On the reduction principle for differential equations with piecewise constant argument of generalized type

In this paper we introduce a new type of differential equations with piecewise constant argument (EPCAG), more general than EPCA. The Reduction Principle is proved for EPCAG. The structure of the set of solutions is specified. We establish also the existence of global integral manifolds of quasilinear EPCAG in the so called critical case and investigate the stability of the zero solution

A blinded, randomized, controlled trial assessing conservative management strategies for frozen shoulder

BACKGROUND: There is little evidence for the optimal form of nonoperative treatment in the management of frozen shoulder. This study assesses the efficacy of current physiotherapy strategies. METHODS: All primary care referrals of frozen shoulder to our physiotherapy department were included during a 12-month period. Of these referrals, 17% met the inclusion criteria for primary idiopathic frozen shoulder. The 75 patients were randomly assigned to 1 of 3 groups: group exercise class, individual physiotherapy, and home exercises alone. A single independent physiotherapist, who was blinded to the treatment groups, made all assessments. Range of motion, Constant score, Oxford Shoulder Score, Short Form 36, and Hospital Anxiety and Disability Scale (HADS) outcome measures were performed at baseline, 6 weeks, 6 months, and 1 year. RESULTS: The exercise class group improved from a mean Constant score of 39.8 at baseline to 71.4 at 6 weeks and 88.1 at 1 year. There was a significant improvement in shoulder symptoms on Oxford and Constant scores (P < .001). This improvement was greater than with individual physiotherapy or home exercises alone (P < .001). The improvement in range of motion was significantly greater in both physiotherapy groups over home exercises (P < .001). HADS scores significantly improved during the course of treatment (P < .001). The improvement in HADS anxiety score was significantly greater in both physiotherapy intervention groups than in home exercises alone. CONCLUSIONS: A hospital-based exercise class can produce a rapid recovery from a frozen shoulder with a minimum number of visits to the hospital and is more effective than individual physiotherapy or a home exercise program

Metabolic Synergy between Human Symbionts \u3ci\u3eBacteroides\u3c/i\u3e and \u3ci\u3eMethanobrevibacter\u3c/i\u3e

ABSTRACT Trophic interactions between microbes are postulated to determine whether a host microbiome is healthy or causes predisposition to disease. Two abundant taxa, the Gram-negative heterotrophic bacterium Bacteroides thetaiotaomicron and the methanogenic archaeon Methanobrevibacter smithii, are proposed to have a synergistic metabolic relationship. Both organisms play vital roles in human gut health; B. thetaiotaomicron assists the host by fermenting dietary polysaccharides, whereas M. smithii consumes end-stage fermentation products and is hypothesized to relieve feedback inhibition of upstream microbes such as B. thetaiotaomicron. To study their metabolic interactions, we defined and optimized a coculture system and used software testing techniques to analyze growth under a range of conditions representing the nutrient environment of the host. We verify that B. thetaiotaomicron fermentation products are sufficient for M. smithii growth and that accumulation of fermentation products alters secretion of metabolites by B. thetaiotaomicron to benefit M. smithii. Studies suggest that B. thetaiotaomicron metabolic efficiency is greater in the absence of fermentation products or in the presence of M. smithii. Under certain conditions, B. thetaiotaomicron and M. smithii form interspecies granules consistent with behavior observed for syntrophic partnerships between microbes in soil or sediment enrichments and anaerobic digesters. Furthermore, when vitamin B12, hematin, and hydrogen gas are abundant, coculture growth is greater than the sum of growth observed for monocultures, suggesting that both organisms benefit from a synergistic mutual metabolic relationship. IMPORTANCE The human gut functions through a complex system of interactions between the host human tissue and the microbes which inhabit it. These diverse interactions are difficult to model or examine under controlled laboratory conditions. We studied the interactions between two dominant human gut microbes, B. thetaiotaomicron and M. smithii, using a seven-component culturing approach that allows the systematic examination of the metabolic complexity of this binary microbial system. By combining high-throughput methods with machine learning techniques, we were able to investigate the interactions between two dominant genera of the gut microbiome in a wide variety of environmental conditions. Our approach can be broadly applied to studying microbial interactions and may be extended to evaluate and curate computational metabolic models. The software tools developed for this study are available as user-friendly tutorials in the Department of Energy KBase

Accessing elite nurses for research: reflections on the theoretical and practical issues of telephone interviewing

Elite groups are interesting as they frequently are powerful (in terms of position, knowledge and influence) and enjoy considerable authority. It is important, therefore, to involve them in research concerned with understanding social contexts and processes. This is particularly pertinent in healthcare, where considerable strategic development and change are features of everyday practice that may be guided or perceived as being guided, by elites. This paper evolved from a study investigating the availability and role of nurses whose remit involved leading nursing research and development within acute NHS Trusts in two health regions in Southern England. The study design included telephone interviews with Directors of Nursing Services during which time the researchers engaged in a reflective analysis of their experiences of conducting research with an `elite' group. Important issues identified were the role of gatekeepers, engagement with elites and the use of the telephone interview method in this context. The paper examines these issues and makes a case for involving executive nurses in further research. The paper also offers strategies to help researchers design and implement telephone interview studies successfully to maximise access to the views and experiences of `hard to reach groups', such as elites, while minimising the associated disruption

