A change in metal cation switches selectivity of a phospholipid sensor from phosphatidic acid to phosphatidylserine.

Phosphatidic acid and phosphatidylserine are anionic phospholipids with emerging signalling roles in cells. Determination of how phosphatidic acid and phosphatidylserine change location and quantity in cells over time requires selective fluorescent sensors that can distinguish these two anionic phospholipids. However, the design of such synthetic sensors that can selectively bind and respond to a single phospholipid within the complex membrane milieu remains challenging. In this work, we present a simple and robust strategy to control the selectivity of synthetic sensors for phosphatidic acid and phosphatidylserine. By changing the coordination metal of a dipicolylamine (DPA) ligand from Zn(II) to Ni(II) on the same synthetic sensor with a peptide backbone, we achieve a complete switch in selectivity from phosphatidic acid to phosphatidylserine in model lipid membranes. Furthermore, this strategy was largely unaffected by the choice and the position of the fluorophores. We envision that this strategy will provide a platform for the rational design of targeted synthetic phospholipid sensors to probe plasma and intracellular membranes.

Simplifying the Decision-Making Process in the Treatment of Kienböck's Disease.

Background In recent years, the classification and treatment algorithm for adult Kienböck's disease (KD) has expanded. However, the priority of the investigations done in determining its management has not been discussed, as not every patient with KD requires magnetic resonance imaging (MRI) or wrist arthroscopy. Materials and Methods We discuss the role of these investigations and emphasize the importance of computed tomography (CT) imaging in evaluating the cortical integrity of the lunate and its role in the decision-making process and management of KD. Results We put forward an investigative algorithm that places into context the investigative roles of MRI, arthroscopy, and CT. Conclusion KD is a rare condition, and there is a lack of comparative studies to help us choose the preferred treatment. The decision on the management options in adult KD may be made by determining the integrity of the lunate cortex and deciding whether the lunate is salvageable or not by CT scan. MRI may provide useful information on the vascular status if the lunate cortex is intact, and the lunate is salvageable. If the lunate is fragmented, it is not salvageable, and MRI does not provide useful information. Arthroscopy has a role in selective cases.

A Comparison of Rib Osteochondral Graft to Medial Femoral Trochlear Osteocartilaginous Graft for the Salvage of the Fragmented Scaphoid Proximal Pole: A Single-Center Experience with Minimum 2-Year Follow-Up.

Purpose Fragmented fractures of the proximal pole of the scaphoid that cannot be internally fixed may be salvaged by four-corner arthrodesis or proximal row carpectomy. Replacement of the proximal scaphoid with costal-osteochondral graft (COG) or the medial femoral trochlea (MFT) graft are two alternative solutions for this clinical presentation. The purpose of this study was to compare the clinical and radiographic results of the COG and the MFT graft with a minimum 2-year follow-up from a single centre. Methods A retrospective study was performed to investigate the outcome of COG and MFT with a minimum 2 year follow up. Demographic data and clinical assessment including wrist range of motion and grip strength measurements and Oxford Knee score were collected. Patients completed the outcome measures of Disabilities of Arm, Shoulder, and Hand (DASH), the Patient-Rated Wrist Evaluation (PRWE), and a ten-point visual analogue score for pain (VAS). Radiological examination was performed on all wrists at follow-up. Results The visual analogue score, DASH and PRWE were similar between the two groups. There was radiographic evidence of arthritis between the radial styloid and distal scaphoid in all patients that underwent COG but no evidence in those that underwent MFT graft reconstruction. There were different complications in each group. Thirty percent of patients that underwent MFT reconstruction had persistent knee pain at follow up. Conclusion Though there are notable differences in the follow-up period, patients undergoing MFT risk developing knee pain, while those undergoing COG risk radiographic progression of wrist arthritis. Level of Evidence III - Comparative study.

The Impact of a Digital Contraceptive Decision Aid on User Outcomes: Results of an Experimental, Clinical Trial.

