Recent estimates report that 2.4 billion people with health conditions globally could benefit from rehabilitation. While the benefits of rehabilitation for individuals and society have been described in the literature, many individuals, especially in low- and middle-income countries do not have access to quality rehabilitation. As the need for rehabilitation continues to increase, it is crucial that health systems are adequately prepared to meet this need. Practice- and policy-relevant evidence plays an important role in health systems strengthening efforts. The aim of this paper is to report on the outcome of a global consultative process to advance the development of a research framework to stimulate health policy and systems research (HPSR) for rehabilitation, in order to generate evidence needed by key stakeholders.A multi-stakeholder participatory technical consultation was convened by WHO to develop a research framework. This meeting included participants from selected Member States, rehabilitation experts, HPSR experts, public health researchers, civil society and other stakeholders from around the world. The meeting focused on introducing systems approaches to stakeholders and deliberating on priority rehabilitation issues in health systems. Participants were allocated to one of four multi-stakeholder groups with a facilitator to guide the structured technical consultations. Qualitative data in the form of written responses to guiding questions were collected during the structured technical consultations. A technical working group was then established to analyse the data and extract its emerging themes. This informed the development of the HPSR framework for rehabilitation and a selection of preliminary research questions that exemplify how the framework might be used.A total of 123 individuals participated in the multi-stakeholder technical consultations. The elaborated framework is informed by an ecological model and puts forth elements of the six WHO traditional building blocks of the health system, while emphasizing additional components pertinent to rehabilitation, such as political priority, engagement and participatory approaches, and considerations regarding demand and access. Importantly, the framework highlights the multilevel interactions needed across health systems in order to strengthen rehabilitation. Additionally, an initial set of research questions was proposed as a primer for how the framework might be used.Strengthening health systems to meet the increasing need for rehabilitation will require undertaking more HPSR to inform the integration of rehabilitation into health systems globally. We anticipate that the proposed framework and the emerging research questions will support countries in their quest to increase access to rehabilitation for their populations. Rehabilitation refers to “a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions in interaction with their environment” , where “The effects of a lack of access to appropriate rehabilitation services can be seen in worsened individual health outcomes and limited participation in society; this in turn has a marked effect on the achievement of several Sustainable Development Goals (SDGs), including SDG 3  and SDG 8 (decent work and economic growth) , 5.Despite the benefits of rehabilitation to individuals and society at large, there remain persisting needs for rehabilitation globally. According to recent estimates, 2.4 billion people with health conditions could be in need of rehabilitation globally; this need has increased by 63% since 1990 , 8. ThisSignificantly, however, this need for rehabilitation is not matched with the demand for rehabilitation. Here “demand” refers to the number of people actually accessing services and therefore represents a proportion of the total need. The provision of rehabilitation has generally been under-prioritized in countries. Limitations posed by human and financial resource constraints to provide rehabilitation are factors . RehabilMultidisciplinary in nature, health policy and systems research (HPSR) aims to draw a comprehensive picture of how health systems respond and adapt to health policies. HPSR also aims to describe how health policies can shape and are themselves shaped by health systems and the broader determinants of health . Such a Situating rehabilitation within health systems instead of as a vertical programme driven by stand-alone delivery mechanisms enables a more holistic appreciation of what comprises rehabilitation, while recognizing that rehabilitation is susceptible to broader systemic influences. To date, however, there has been little guidance on how HPSR might be applied to rehabilitation. In the context of achieving universal health coverage (UHC) and the SDGs, an HPSR approach towards rehabilitation is needed. Given these gaps, this paper presents a framework for stimulating HPSR for the purpose of strengthening rehabilitation and proposes an initial set of research questions to demonstrate the potential of the framework.In July 2019, the Rehabilitation Programme and the Alliance for Health Policy and Systems Research (the Alliance) at WHO jointly organized a 2-day global consultative meeting in Geneva. The aim of the meeting was to develop an emerging HPSR agenda for rehabilitation. Participants from selected Member States, rehabilitation experts, HPSR experts, public health researchers, civil society and other stakeholders were invited . SpecifiPotential participants were identified by members of the WHO Rehabilitation Programme through a pre-existing global database of rehabilitation stakeholders. Specifically, purposive sampling was employed to achieve maximum variation with regards to the regions, countries and types of organizations in attendance so that the consultation and final products would have relevance for the diverse needs of countries . In addiA summary of the types of stakeholders in attendance is provided in Table On day 1 of the meeting, participants were taken through a series of presentations to orient them to the imperative for developing an HPSR agenda for rehabilitation, systems-level design, evaluation and research questions, as well as potential enablers and barriers to advancing this HPSR agenda for rehabilitation. A preliminary HPSR framework for rehabilitation  governance and leadership for