Dopamine production in neurotensin receptor 1 neurons is required for diet-induced obesity and increased day eating on a high-fat diet.

OBJECTIVE: This study aimed to determine a dopaminergic circuit required for diet-induced obesity in mice. METHODS: We created conditional deletion mutants for tyrosine hydroxylase (TH) using neurotensin receptor 1 (Ntsr1) Cre and other Cre drivers and measured feeding and body weight on standard and high-fat diets. We then used an adeno-associated virus to selectively restore TH to the ventral tegmental area (VTA) Ntsr1 neurons in conditional knockout (cKO) mice. RESULTS: Mice with cKO of TH using Vglut2-Cre, Cck-Cre, Calb1-Cre, and Bdnf-Cre were susceptible to obesity on a high-fat diet; however, Ntsr1-Cre Th cKO mice resisted weight gain on a high-fat diet and did not experience an increase in day eating unlike their wild-type littermate controls. Restoration of TH to the VTA Ntsr1 neurons of the Ntsr1-Cre Th cKO mice using an adeno-associated virus resulted in an increase in weight gain and day eating on a high-fat diet. CONCLUSIONS: Ntsr1-Cre Th cKO mice failed to increase day eating on a high-fat diet, offering a possible explanation for their resistance to diet-induced obesity. These results implicate VTA Ntsr1 dopamine neurons as promoting out-of-phase feeding behavior on a high-fat diet that could be an important contributor to diet-induced obesity in humans.

Does timely reporting of preoperative CT scans influence outcomes for patients following emergency laparotomy?

INTRODUCTION: Timely preoperative computed tomography (CT) scans are important for patients requiring emergency laparotomy. United Kingdom guidelines state that a CT scan should be reported within 1h for 'critical' patients (will alter management at the time) and within 12h for 'urgent' patients (will alter management but not necessarily that day). METHODS: An observational study included patients who were added to the National Emergency Laparotomy Audit (NELA) at a National Health Service trust from 2014 to 2021. The association of compliance with timings guidance and mortality was investigated. Multivariable logistic regression was used to determine the odds ratio of adherence to guidelines according to age, gender, night time admission, American Society of Anesthesiology (ASA) score, NELA mortality risk and category of scan. Further models determined the influence of adherence to guidelines on mortality, also adjusted for these variables. RESULTS: There were 1,299 patients (48% 'critical' and 52% 'urgent' CT scans). Only 360/1,299 (28%) of scans were undertaken with adherence to the timing guidelines. Critical scans were less likely to adhere to guidelines. Although univariable analysis suggested that adherence to guidelines was associated with reduced mortality, this was not the case in the multivariable model: only age, ASA and NELA mortality risk remained significantly associated with mortality. CONCLUSIONS: A minority of patients met the recommended preoperative CT report timings, and this was less likely for scans designated 'critical'. This did not appear to affect mortality when adjusted for key variables of risk. This illustrates the phenomenon of guideline adherence appearing to affect patient outcomes as a product of selection bias rather than causality.

GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans.

GLP-1 receptor agonists (GLP-1RAs) are effective anti-obesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to obese patients and observed heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1R neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMHGLP-1R neurons selectively during eating behavior. We further identified an intricate interplay between DMHGLP-1R neurons and arcuate NPY/AgRP neurons (ARCNPY/AgRP), to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering novel neural targets for obesity and metabolic diseases.

Awareness of sickle cell disease among nursing undergraduates in Farasan: Its interference with malaria.