BACKGROUND: Nearly 40% of unplanned pregnancies in the USA are the result of inconsistent or incorrect contraceptive use. Finding ways to increase women's comfort and satisfaction with contraceptive use is therefore critical to public health. One promising pathway for improving patient outcomes is through the use of digital decision aids that assist women and their physicians in choosing a contraceptive option that women are comfortable with. Testing the ability of these aids to improve patient outcomes is therefore a necessary first step toward incorporating this technology into traditional physician appointments. PURPOSE: To evaluate the effectiveness of a novel contraceptive decision aid at minimizing decisional conflict and increasing comfort with contraception among adult women. METHODS: In total, 310 adult women were assigned to use either the Tuune contraceptive decision aid or a control aid modeled after a leading online contraceptive prescriber's patient intake form. Participants then completed self-report measures of decisional conflict, contraceptive expectations, satisfaction, and contraceptive use intentions. Individual between-subjects analysis of variance (ANOVA) models were used to examine these outcomes. RESULTS: Women using the Tuune decision aid (vs. those using the control aid) reported lower decisional conflict, more positive contraceptive expectations, greater satisfaction with the decision aid and recommendation, and more positive contraceptive use intentions. CONCLUSIONS: Use of Tuune improved each of the predicted patient outcomes relative to a control decision aid. Online decision aids, particularly when used alongside physician consultations, may be an effective tool for increasing comfort with contraceptive use. CLINICAL TRIALS REGISTRATION #: NCT05177783, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT05177783.

Digital decision aids that help women and their physicians choose contraceptive options that women are most comfortable with present one promising way to improve contraceptive use outcomes, such as avoiding unplanned pregnancies. However, current decision aids have been found to struggle in helping improve women's satisfaction with and confidence in their contraceptive choices. The aim of this study was to test the effectiveness of a new digital decision aid, named Tuune, at helping improve women's confidence and comfort with contraception. Three hundred and ten adult women were randomly assigned to use and then receive a contraceptive recommendation from either the Tuune decision aid or a control aid designed after leading traditional health intake forms. Women's confidence and satisfaction with the aids, as well as their contraceptive recommendation, were then compared between groups. We found good evidence to suggest that women using the Tuune contraceptive decision aid were more satisfied and positive about their contraceptive choices and reported greater intentions to use contraception with increased confidence compared to women who used the control decision aid. New online decision aids, like Tuune, may be an effective tool for increasing women's comfort and experiences using contraception.

The mediating role of reflective functioning and general psychopathology in the relationship between childhood conduct disorder and adult aggression among offenders.

BACKGROUND: The nature of the pathway from conduct disorder (CD) in adolescence to antisocial behavior in adulthood has been debated and the role of certain mediators remains unclear. One perspective is that CD forms part of a general psychopathology dimension, playing a central role in the developmental trajectory. Impairment in reflective functioning (RF), i.e., the capacity to understand one's own and others' mental states, may relate to CD, psychopathology, and aggression. Here, we characterized the structure of psychopathology in adult male-offenders and its role, along with RF, in mediating the relationship between CD in their adolescence and current aggression. METHODS: A secondary analysis of pre-treatment data from 313 probation-supervised offenders was conducted, and measures of CD symptoms, general and specific psychopathology factors, RF, and aggression were evaluated through clinical interviews and questionnaires. RESULTS: Confirmatory factor analyses indicated that a bifactor model best fitted the sample's psychopathology structure, including a general psychopathology factor (p factor) and five specific factors: internalizing, disinhibition, detachment, antagonism, and psychoticism. The structure of RF was fitted to the data using a one-factor model. According to our mediation model, CD significantly predicted the p factor, which was positively linked to RF impairments, resulting in increased aggression. CONCLUSIONS: These findings highlight the critical role of a transdiagnostic approach provided by RF and general psychopathology in explaining the link between CD and aggression. Furthermore, they underscore the potential utility of treatments focusing on RF, such as mentalization-based treatment, in mitigating aggression in offenders with diverse psychopathologies.

Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction.

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in Caenorhabditis elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

The effect of a music-based caregiving intervention on pain intensity in nursing home patients with dementia: a cluster-randomized controlled study.

ABSTRACT: Treatment of chronic pain in patients with dementia is challenging because they have reduced ability to report pain and are particularly vulnerable to side effects of analgesics. Different types of music-based therapy have been recommended and are used as an alternative to analgesics, but the evidence is lacking. Therefore, we performed a cluster-randomized controlled study (RCT) to reduce pain intensity using music-based caregiving (MBC) over 8 weeks in nursing home patients with dementia and chronic pain. We also investigated if the amount of MBC and different chronic pain syndromes would impact on the effect. Of the 645 patients, 498 patients from 36 wards in 12 nursing homes were screened for dementia and pain. Using the Clinical Dementia Rating Scale and the Mobilization-Observation-Behavior-Intensity-Dementia Pain Scale (range 0-10), 279 (71% females, 42% severe dementia) nursing home patients were randomized to intervention group (n = 134, 18 wards) or control group (n = 145, 18 wards). The main outcome was change in pain intensity before and after the intervention. The study did not reveal any effect of MBC on pain intensity when compared with the control group (B = -0.15, 95% CI [-0.72 to 0.43]). No significant difference was found within the intervention group analyzing the impact of intervention time (B = 0.73, 95% CI [-0.55 to 2.02]) or chronic primary vs secondary pain syndromes (B = 0.45, 95% CI [-0.05 to 0.96]). Our data from this first RCT on music and pain intensity in patients with dementia and chronic pain did not find an effect of MBC on pain.