rehabilitation through political buy-in and commitment, and embedding rehabilitation within the overall health and SDG agenda; 2) accessible, equitable and user-centred service delivery models that integrate rehabilitation within all levels of care, especially primary care; (3) availability of financial and nonfinancial resources to provide rehabilitation; (4) stakeholder engagement across various sectors, including health, finance, civil society, communities, end-users, public and private sectors; and (5) social support structures. The relationship between the common themes identified and the research areas is depicted in Table  accessibBased on this analysis, we present a framework to stimulate thinking on how HPSR approaches might increasingly support researchers, policy-makers and practitioners to address the pressing questions of how health systems can respond to the high need for rehabilitation in countries.The presented framework is informed by an ecological model, which recognizes the presence of multiple layers that may influence an individual . Its Fi multipleWhile the primary focus of research might be at any level, it is important to note that these levels are not independent of one another. Rather, research findings in one level will undoubtedly have relevance for another. For example, findings which depict the national policy landscape of rehabilitation in a country will have implications for rehabilitation service delivery at the subnational and facility levels. Alternatively, there might be processes which occur at more than one level and thus require concurrent examination. An example of this might include assessing existing health facility assessment tools for rehabilitation services alongside a country’s overarching strategy for ongoing monitoring and evaluation of rehabilitation.Since each of the levels exist within a broader context beyond the national level, research must account for these broader country, regional and global contexts which have a bearing on rehabilitation in a country. These considerations include political, social, economic, demographic and epidemiological factors. All these considerations of the levels and broader contexts might be represented in a framework as depicted in Fig. Given the above proposed framing, we outline several research questions for rehabilitation that are stimulated by HPSR approaches. The proposed research questions are presented alongside their related common themes and research areas Table , althougInherent to HPSR is its question-driven nature. This means that the methods to be used will serve the questions being asked, and not vice versa. Therefore, in answering these questions, there is a multiplicity of research methods and approaches that can be used, including quantitative, qualitative and mixed methods , 23.This paper reports on the outcome of the global consultative meeting on HPSR for rehabilitation which took place following the second Global Rehabilitation 2030 meeting. In particular, this paper proposes a framework to stimulate HPSR in rehabilitation with the intention to align the discourse regarding rehabilitation with a more systemic perspective. This supports current evidence which examines rehabilitation from a health systems perspective , and goeThe framework and research questions support the goals of the Rehabilitation 2030 agenda by facilitating evidence-informed policy implementation, which in turn supports policy-makers’ efforts to strengthen health systems for rehabilitation , 25. TheThe presented framework lends itself for use in its current or an adapted form by a range of stakeholders. First, policy-makers may identify where additional research is needed to inform rehabilitation-relevant policy development and implementation. Second, researchers in collaboration with policy-makers may use this framework to guide areas for research inquiry relevant to rehabilitation in countries. Third, rehabilitation professional organizations can generate hypotheses about the forces that are important for training and deploying a rehabilitation workforce. Fourth, civil society might employ the framework to identify what advocacy areas need special attention when addressing equitable access to high-quality rehabilitation in countries.Additional considerations ought to be addressed when discussing an HPSR framework for rehabilitation. The first consideration relates to whether and how equity is promoted through the exercise . Pratt eAnother consideration that ought to be addressed is the process for stakeholder engagement and the extent to which decision-making is truly shared. The framework development process ensured that it captured contextually relevant information related to countries and was up to date with the current discourse on HPSR. Thus, a combination of bottom-up and top-down approaches were used in its development. This iterative process included top-down approaches to synthesize the relevant literature to present a preliminary framework. This was then followed by a bottom-up process for the generation of themes and questions from a diverse set of stakeholders. Finally, a top-down approach enabled the synthesis of all the collected themes and questions. The process therefore exemplified shared decision-making in the development of the framework . In pracThe proposed framework for stimulating HPSR in rehabilitation has several strengths. First, the participatory approach involving a diverse set of stakeholders from several countries and professional contexts ensured that the resulting framework and questions were relevant to all countries’ health systems. Second, the framework goes beyond the six WHO traditional building blocks of the health system   to incluIn conclusion, we reported on the outcome of a global consultative process which aimed to advance HPSR for rehabilitation. Through a participatory multi-stakeholder approach, a framework was proposed to stimulate HPSR in rehabilitation in countries in order to generate policy-relevant evidence. Additionally, an initial set of questions which demonstrate how the framework might be used in countries was proposed. We anticipate that this work will make a critical contribution towards building HPSR capacity and generating evidence for rehabilitation by shifting the narrative of rehabilitation towards more systemic approaches in health systems.