Qualitative Evaluation of RADx-UP Projects Addressing COVID-19 Testing Disparities Among Underserved Populations

In this article, we present findings from a May 2022 to March 2023 qualitative evaluation of Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) projects addressing COVID-19 testing disparities among underserved populations. Interviews with academic and community partners from 13 RADx-UP projects revealed that despite the pandemic, projects were able to build trust and relationships with underserved populations. By prioritizing community voices during a public health emergency, RADx-UP projects improved health equity and pandemic preparedness in these communities, successfully conducted community-engaged research, and built long-lasting community partnerships. (Am J Public Health. Published online ahead of print March 28, 2024:e1-e6. https://doi.org/10.2105/AJPH.2024.307632)

Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding

Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound "micro-receptors." In such structures, the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A and B chains. This "open" conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed by segmental flexibility in the native state as probed by heteronuclear NMR spectroscopy and multiple conformer simulations of crystallographic protomers as described in the companion article. We propose a model of the SCI's IR-bound state based on molecular-dynamics simulations of a micro-receptor complex. In this model, a loop defined by the SCI's B and C domains encircles the C-terminal segment of the IR α-subunit. This binding mode predicts a conformational transition between an ultra-stable closed state (in the free hormone) and an active open state (on receptor binding). Optimization of this switch within an ultra-stable SCI promises to circumvent insulin's complex global cold chain. The analog's biphasic activity, which serendipitously resembles current premixed formulations of soluble insulin and microcrystalline suspension, may be of particular utility in the developing world

Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level.

Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction

Diurnal rhythms in neural activation in the mesolimbic reward system: critical role of the medial prefrontal cortex

Previous evidence suggests a circadian modulation of drug‐seeking behavior and responsiveness to drugs of abuse. To identify potential mechanisms for rhythmicity in reward, a marker of neural activation (c F os) was examined across the day in the mesolimbic reward system. Rats were perfused at six times during the day [zeitgeber times ( ZT s): 2, 6, 10, 14, 18, and 22], and brains were analysed for c F os and tyrosine hydroxylase ( TH )‐immunoreactive ( IR ) cells. Rhythmic expression of c F os was observed in the nucleus accumbens ( NA c) core and shell, in the medial prefrontal cortex (m PFC ), and in TH ‐ IR and non‐ TH ‐ IR cells in the ventral tegmental area ( VTA ), with peak expression during the late night and nadirs during the late day. No significant rhythmicity was observed in the basolateral amgydala or the dentate gyrus. As the m PFC provides excitatory input to both the NA c and VTA , this region was hypothesised to be a key mediator of rhythmic neural activation in the mesolimbic system. Hence, the effects of excitotoxic m PFC lesions on diurnal rhythms in c F os immunoreactivity at previously observed peak ( ZT 18) and nadir ( ZT 10) times were examined in the NA c and VTA . m PFC lesions encompassing the prelimbic and infralimbic subregions attenuated peak c F os immunoreactivity in the NA c, eliminating the diurnal rhythm, but had no effect on VTA rhythms. These results suggest that rhythmic neural activation in the mesolimbic system may contribute to diurnal rhythms in reward‐related behaviors, and indicate that the m PFC plays a critical role in mediating rhythmic neural activation in the NA c. Previous evidence suggests a circadian modulation of drug‐seeking behavior and responsiveness to drugs of abuse. To identify potential mechanisms for rhythmicity in reward, a maker of neural activation (c F os) was examined across the day in the mesolimbic reward system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99016/1/ejn12224.pd

A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma

Among 249 patients with teratoma-associated encephalitis, 211 had N-methyl-D-aspartate receptor antibodies and 38 were negative for these antibodies. Whereas antibody-positive patients rarely developed prominent brainstem-cerebellar symptoms, 22 (58%) antibody-negative patients developed a brainstem-cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (range = 12-41), 91% were women, and 74% had full recovery after therapy and tumor resection. These findings uncover a novel phenotype of paraneoplastic opsoclonus that until recently was likely considered idiopathic or postinfectious. The triad of young age (teenager to young adult), systemic teratoma, and high response to treatment characterize this novel brainstem-cerebellar syndrome753435441United States Department of Health & Human Services National Institutes of Health (NIH) - USA; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI); Fundacio la Marato de TV3; Instituto de Salud Carlos III; KWF Kankerbestrijding; McKnight Neuroscience of Brain Disorders award; Instituto de Salud Carlos III; ICRE