Aim: The present study was conducted to generate data on awareness and incidence of sickle cell disease (SCD) and also to adduce the widespread myths peddled about SCD. Materials and Methods: Students studying in the Department of Nursing were recruited. A pretested, self-administered sickle cell assessment questionnaire was distributed electronically through WhatsApp group to collect necessary data. Participants were screened for malaria by thin blood smear analyses, and their hemoglobin (Hb) contents (g/dL) were determined by Sahli's haemoglobinometer. Statistical analyses were done using Origin (version 8.1, USA). A reliability study was performed for the validity of questionnaire data. Results: Study participants had significantly high awareness regarding SCDs (89.9%, P < 0.001). Most participants (96.3%) were aware about government policy regarding premarital screening for genetic disorders and replied that the government has strict health policies backed by equally robust laboratory diagnostics. Moreover, none of the participants had SCDs, although their parents had a consanguineous marriage. Thin blood smear analyses of participants did not reveal any cases of Plasmodium falciparum. However, significant percentages (33.1%) were found to be anemic, probably due to their dietary habits and lifestyles, as has been reflected by questionnaire analyses. Furthermore, a very less number of students had knowledge about genetic variations that might occur in malaria-endemic regions after long exposure to offer protection from malaria. Knowledge about management practices was also lacking among study participants (29%). Conclusion: This research points to the necessity that the nursing study plan should focus on providing specific training on management skills and preventive measures for SCDs, which is of paramount importance.

Mistreatment of nurses by patients and its impact on their caring behaviors: The roles of psychological detachment and supervisor positive gossip.

BACKGROUND: Mistreatment by patients is a detrimental phenomenon predominant in healthcare organizations. However, there is a lack of nursing literature regarding the underlying mechanisms and boundary conditions that exist between mistreatment by patients and its detrimental consequences. AIM: By integrating the Job Demands-Resources Model and the Conservation of Resources Theory, the study aimed to unveil the mediating role of psychological detachment from work in the relationship between mistreatment by patients and nurses' caring behaviors, as well as the moderating effect of supervisor positive gossip. METHODS: This multicenter, cross-sectional study involved 341 nurses from five hospitals across two cities in Egypt. Data were collected using an introductory information form, the Mistreatment by Patients Scale, the Psychological Detachment Scale, the Caring Behaviors Scale, and the Supervisor Positive Gossip Scale. The study's hypotheses were tested using the PROCESS macro. RESULTS: The results showed that mistreatment by patients was negatively related to nurses' caring behaviors via an increased psychological detachment. Further, higher levels of supervisor positive gossip were shown to weaken the direct effect of mistreatment by patients in increasing nurses' psychological detachment, as well as the indirect negative effect of mistreatment by patients on nurses' caring behaviors via psychological detachment. CONCLUSIONS: Mistreatment by patients contributes to nurses' psychological detachment and decreased caring behaviors; however, these negative outcomes can be mitigated by supervisor positive gossip. IMPLICATION FOR NURSING POLICYMAKING: Nursing managers should adopt strategies to deter the rise of mistreatment by patients, and utilize positive gossip to support nurses exposed to such mistreatment to alleviate its consequences.

Exploring the relationship between nursing students' knowledge and attitudes towards climate change and their psychological distress: a cross-national investigation.

BACKGROUND: Climate change poses a worldwide challenge with anticipated exacerbation in the future, resulting in irreversible consequences. Nursing students may be vulnerable to experiencing psychological effects associated with climate change. AIM: The current study aimed to investigate the relationship between nursing students' knowledge and attitudes toward climate change and their psychological distress. METHOD: This descriptive cross-sectional study recruited 377 nursing students from three universities located in Saudi Arabia, Jordan, and Egypt in the Middle East. Data collection was conducted using scales for assessing nursing students' knowledge and attitudes towards climate change and their psychological distress. Correlations were assessed and multiple regression analysis was conducted to explore the predictors of students' psychological distress. RESULTS: The current study showed that knowledge regarding climate change significantly and positively correlated to the attitude toward climate change (r = 0.213), then again, the score of psychological distress significantly and negatively correlated to the score of students' knowledge and attitude regarding climate change (r = - 0.182 and - 0.110 respectively). Regression analyses showed that academic achievement had the strongest positive impact on students' psychological distress, while knowledge regarding climate change and attitude toward climate change had negative impacts (ß = 0.381, ß=-0.205, and ß=-0.045 respectively). Moreover, knowledge and attitude regarding climate change were found to be significant predictors of students' psychological distress, collectively accounting for 18.2% of the observed variance. CONCLUSIONS/IMPLICATION FOR FUTURE PRACTICE: The findings highlight the importance of incorporating climate change into nursing education programs. By enhancing nursing students' knowledge and attitudes towards climate change, there is potential to reduce their psychological distress. This study underscores the need for curriculum reforms that integrate climate change topics, aiming to foster a well-informed and resilient future nursing workforce.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease.

ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Dorsal motor vagal neurons can elicit bradycardia and reduce anxiety-like behavior.

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole-cell patch-clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs and is capable of cardioinhibition and robust anxiolysis.

Replicating shear-mediated self-assembly of spider silk through microfluidics.

The development of artificial spider silk with properties similar to native silk has been a challenging task in materials science. In this study, we use a microfluidic device to create continuous fibers based on recombinant MaSp2 spidroin. The strategy incorporates ion-induced liquid-liquid phase separation, pH-driven fibrillation, and shear-dependent induction of ß-sheet formation. We find that a threshold shear stress of approximately 72 Pa is required for fiber formation, and that ß-sheet formation is dependent on the presence of polyalanine blocks in the repetitive sequence. The MaSp2 fiber formed has a ß-sheet content (29.2%) comparable to that of native dragline with a shear stress requirement of 111 Pa. Interestingly, the polyalanine blocks have limited influence on the occurrence of liquid-liquid phase separation and hierarchical structure. These results offer insights into the shear-induced crystallization and sequence-structure relationship of spider silk and have significant implications for the rational design of artificially spun fibers.

Retraction: Hematocolpos: An Unusual Cause of Right Iliac Fossa Pain.

[This retracts the article DOI: 10.7759/cureus.18835.].

How nursing practice environments limit implicit rationing of care and nurse-assessed adverse events: the role of flow at work.

BACKGROUND: The nursing practice environment is beneficial in curbing implicit rationing of nursing care and adverse patient events. However, the underlying mechanisms of these relationships remain unexplored. AIM: To test whether flow at work mediates the relationship between the nursing practice environment, implicit rationing of nursing care, and nurse-assessed adverse patient events. METHODS: This cross-sectional study involved 231 nurses from five hospitals in Port Said, Egypt. The participants completed Arabic-translated versions of the Practice Environment Scale of the Nursing Work Index, the Work-Related Flow Inventory, the Perceived Implicit Rationing of Nursing Care instrument, and the Adverse Patient Events scale. Structural equation modeling was used to test the hypothetical model. RESULTS: The favorable nursing practice environment positively predicted nurses' flow at work (ß = 0.64, p < 0.001), while inversely predicting implicit rationing of nursing care (ß = -0.23, p = 0.014) and adverse patient events (ß = -0.35, p < 0.001). Nurses' flow at work inversely predicted implicit rationing of nursing care (ß = -0.30, p = 0.002) and adverse patient events (ß = -0.29, p = 0.002). Moreover, nurses' flow at work acted as a mediator, linking the nursing practice environment to the rationing of nursing care and adverse patient events, with 500 bootstrap results for the indirect effects (ß = -0.24, p = 0.001, 95% CI: -0.43 to -0.09; and ß = -0.44, p = 0.003, 95% CI: -0.79 to -0.16, respectively). CONCLUSION: Nurses working in a favorable nursing practice environment are more likely to experience flow at work, limiting implicit rationing of nursing care and adverse patient events. IMPLICATIONS FOR NURSING MANAGEMENT: Nursing administrators should strive to create a healthy nursing practice environment to foster nurses' flow and thereby reduce the frequency of implicit rationing of nursing care and adverse patient events.

Hypophosphatasia: presentation and response to asfotase alfa.