In this study, we compare the efficacy and diagnostic concordance of the ICDAS, the radiographic criterion and the instrument known as the DIAGNOdent fluorescence laser pen on occlusal caries lesions using a histological section as the gold standard. Of 100 teeth that did not present cavitated occlusal lesions or occlusal fillings, 80 were chosen through a randomization program and examined by two previously trained and calibrated researchers. Subsequently, the teeth were sectioned with a diamond disk and observed under an optical microscope. The results were studied for caries with a limit established in enamel and caries with extension to dentin. The intra-examiner (0.821–0.933) and inter-examiner (0.817–0.924) reproducibility obtained for both ICDAS and DIAGNOdent for the diagnosis of borderline enamel caries was high. Similarly, intra-examiner (0.686–1.000) and inter-examiner (0.809–0.944) reproducibility for diagnosis of caries with dentin extension was also high for both methods. The sensitivity obtained was 0.76 (ICDAS), 0.87 (DIAGNOdent) and 0.58 (Rx), whereas the specificity obtained was 0.66 (ICDAS), 0.4 (DIAGNOdent) and 0.77 (Rx) for lesions limited to enamel. For lesions with extension to dentin, the sensitivity obtained was 0.73 (ICDAS), 0.82 (DIAGNOdent) and 0.09 (Rx), and the specificity obtained was 0.79 (ICDAS), 0.52 (DIAGNOdent) and 0.97 (Rx). Sensitivity increases in both cases by combining diagnostic methods. In conclusion, ICDAS and DIAGNOdent are better diagnostic methods than Rx for the detection of occlusal caries, and the combination of these methods helps to obtain a better diagnosis. Dental caries is an infectious and multifactorial disease that affects the hard tissues of the tooth. It accounts for—along with the common cold—one of the most prevalent diseases among humans. This term is used to describe the results (signs and symptoms) of a localized chemical dissolution on the tooth surface caused by metabolic processes taking place in the biofilm covering the treated area . In receThis concept of the process has caused dentistry professionals to reconsider the diagnostic criteria used to evaluate the presence or absence of disease. Until now, many professionals focused on the disease only as clinically detectable visible lesions to be treated exclusively with surgical treatment; however, currently, it is being diagnosed in much earlier stages with a medical treatment approach aimed at stopping the disease.Among all the diagnostic methods for caries, the visual and tactile diagnostic method stands out, which consists of examining the tooth surface with the naked eye or with the help of a probe. Among the criteria for visual diagnosis, one of the most used is the International Caries Detection and Assessment System (ICDAS II) criterion. . ExploraFluorescence is a property of some artificial and natural materials that absorb energy at certain wavelengths and emit light at longer wavelengths. Three different types of fluorescence have been distinguished: blue, with origin in the ultraviolet region of the spectrum; yellow and orange in the ultraviolet region; and red, corresponding to the infrared region of the spectrum . The pre®, which also enables the diagnosis of proximal lesions (sensitivity of 0.6 and specificity of 1). Due to difficult access to interproximal surfaces, this device features two different tips for each location. The system has shown good performance and reproducibility for the detection and quantification of occlusal and smooth-surface carious lesions in in vitro studies but with somewhat more contradictory results in vivo, both in primary and permanent dentition  oFor ICDAS, the sensitivity obtained in this study was 0.76 and 0.73 for enamel and dentin, respectively. In 2008, Rodriguez et al.  obtainedThe specificity obtained with the DIAGNOdent method was 0.4 and 0.52 for enamel and dentin, respectively, which is lower than that reported in studies, such that by Rodrigues et al. (2008) (0.56)  or in a As we can see in several studies, including ours, the specificity obtained with the DIAGNOdent system is lower than that obtained with visual diagnosis using ICDAS II, with radiography being the method offering the highest specificity. However, when it comes to sensitivity, it