Attachment style and children and young people with chronic dermatological conditions.

BACKGROUND: Dermatological conditions are common in childhood and, in their more severe forms, can cause pain, disability and social marginalisation. Despite attachment being a known factor contributing to psychological and physiological development in childhood and several adult studies showing associations between attachment and dermatology outcomes (Tomas-Aragones, 2018), attachment in young dermatology patients has not been investigated. OBJECTIVES: This study examined if (1) 8-16-year-olds with chronic dermatological conditions were more likely to show attachment insecurity than general population peers; (2) attachment style was linked to psychological functioning; and (3) facial involvement was associated with attachment insecurity. METHOD: One hundred and twenty-two 8-16-year-olds attending a specialist paediatric dermatological service were compared on the Child Attachment Interview (CAI) to general population data. The Strengths and Difficulties Questionnaire (SDQ) was used to measure psychosocial functioning. RESULTS: The dermatology group was significantly more likely to be insecurely attached than their general population peers (χ2 [1] = 4.76, p < .05). The secure group self-reported significantly better psychological functioning on all indices compared with the insecure group (Total Difficulties: F[1,89] = 15.30, p < .001). There were no significant differences between secure and insecure groups on parent-reported psychological measures (Total Difficulties: F[1,94] = 0.67, p = .42). Children with facial involvement were not significantly more likely to be insecurely attached. CONCLUSIONS: Increased risk of attachment insecurity, particularly in the anxious pre-occupied category, as well as an association between attachment and psychosocial functioning resonated with adult studies suggesting that further research about the role of attachment with young dermatology patients is warranted.

A dual encapsulation strategy to generate anion-responsive luminescent lanthanide hydrogels.

We report a new method to generate ion-responsive luminescent hydrogels, involving encapsulation of a luminescent lanthanide probe within crosslinked amphiphilic polymer particles and subsequent entrapment within a hydrogel. The resulting hydrogels are capable of reversible bicarbonate sensing, exhibit no leaching, and can be tuned for a range of sensing applications.

A macrocyclic fluorescent probe for the detection of citrate.

We present a macrocyclic fluorescent probe for the detection of citrate. This receptor binds citrate through hydrogen-bonding interactions in aqueous solutions, and exhibits a turn-on in fluorescence in response to binding. The presence of common biologically relevant dicarboxylate species does not significantly impact the fluorescence response. We have demonstrated the utility of this probe with the staining of murine splenocytes, and identified different basal levels of citrate present in immune cell subsets via flow cytometry analysis.

Review: Use of assisted reproduction in seasonal-calving dairy herds.

A unique aspect of seasonal-calving pasture-based systems of dairy production is the intense focus placed on achieving a concentrated herd-calving period in late winter and early spring. Hence, excellent reproductive performance is required during a short breeding period. A concentrated calving period also produces a problem in the form of a large number of male dairy calves being born at the same time; as these calves have little economic value due to poor beef merit, they present a potential welfare concern. A solution exists in the form of sex-sorted semen, but this is typically associated with poorer pregnancy per artificial insemination, and hence, the use of sex-sorted semen must be carefully considered. The logical strategy to use sex-sorted semen is to target the best genetic merit dams in the herd to generate replacement heifers, thereby accelerating herd genetic gain. On the other hand, if all dairy farmers adopt such a strategy, there will be a corresponding reduction in elite genetic merit male dairy calves being born, potentially reducing availability of the next generation of future bulls to be used for artificial insemination. Use of in vitro embryo production on elite dairy donors could avoid this problem by acting as a multiplier, potentially in tandem with Y-sorted semen to skew the offspring sex ratio towards more male calves. Use of sex-sorted semen on the best genetic merit dams can also facilitate a marked increase in the usage of beef semen on any dams that are deemed unsuitable for sex-sorted semen. The use of "beef on dairy" requires selection of beef bulls that generate offspring with traits that meet the key requirements of both the dairy farmer (e.g., gestation length and calving ease) and the beef farmer that must be motivated to purchase the calves (e.g., growth rate, age at slaughter, carcass value). Beef breed dams that have elite genetic merit for these traits could also be considered for in vitro embryo production, potentially in tandem with Y-sorted semen, to facilitate genetic gain for the growing "beef-on-dairy" market. It is possible to transfer a beef embryo (75-100% beef breed genetics) into dairy dams that are not required to generate replacements, but this is likely to remain a niche practice as there are many barriers to widespread adoption. Such combinations of assisted reproduction have the potential to improve the efficiency and sustainability metrics of seasonal-calving pasture-based dairy herds.

