced hospital length of stay (mean [SD] 15.6d [13.3d] for TCU patients and 28.6d [67.4d] days for usual care). TCU was deemed the more cost-effective model of care. LIMITATIONS: The main limitation was the potential inclusion of patients not eligible for SAFE in our usual group. To minimize this selection bias, we expanded the geographical pool of ALC patients to patients with SAFE admission potential in other area hospitals. CONCLUSIONS: Through rehabilitative and restorative care, TCUs can reduce hospital length of stay, increase potential for independent living, and reduce risk for subsequent institutionalization.

A persistent barrier to achieving efficiency within the Canadian healthcare system has been days accumulated by patients who no longer require the intensity of hospital care but are waiting to be discharged to more appropriate care settings. Prolonged hospital stays are known to expose patients to various health risks.Transitional care units are care settings designed to improve care continuation for patients moving between different locations or levels of care. They an opportunity to address the capacity pressures and health risks associated with prolonged hospital stays.Studies have demonstrated the effectiveness of transitional care units to improve outcomes among older adults, such as reducing hospital length of stay, nursing home placement, and falls, as well as improving functional status, quality of life, and likelihood of being discharged home. However, the financial implications of transitional care units, in terms of resources required to operate their services, and value for money are not well understood.This study found that a nursing home-based, function-focused transitional care unit reduced the length of stay in hospitals and the risk for subsequent institutionalization among frail, older adults. This was achieved at a lower total cost of care. Older adults who received transitional care were able to remain at home for three weeks longer without requiring institutional care compared to those who did not receive transitional care. Considering the growing investments in transitional care, this research provides evidence supporting nursing home-based transitional care programs.

The Role of the Medical Director in Ontario Long-Term Care Homes: Impact of COVID-19.

OBJECTIVES: The pandemic has uncovered a broad lack of understanding of the role of the Medical Director in Canadian Long-Term Care (LTC) Homes. Our objectives were to identify the current demographics and practices of LTC Medical Directors, discover how the pandemic affected their practice habits, and inform the content of the Ontario Long-Term Care Clinicians Medical Director Course, to ensure that Medical Directors have the requisite knowledge of the responsibilities of their role. DESIGN: Email survey. SETTING AND PARTICIPANTS: Medical directors in Ontario long-term care homes. METHODS: Responses to open-ended, close-ended, multiple-choice, and free-text questions. RESULTS: A total of 156 medical directors (approximately 24%) completed the survey. Ninety-four percent were family physicians. Approximately 40% of participants had been a medical director for fewer than 5 years, whereas more than 11% have been in the role for greater than 30 years. More than 60% spend fewer than 2 hours per week in their administrative role, with fewer than 23% completing formal evaluations of the attending clinicians. Greater than 75% are either satisfied or extremely satisfied in their medical director role, citing excellent engagement and collaboration with team members. Feelings of dissatisfaction were associated with pandemic stress, increased hours and responsibility, inadequate remuneration, lack of ability to make decisions and lack of acknowledgement that physicians add value to the interdisciplinary team. CONCLUSION AND IMPLICATIONS: It is clear that medical directors are in a unique position to impact the care of residents within LTC. It is imperative to engage medical directors as integral members of the LTC health care team. This can be achieved by acknowledging their medical expertise for improving outcomes, providing them with the authority for decision making, compensating them appropriately, and clearly defining the role. By making these changes, we can ensure that there is a higher likelihood to sustain effective medical leadership in LTC.

Program Evaluation of SeeMe™: Understanding Frailty Together.