is slightly higher in the case of DIAGNOdent compared to ICDAS and much higher than that of these two methods compared to radiography. The combination of the systems can achieve sensitivity and specificity similar to or greater than those obtained separately.To determine diagnostic efficacy, the area under the curve was calculated for ICDAS, DIAGNOdent and radiography, as well as the combination of the three methods with respect to histology, which is considered the Gold Standard. The AUC for ICDAS was 0.71 and 0.76, similar to the results reported in other studies, such as that of Diniz et al. (0.86)  or higheThe obtained intra-examiner ICDAS reproducibility was 0.871 and 0.821, in lesions limited to enamel, and 1.000 and 0.868 in lesions extended to dentin. In other studies, such as those by Oancea et al., Heinrich-Weltzien et al., Pinelli et al., Attrill et al. or Bakhshandeh et al., similar values were obtained between 0.75 and 0.95 ,32,33,34Regarding DIAGNOdent, the obtained intra-examiner reproducibility was 0.933 and 0.890 in lesions limited to enamel and 0.923 and 0.919 in lesions with extension to dentin. These results are similar to those reported by other authors, whose values ranged between 0.79 and 0.98 ,32,35,36In the present study, we demonstrated the diagnostic reliability of both the most experienced and the most novice examiner; therefore, we can conclude that the DIAGNOdent can be used by any professional without the need for previous experience, obtaining similar results. Some authors go so far as to state that prior training and calibration does not significantly affect the results obtained by DIAGNOdent .The combination of the investigated methods improves sensitivity, that is, the ability to detect lesions at the D1 level, compared to the use of the different methods individually. This produces a decrease in specificity, resulting in false positives. Because the objective of this study is to evaluate the diagnostic validity of the different methods for the diagnosis of incipient caries, the treatment of which, in most cases, consists of a non-invasive remineralizing regimen for the patient, it could be interesting to investigate the combination of the different diagnostic methods to increase sensitivity. This would lead to a loss of specificity, but because the treatment to be performed on the patient is non-invasive, without harm to the patient in the event that there is no injury, there would be no contraindication to the application of the remineralizing agent.In the case of dentin lesions (D3), the diagnostic efficiency decreases with the combination of the different diagnostic methods. For this type of lesion, it would be recommended to rely on the result obtained using the ICDAS criterion, as it achieves the greatest area under the ROC curve. In this case, given that the recommended treatment would be surgical, it is important to avoid false positives as much as possible, with the ICDAS being the diagnostic method that has shown greatest validity in this regard.A possible limitation of the study is the fact that it is an in vitro and not an in vivo study, as in some in vivo studies, the sensitivity obtained with DIAGNOdent is greater than in in vitro studies ,39. None-The combination of the three methods does not significantly improve the diagnostic capacity of occlusal caries lesions, despite showing an improvement over the results of the different methods separately.-A combination of the different methods would be advisable, the radiographic method being the most dispensable, as both the ICDAS II criterion and the DIAGNOdent diagnostic method are more effective independently, obtaining the best results with the combination of the two methods.-The reproducibility of the ICDAS II criteria and the DIAGNOdent system is high for the diagnosis of lesions limited to enamel, as well as those that go deep into dentin.-Both the ICDAS II criterion and the DIAGNOdent system present good results after brief training, similar to those obtained by examiners with more experience.After analyzing the results obtained in this study and in other similar studies, we can conclude that:It would be advisable to carry out new studies that would emphasize an in vivo evaluation of the different diagnostic methods.