Transmembrane Transport of Inorganic Phosphate by a Strapped Calix[4]pyrrole.

Synthetic anion receptors are increasingly being explored for the transport of anions across lipid membranes because of their potential therapeutic applications. A considerable amount of research focuses on the transport of chloride, whereas the transmembrane transport of inorganic phosphate has not been reported to date, despite the biological relevance of this anion. Here we present a calix[4]pyrrole with a bisurea strap that functions as a receptor and transporter for H2PO4-, relying on the formation of eight hydrogen bonds and efficient encapsulation of the anion. Using a phosphate-sensitive lanthanide probe and 31P NMR spectroscopy, we demonstrate that this receptor can transport phosphate into vesicles by H2PO4-/Cl- antiport, H2PO4- uniport, and Cs+/H2PO4- symport mechanisms. This first example of inorganic phosphate transport by a neutral receptor opens perspectives for the future development of transporters for various biological phosphates.

Structural and functional properties of the transporter SLC26A6 reveal mechanism of coupled anion exchange.

Members of the SLC26 family constitute a conserved class of anion transport proteins, which encompasses uncoupled transporters with channel-like properties, coupled exchangers and motor proteins. Among the 10 functional paralogs in humans, several participate in the secretion of bicarbonate in exchange with chloride and thus play an important role in maintaining pH homeostasis. Previously, we have elucidated the structure of murine SLC26A9 and defined its function as an uncoupled chloride transporter (Walter et al., 2019). Here we have determined the structure of the closely related human transporter SLC26A6 and characterized it as a coupled exchanger of chloride with bicarbonate and presumably also oxalate. The structure defines an inward-facing conformation of the protein that generally resembles known structures of SLC26A9. The altered anion selectivity between both paralogs is a consequence of a remodeled ion binding site located in the center of a mobile unit of the membrane-inserted domain, which also accounts for differences in the coupling mechanism.

Expedient synthesis and luminescence sensing of the inositol pyrophosphate cellular messenger 5-PP-InsP5.

Inositol pyrophosphates are important biomolecules associated with apoptosis, cell growth and kinase regulation, yet their exact biological roles are still emerging and probes do not exist for their selective detection. We report the first molecular probe for the selective and sensitive detection of the most abundant cellular inositol pyrophosphate 5-PP-InsP5, as well as an efficient new synthesis. The probe is based on a macrocyclic Eu(iii) complex bearing two quinoline arms providing a free coordination site at the Eu(iii) metal centre. Bidentate binding of the pyrophosphate group of 5-PP-InsP5 to the Eu(iii) ion is proposed, supported by DFT calculations, giving rise to a selective enhancement in Eu(iii) emission intensity and lifetime. We demonstrate the use of time-resolved luminescence as a bioassay tool for monitoring enzymatic processes in which 5-PP-InsP5 is consumed. Our probe offers a potential screening methodology to identify drug-like compounds that modulate the activity of enzymes of inositol pyrophosphate metabolism.

Transmembrane transport of fluoride studied by time-resolved emission spectroscopy.

Here we present a new method to monitor fluoride transmembrane transport into liposomes using a europium(III) complex. We take advantage of the long emission lifetime of this probe to measure the transport activity of a fluorescent transporter. The high sensitivity, selectivity, and versatility of the assay allowed us to study different types of fluoride transporters and unravel their mechanisms of action.

Identification of prescription opioid misuse and abuse behaviors and risk factors in chronic pain patients using the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ).