Hypophosphatasia (HPP) is a rare bone disease with limited scientific evidence on the tolerability and safety of its novel treatment, Asfotase Alfa (AA). We report 7 HPP patients' heterogenous presentations and the significant improvement in various clinical outcomes attained with AA shedding light on this highly effective and safe therapy. INTRODUCTION: Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder characterized by a deficiency in the tissue non-specific alkaline phosphatase (TNSALP) due to loss of function mutation in the ALPL gene. HPP is associated with impaired skeletal mineralization due to elevations in inorganic pyrophosphate and altered phosphate : pyrophosphate ratio. Asfotase alfa (AA) "enzyme replacement" was approved for treatment of HPP in 2015. We present 7 patients with HPP, 5 with pediatric-onset, and 2 with adult-onset, who have been treated with AA and describe the efficacy and safety in these patients. METHODS: 7 patients (4 females, 3 males) aged 19-68 years with HPP were included in this study. Diagnosis of HPP was confirmed by DNA analysis. AA was administered in doses of 6mg/kg/week with a mean follow-up of 6 months (SD= 5). RESULTS: Subjective improvement in muscle strength, muscle pain, walking ability, and walking distance with a reduction in the use of gait aids was seen "with AA in HPP patients." Muscle strength and pain improved by up to 70% from baseline as quantified subjectively by patients. Walking distance improved by up to 100%. Patients also reported improved cognition, mood, and energy levels, with up to 90% improvement in mood and 75% improvement in energy levels. 4 out of 6 patients first noted clinical signs of improvement after 3 months of being on therapy. 1 out of the 7 patients sustained a toe fracture 10 months from being on AA. AA was well-tolerated with injection site reactions being the most reported adverse effect. CONCLUSION: HPP treatment with AA in individuals with both pediatric and adult-onset forms resulted in significant subjective improvement in musculoskeletal and cognitive manifestations in addition to patients' quality of life. The drug was well tolerated in 6 patients. 1 patient discontinued therapy because of minor adverse effects with myalgias.

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety.

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons increases feeding and body weight and reduces liraglutide's satiating effects. Our results thus demonstrate a widely applicable method for molecular connectomics, reveal the molecular organization of AgRP neuron afferents, and shed light on a neurocircuit through which GLP-1RAs suppress appetite.

Dorsal Motor Vagal Neurons Can Elicit Bradycardia and Reduce Anxiety-Like Behavior.

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole cell patch clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs capable of cardioinhibition and robust anxiolysis.

The Relationship Between Knee Osteoarthritis-Related Pain Severity and Daily Activities Involving the Upper and Lower Limbs in Saudi Adults: A Cross-Sectional Study.

Introduction Earlier research has shown an association between pain intensity and everyday activities in adults. However, it is vital to examine the relationship within the context of Saudi people who have knee osteoarthritis. Therefore, this study aimed to explore the connection between pain intensity and daily activities involving the lower and upper limbs among patients with knee osteoarthritis in Saudi Arabia. Methods This study enrolled 209 individuals aged 55 years and above who were diagnosed with radiographic knee osteoarthritis by physicians from five hospitals in Riyadh, Saudi Arabia, between March 2016 and March 2017. Participants were divided into two groups based on their pain intensity, measured using the visual analog scale. The first group included 141 individuals with mild or moderate pain, while the second group comprised 68 individuals with severe pain. The study assessed the physical functioning of these individuals by evaluating their ability to perform daily activities involving the lower and upper limbs, using the Physical Functioning Subscale of the 36-item Short Form Health Survey, which includes 10 items. Results Adjusted logistic regression analysis revealed that individuals experiencing severe pain related to knee osteoarthritis were more likely to encounter difficulties in climbing several flights of stairs (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.09-1.29), and one flight of stairs (OR = 1.19, 95% CI = 1.06-1.34), with challenges in bending, kneeling, or stooping (OR = 1.14, 95% CI = 1.05-1.23), walking more than one mile (OR = 1.15, 95% CI = 1.06-1.25), walking several blocks (OR = 1.17, 95% CI = 1.08-1.27), and walking one block (OR = 1.19, 95% CI = 1.06-1.34) than those with mild or moderate pain. Conclusion Our study results highlight the significant impact of severe pain on activities like climbing stairs, bending, kneeling, stooping, and walking longer distances among people with knee osteoarthritis in Saudi Arabia.

Associations Among Knee Osteoarthritis Severity, Body Mass Index, and Physical Functions in Saudi Arabian Adults: A Multi-Center Cross-Sectional Study.