Background: Perley Health has implemented SeeMe™: Understanding frailty together (www.perleyhealth.ca), a comprehensive approach to care that integrates the assessment and management of frailty, with an emphasis on goals of care planning. Methods: Program evaluation over the first year of SeeMe™ used a mixed-methods approach involving quantitative data from surveys, goals of care preferences, hospital transfers, and qualitative data from interviews. Results: The SeeMe™ training is an effective way to educate nurses and physicians in long-term care about frailty. For residents with documented care preferences prior to SeeMe™, there was a 15% reduction in the number of residents who preferred to be transferred to hospital post-SeeMe™ implementation. There was no significant decrease in hospital transfers during the first year the program was introduced. Conclusion: After the roll-out of SeeMe™, nurses, physicians, and families reported high satisfaction with the program, and nurses reported an increase in knowledge and confidence. There was also a reduction in the number of residents and families selecting to transfer to hospital. This suggests that the education from SeeMe™ influenced residents and families to choose less invasive interventions in the context of frailty and quality of life goals.

The solid state of anti-inflammatory morniflumate diniflumate: A cocrystalline salt.

Morniflumate diniflumate, a molecular compound involving niflumic acid and its ß-morpholino ethyl ester (morniflumate) in the mole ratio 2:1, is found to crystallize in a triclinic P - 1 space group with a unit-cell volume of 2203.4(5) Å3. It is a cocrystal between a morniflumate+ niflumate- salt and a neutral niflumic acid molecule. The co-crystalline salt forms endothermically with a positive excess volume and it melts incongruently at 382.3(8) K. Differential scanning calorimetry executed at heating rates above 20 K⋅min-1, leads to congruent melting at 387.8(9)K with an enthalpy change of ΔfusH = 80(2) J g-1. The rare occurrence that incongruent and congruent melting can be observed for the same cocrystal may be due to the conformational versatility of the niflumic acid molecule and its slow conversion between the different conformations due to weak intramolecular hydrogen bonding.

Aerosol SARS-CoV-2 in hospitals and long-term care homes during the COVID-19 pandemic.

BACKGROUND: Few studies have quantified aerosol concentrations of SARS-CoV-2 in hospitals and long-term care homes, and fewer still have examined samples for viability. This information is needed to clarify transmission risks beyond close contact. METHODS: We deployed particulate air samplers in rooms with COVID-19 positive patients in hospital ward and ICU rooms, rooms in long-term care homes experiencing outbreaks, and a correctional facility experiencing an outbreak. Samplers were placed between 2 and 3 meters from the patient. Aerosol (small liquid particles suspended in air) samples were collected onto gelatin filters by Ultrasonic Personal Air Samplers (UPAS) fitted with <2.5µm (micrometer) and <10 µm size-selective inlets operated for 16 hours (total 1.92m3), and with a Coriolis Biosampler over 10 minutes (total 1.5m3). Samples were assayed for viable SARS-CoV-2 virus and for the viral genome by multiplex PCR using the E and N protein target sequences. We validated the sampling methods by inoculating gelatin filters with viable vesicular stomatitis virus (VSV), and with three concentrations of viable SARS-CoV-2, operating personal samplers for 16hrs, and quantifying viable virus recovery by TCID50 assay. RESULTS: In total, 138 samples were collected from 99 rooms. RNA samples were positive in 9.1% (6/66) of samples obtained with the UPAS 2.5µm samplers, 13.5% (7/52) with the UPAS 10µm samplers, and 10.0% (2/20) samples obtained with the Coriolis samplers. Culturable virus was not recovered in any samples. Viral RNA was detected in 15.1% of the rooms sampled. There was no significant difference in viral RNA recovery between the different room locations or samplers. Method development experiments indicated minimal loss of SARS-CoV-2 viability via the personal air sampler operation.

A Case-Control Study of the Sub-Acute Care for Frail Elderly (SAFE) Unit on Hospital Readmission, Emergency Department Visits and Continuity of Post-Discharge Care.