OBJECTIVES: To identify patient risk factors associated with prescription opioid misuse and abuse as well as groupings of misuse and abuse behaviors as measured by the Prescription Opioid Misuse and Abuse Questionnaire (POMAQ). METHODS: Adults with chronic pain requiring long-term treatment with opioids completed the POMAQ and other study questionnaires. Latent class analysis (LCA) was used to examine underlying subgroups exhibiting particular risk profiles. Patient demographic and clinical characteristics were examined as covariates and the concordance between the identified latent classes at-risk classifications and the POMAQ clinical scoring algorithm was assessed. RESULTS: Analysis of data from 809 patients revealed four classes: "chronic pain, low risk" (n = 473, low to no prevalence of POMAQ behaviors), "chronic pain, comorbid condition" (n = 152, high prevalence of anti-anxiety, sleeping pill, and antihistamine use), "at risk" (n = 154, taking more opioids than prescribed and drinking alcohol with opioids more frequently than other groups), and "high risk" (n = 30, highest prevalence of each behavior). The "high risk" group was associated with being younger, less educated, and unemployed compared to other groups. When examining the LCA classes by groups defined by the original POMAQ clinical scoring algorithm, the "high risk" class had the highest proportion of participants identified with abuse behaviors (46.7%), compared to just 4.7% in the "chronic pain, low risk" group. CONCLUSIONS: Findings suggest there are four distinct subgroups of patients defined by chronic opioid misuse and abuse behaviors and support the use of the POMAQ to identify risk factors associated with prescription opioid misuse and abuse.

Multidisciplinary Pain Management: A Tale of Two Outcomes.

Economic implications of pain management. By Loeser JD. Acta Anaesthesiol Scand 1999; 43:957-95. Reprinted with permission. Multidisciplinary pain management was an invention of John J. Bonica, M.D. He started the Multidisciplinary Pain Clinic at the University of Washington in 1960. This clinical service evolved over the years, and when John Loeser, M.D., became its director in 1982, he collaborated with Bill Fordyce, Ph.D., to create what was known as "the structured program." The program has served as the model for pain treatment programs throughout the world, many of which have fared better than that at the University of Washington. The migration of Stephen Butler, M.D., to Uppsala, Sweden, in 2000 has given us the opportunity to contrast multidisciplinary pain management in the Nordic countries with that in the United States.

Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries.

OBJECTIVES: Peripheral neuropathies that occur secondary to nerve injuries may be painful or painless, and including a low-grade inflammation and pro-inflammatory cytokines associated with both regeneration and damage of peripheral nerve cells and fibers. Currently, there are no validated methods that can distinguished between neuropathic pain and painless neuropathy. The aim of this study was to search for proinflammatory and anti-inflammatory proteins associated with pain and experimental pain sensitivity in subjects with surgeon-verified nerve injuries in the upper extremities. METHODS: One hundred and thirty-one subjects [69 with neuropathic pain, NP; 62 with painless neuropathy, nP] underwent a conditioned pain modulation (CPM) test that included a cold pressor task (CPT) conducted with the non-injured hand submerged in cold water (4 °C) until pain was intolerable. CPM was assessed by pain ratings to pressure stimuli before and after applying the CPT. Efficient CPM effect was defined as the ability of the individual's CS to inhibit at least 29% of pain (eCPM). The subjects were assigned to one of two subgroups: pain sensitive (PS) and pain tolerant (PT) after the time they could tolerate their hand in cold water (PS<40 s and PT=60 s) . Plasma samples were analyzed for 92 proteins incorporated in the inflammation panel using multiplex Protein Extension Array Technology (PEA). Differentially expressed proteins were investigated using both univariate and multivariate analysis (principal component analysis-PCA and orthogonal partial least-squares discriminant analysis-OPLS-DA). RESULTS: Significant differences in all protein levels were found between PS and PT subgroups (CV-ANOVA p<0.001), but not between NP and nP groups (p=0.09) or between inefficient CPM (iCPM) and eCPM (p=0.53) subgroups. Several top proteins associated with NP could be detected using multivariate regression analysis such as stromelysin 2 (MMPs), interleukin-2 receptor subunit beta (IL2RB), chemokine (C-X-C motif) ligand 3 (CXCL3), fibroblast growth factor 5 (FGF5), chemokine (C-C motif) ligand 28 (CCL28), CCL25, CCL11, hepatocyte growth factor (HGF), interleukin 4 (IL4), IL13. After adjusting for multiple testing, none of these proteins correlated significantly with pain. Higher levels of CCL20 (p=0.049) and CUB domain-containing protein (CDCP-1; p=0.047) were found to correlate significantly with cold pain sensitivity. CDCP-1 was highly associated with both PS and iCPM (p=0.042). CONCLUSIONS: No significant alterations in systemic proteins were found comparing subjects with neuropathic pain and painless neuropathy. An expression of predominant proinflammatory proteins was associated with experimental cold pain sensitivity in both subjects with pain and painless neuropathy. One these proteins, CDC-1 acted as "molecular fingerprint" overlapping both CPM and CPT. This observation might have implications for the study of pain in general and should be addressed in more detail in future experiments.