Background The purpose of this study was to investigate the associations among knee osteoarthritis severity, body mass index, and physical functions in Saudi Arabian adults. Methodology In this multi-center, cross-sectional study, we performed a secondary data analysis that included 189 adults aged 55 years or above with doctor-diagnosed knee osteoarthritis enrolled in five hospitals in Riyadh, Saudi Arabia, between March 2016 and March 2017. According to knee osteoarthritis severity, all of the individuals were divided into the following three groups: mild (n = 36), moderate (n = 75), and severe (n = 78). A high body mass index was defined as a body mass index score of >25 kg/m2. Physical function was evaluated using the 36-item physical functioning subscale. Results Severe knee osteoarthritis had a significantly 6.47-fold (95% confidence interval (CI) = 2.95-14.22, p < 0.0001) higher risk of physical function than those with mild knee osteoarthritis after adjusting for age, sex, educational status, occupational status, affected knee with osteoarthritis, knee pain, and body mass index. However, moderate knee osteoarthritis had a 1.22-fold higher risk of physical function, but the association was not statistically significant (95% CI = 0.60-2.49, p = 0.578). Conclusions Severe but not moderate knee osteoarthritis was more likely to have the worst physical function than mild knee osteoarthritis among adults with a high body mass index in Saudi Arabia.

Prevalence and molecular characterization of Giardia intestinalis isolated from children and calves in Babylon province, Iraq.

Background and Aim: Giardia intestinalis is one of the most prevalent intestinal parasites in humans and animals, and children in close contact with livestock are particularly at risk of infection. This study aimed to detect assemblages of G. intestinalis and determine the origin of zoonotic transmission of Giardia in children and calves in different parts of Babylon province, Iraq. Materials and Methods: One hundred stool samples from children (68 boys and 32 girls) and 100 fecal samples from calves (46 males and 54 females) of different ages were randomly collected. Molecular techniques were used to estimate the prevalence of G. intestinalis in children and calves. A nested polymerase chain reaction (PCR) was performed by targeting the triose phosphate isomerase gene in the samples to detect G. intestinalis assemblages. Results: The overall rates of infection with G. intestinalis in children and calves were 21% and 34%, respectively, using the conventional microscopic method. The results illustrated that 61.90% (13/21) and 38.09% (8/21) of positive samples from children were allocated to assemblages A and B, respectively (p > 0.05). In calves, assemblages A and B were detecte in 82.35% (28/34) and 17.64% (6/34) of positive samples from calves, respectively (p ≤ 0.001). Ten PCR products were sequenced and submitted to the GenBank database. Phylogenetic analysis detected five human sequences each belonging to G. intestinalis assemblages A (OM850335-OM850339) and B (OM850340-OM850344). Similarly, five calf sequences each belonged to G. intestinalis assemblages A (ON75756-ON757660) and B (ON757661-ON757665). Conclusion: The detection of large numbers of G. intestinalis assemblage A in both humans and cattle indicated that cattle could be a main source of zoonotic G. intestinalis infection in children in Babylon province, Iraq.

Adult-onset acute disseminated encephalomyelitis: a rare case report in a 26-year-old female and review of literature.

Acute disseminated encephalomyelitis is a demyelinating autoimmune condition that mostly affects the central nervous system. We present a case of a woman who presented with paralysis and speech deficits following an episode of upper respiratory tract infection. Brain and spinal cord imaging were used to confirm the diagnosis.

NMR assignment and dynamics of the dimeric form of soluble C-terminal domain major ampullate spidroin 2 from Latrodectus hesperus.

Spider dragline silk has attracted great interest due to its outstanding mechanical properties, which exceed those of man-made synthetic materials. Dragline silk, which is composed of at least major ampullate spider silk protein 1 and 2 (MaSp1 and MaSp2), contains a long repetitive domain flanked by N-terminal and C-terminal domains (NTD and CTD). Despite the small size of the CTD, this domain plays a crucial role as a molecular switch that regulates and directs spider silk self-assembly. In this study, we report the 1H, 13C, and 15N chemical shift assignments of the Latrodectus hesperus MaSp2 CTD in dimeric form at pH 7. Our solution NMR data demonstrated that this protein contains five helix regions connected by a flexible linker.