OBJECTIVES: In Canada, alternate-level-of-care (ALC) beds in hospitals may be used when patients who do not require the intensity of services provided in an acute care setting are waiting to be discharged to a more appropriate care setting. However, when there is a lack of care options for patients waiting to be discharged, it contributes to prolonged hospital stays and bottlenecks in the health care system manifested as "hallway medicine." We examined the effectiveness of a function-focused transitional care program, the Sub-Acute care for Frail Elderly (SAFE) Unit, in reducing the length of stay (LOS) in hospital, as well as post-discharge acute care use and continuity of care. DESIGN: Case-control study. SETTING AND PARTICIPANTS: A 450-bed nursing home located in Ontario, Canada, where the SAFE Unit is based. The study population included frail, older patients aged 60 years and older who received care in the SAFE Unit between March 1, 2018, and February 28, 2019 (n = 153) to controls comprising of other hospitalized patients (n = 1773). METHODS: We linked facility-level to provincial health administrative databases on hospital admissions and emergency department (ED) visits, and the Ontario Health Insurance Plan claims database for physician billings to investigated the LOS during the index hospitalization, 30-day odds of post-discharge ED visits, hospital readmission, and follow-up with family physicians. RESULTS: SAFE patients had a median hospital LOS of 13 days [interquartile range (IQR): 8-19 days], with 75% having fewer than 1 day in an ALC bed. In comparison, the median LOS in the control group was 15 days (IQR: 10-24 days), with one-third of those days spent in an ALC bed (median: 5 days, IQR: 3-10 days). SAFE patients were more likely (64.1%) to be discharged home than control patients (46.3%). Both groups experienced similar 30-day odds of ED visits, hospital readmission and follow-up with a family physician. CONCLUSIONS AND IMPLICATIONS: Frail older individuals in the SAFE Unit experienced shorter hospital stays, were less likely to be discharged to settings other than home and had similar 30-day acute care outcomes as control patients post-discharge.

The phase relationship between the pyrazinamide polymorphs α and γ.

Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. It possesses at least four crystalline polymorphs. Polymorphism may cause solubility problems as the case of ritonavir has clearly demonstrated; however, polymorphs also provide opportunities to improve pharmaceutical formulations, in particular if the stable form is not very soluble. The four polymorphs of pyrazinamide constitute a rich system to investigate the usefulness of metastable forms and their stabilization. However, despite the existence of a number of papers on the polymorphism of pyrazinamide, well-defined equilibrium conditions between the polymorphs appear to be lacking. The main objectives of this paper are to establish the temperature and pressure equilibrium conditions between the so-called α and γ polymorphs of pyrazinamide, its liquid phase, and vapor phase and to determine the phase-change inequalities, such as enthalpies, entropies, and volume differences. The equilibrium temperature between α and γ was experimentally found at 392(1) K. Moreover, vapor pressures and solubilities of both phases have been determined, clearly indicating that form α is the more stable form at room temperature. High-pressure thermal analysis and the topological pressure-temperature phase diagram demonstrate that the γ form is stabilized by pressure and becomes stable at room temperature under a pressure of 260 MPa.

Establishing an integrated model of subacute care for the frail elderly.

The current health system in Ontario is not designed to meet the needs of frail older adults. This is particularly true for older adults hospitalized due to exacerbation of chronic illness or medical crisis. This article describes the Subacute Care Unit for the Frail Elderly (SAFE) program, one which is designed to serve frail older patients who are at risk of deconditioning or disability associated with prolonged hospitalization but who may safely return home or to a retirement home following up to 4 weeks of subacute care in a restorative environment. The program centres on an intense restorative and integrated care delivery model. The patient population is medically complex, requiring medical supervision and regular adjustment to the care plan to optimize medical status. Individuals are no longer acutely ill and are considered stable or stabilizing. Care and services are designed to improve outcomes for hospitalized frail older adults by proactively addressing the conditions that contribute to alternate level of care before the deconditioning associated with prolonged hospitalization is experienced.

Involvement of neural crest and paraxial mesoderm in oral mucosal development and healing.

Tissue engineering therapies using adult stem cells derived from neural crest have sought accessible tissue sources of these cells because of their potential pluripotency. In this study, the gingiva and oral mucosa and their associated stem cells were investigated. Biopsies of these tissues produce neither scarring nor functional problems and are relatively painless, and fresh tissue can be obtained readily during different chairside dental procedures. However, the embryonic origin of these cells needs to be clarified, as does their evolution from the perinatal period to adulthood. In this study, the embryonic origin of gingival fibroblasts were determined, including gingival stem cells. To do this, transgenic mouse models were used to track neural crest derivatives as well as cells derived from paraxial mesoderm, spanning from embryogenesis to adulthood. These cells were compared with ones derived from abdominal dermis and facial dermis. Our results showed that gingival fibroblasts are derived from neural crest, and that paraxial mesoderm is involved in the vasculogenesis of oral tissues during development. Our in vitro studies revealed that the neuroectodermal origin of gingival fibroblasts (or gingival stem cells) endows them with multipotential properties as well as a specific migratory and contractile phenotype which may participate to the scar-free properties of the oral mucosa. Together, these results illustrate the high regenerative potential of neural crest-derived stem cells of the oral mucosa, including the gingiva, and strongly support their use in cell therapy to regenerate tissues with impaired healing.

Dairy curd coagulated by a plant extract of Calotropis procera: Role of fat structure on the chemical and textural characteristics.

Milk is often subjected to technological treatments which have impacts on the structure of milk constituents and the characteristics of rennet curds. In this paper, the influence of the dairy fat structure on the biochemical and textural characteristics of curds coagulated by an extract of Calotropis procera leaves was studied. Standardized milks were reconstituted with the same contents in protein (35g·kg-1) and fat (35g·kg-1) but with different structures of fat i.e. homogenized anhydrous milk fat (HAMF), homogenized cream (HC) and non-homogenized cream (NHC). As expected, the size distributions of fat globules in the different milks were different. After their coagulations by the plant extract, the physico-chemical characteristics of the curds and respective wheys were determined. No difference was observed in the coagulation time between the three milks but the whey removed more quickly from HAMF and HC curds than NHC-curd. The biochemical analyses of curds revealed a lower content in dry matter and fat in the NHC-curd compared to HAMF- and HC-curds. Otherwise, the NHC-whey exhibited the highest amount of fat. Observations by confocal microscopy showed that the fat globules were homogenously distributed and well trapped in the protein networks of HAMF- and HC-curds. In the NHC-curd, the fat globules were located in whey pockets, with less connectivity with the protein network. The textural analysis showed that the NHC-curd was more elastic, soft and adhesive than HAMF- and HC-curds. Homogenization significantly reduced the loss of fat during cheese manufacturing and conferred specific textural characteristics to the curds coagulated by an extract of Calotropis procera.

Polar lipid composition of bioactive dairy co-products buttermilk and butterserum: Emphasis on sphingolipid and ceramide isoforms.

Bioactive lipids of the milk fat globule membrane become concentrated in two co-products of the butter industry, buttermilk and butterserum. Their lipid composition is detailed here with special emphasis on sphingolipid composition of nutritional interest, determined using GC, HPLC and tandem mass spectrometry. Butterserum was 2.5 times more concentrated in total fat than buttermilk, with 7.7±1.5vs 19.5±2.9wt% and even more concentrated in polar lipids, with 1.4±0.2vs 8.5±1.1wt%. Both ingredients constitute concentrated sources of sphingomyelin (3.4-21mg/g dry matter) and contained low amounts of bioactive ceramides in a ratio to sphingomyelin of 1:5mol% in buttermilk and 1:10mol% in butterserum. Compared to other natural lecithins, these two co-products are rich in long and saturated fatty acids (C22:0-C24:0), contain cholesterol and could have interesting applications in neonatal nutrition, but also as brain-protective, hepatoprotective and cholesterol lowering ingredients.

Ser2 from Serratia liquefaciens L53: A new heat stable protease able to destabilize UHT milk during its storage.

The heat-stable protease Ser2 is secreted by the species Serratia liquefaciens, a psychrotrophic bacteria frequently found in raw milk. To understand the physicochemical modifications of casein micelles induced by Ser2 and to confirm its implication in UHT milk destabilization, the enzyme was purified and added to microfiltered raw milk before UHT treatment. UHT milk destabilization was investigated during 90days of storage. A visual destabilization appeared after 8days of storage with the presence of sediment. Zeta potential increase and formation of aggregates were observed during the storage. Using tandem mass spectrometry, numerous released peptides from the four caseins were identified at the end of storage. Caseins were hydrolyzed in the preferential order ß->αs1->κ->αs2. No specific peptidic hydrolysed bond was detected. The present study confirmed that the presence of the protease Ser2 in raw milk can be one of the main causes of UHT milk destabilization.

The Pressure-Temperature Phase Diagram of Metacetamol and Its Comparison to the Phase Diagram of Paracetamol.

Understanding the polymorphic behavior of active pharmaceutical ingredients is important for formulation purposes and regulatory reasons. Metacetamol is an isomer of paracetamol and it similarly exhibits polymorphism. In the present article, it has been found that one of the polymorphs of metacetamol is only stable under increased pressure, which has led to the conclusion that metacetamol like paracetamol is a monotropic system under ordinary (= laboratory) conditions and that it becomes enantiotropic under pressure with the I-II-L triple point coordinates for metacetamol TI-II-L = 535 ± 10 K and PI-II-L = 692 ± 70 MPa. However, whereas for paracetamol the enantiotropy under pressure can be foreseen, because the metastable polymorph is denser, in the case of metacetamol this is not possible, as the metastable polymorph is less dense than the stable one. The existence of the stability domain for the less dense polymorph of metacetamol can only be demonstrated by the construction of the topological phase diagram as presented in this article. It is a delicate interplay between the specific volume differences and the enthalpy differences causing the stability domain of the less dense polymorph to be sandwiched between the denser polymorph and the liquid. Metacetamol shares this behavior with bicalutamide and fluoxetine nitrate.

Msx1-Positive Progenitors in the Retinal Ciliary Margin Give Rise to Both Neural and Non-neural Progenies in Mammals.

In lower vertebrates, stem/progenitor cells located in a peripheral domain of the retina, called the ciliary margin zone (CMZ), cooperate with retinal domain progenitors to build the mature neural retina. In mammals, it is believed that the CMZ lacks neurogenic potential and that the retina develops from one pool of multipotent retinal progenitor cells (RPCs). Here we identify a population of Msx1-expressing progenitors in the mouse CMZ that is both molecularly and functionally distinct from RPCs. Using genetic lineage tracing, we report that Msx1 progenitors have unique developmental properties compared with RPCs. Msx1 lineages contain both neural retina and non-neural ciliary epithelial progenies and overall generate fewer photoreceptors than classical RPC lineages. Furthermore, we show that the endocytic adaptor protein Numb regulates the balance between neural and non-neural fates in Msx1 progenitors. These results uncover a population of CMZ progenitors, distinct from classical RPCs, that also contributes to mammalian retinogenesis.

Differential Water Thermodynamics Determine PI3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications.

Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, ß, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the ß subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the ß-isoform do not interact directly with either PI3Kß or PI3Kδ, thereby confounding rationalization of the SAR. Here, we apply explicit solvent molecular dynamics and solvent thermodynamic analysis using WaterMap in an effort to understand the unusual affinity and selectivity trends. We find that differences in solvent energetics and water networks, which are modulated upon binding of different ligands, explain the experimental affinity and selectivity trends. This study highlights the critical role of water molecules in molecular recognition and the importance of considering water networks in drug discovery efforts to rationalize and improve selectivity.