Acinetobacter baumannii (CRAB) in 10 U.S. sites. To describe the impact of the COVID-19 pandemic on the epidemiology of these antibiotic-resistant gram-negative bacteria (AR-GNB), we assessed characteristics of AR-GNB patients with and without a prior SARS-CoV-2 positive (SC2+) viral test.The Centers for Disease Control and Prevention’s Emerging Infections Program (EIP) conducts active laboratory- and population-based surveillance for carbapenem-resistant Enterobacterales (CRE), extended spectrum beta-lactamase-producing Enterobacterales (ESBL-E), and carbapenem-resistant A. baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella aerogenes, K. oxytoca, K. pneumonia, or K. variicola in a 30-day period resistant to ≥1 carbapenem (excluding ertapenem for CRAB) from a normally sterile site or urine. An incident ESBL-E case was defined as the first isolation of E. coli, K. pneumonia, or K. oxytoca in a 30-day period resistant to any third-generation cephalosporin and non-resistant to all carbapenems from a normally sterile site or urine. Patient charts were reviewed.In 2020 among EIP catchment-area residents, an incident CRAB or CRE case was defined as the first isolation of Of 3904 AR-GNB cases with data available, 163 (4%) had a prior SC2+ test . Median time from the most recent SC2+ test to AR-GNB culture date was 20 days (IQR 1–48 days). AR-GNB cases with a SC2+ test versus those without were more likely to be Black, non-Hispanic than another race/ethnicity , aged ≥65 years , and to have prior healthcare exposures  and indwelling devices . They were also more likely to have bacteremia , pneumonia  and be hospitalized around the time of their AR-GNB culture ; median time from SC2+ test to hospital admission was 0.5 day (IQR 0–29.5 days).AR-GNB infections preceded by a SC2+ test were rare but more severe and associated with more healthcare risk factors. This underscores the need for continued infection prevention and control practices and monitoring of these infections during the COVID-19 pandemic.Ghinwa Dumyati, MD, Pfizer: Grant/Research Support.


There is increasing number of head and neck tumors. Modern medical technologies allow to save lives, but lead to cosmetic and functional defects. DSM-V clarifies that “life threatening illness or debilitating medical condition is not necessarily considered a traumatic event”. However, cancer diagnosis and treatment influence on mental health. Patients after surgery of head and neck tumors need special rehabilitation, because of loss or impairment of speech function. This significantly reduces communicative potential, changes social status, reduces rehabilitation potential.During 6 years we have conducted studies to improve methods of psychological and pedagogical diagnostics, optimize speech therapy and psychological support for increasing effectiveness of speech rehabilitation.Speech rehabilitation was carried out with correctional-pedagogical technologies and psychological support. We used Achieving Tendency Scale, Questionnaire measures of Affiliative Tendency and Sensitivity to Rejection, narrative interview, Scale of speech utterance implementation, rehabilitation potential evaluation, general condition assessment by ECOG and Karnovsky, auditory assessment. Speech therapy included methods for eliminating dysphagia, normalizing speech breathing, improving utterance realization. Psychological support kept meaning-narrative approach.Number of patients without difficulties or with slight difficulties in speech utterance implementation increased by 57.1%. Number of patients with high rehabilitation potential increased by 48.8%.Psychological and pedagogical rehabilitation and resocialization after surgery of head and neck tumors has positive effect on mental health of patients, forms special rehabilitation motivation, helps to avoid disability and to transform life in new conditions.No significant relationships.


P-T) conditions is a crucial parameter for modeling heat conduction and temperature distribution within a DAC. Here we report the thermal conductivity of He and Ar over a wide range of high P-T conditions using ultrafast time-domain thermoreflectance coupled with an externally heated DAC. We find that at room temperature the thermal conductivity of liquid and solid He shows a pressure dependence of P0.86 and P0.72, respectively; upon heating the liquid, He at 10.2 GPa follows a T0.45 dependence. By contrast, the thermal conductivity of solid Ar at room temperature has a pressure dependence of P1.25, while a T−1.37 dependence is observed for solid Ar at 19 GPa. Our results not only provide crucial bases for further investigation into the physical mechanisms of heat transport in He and Ar under extremes, but also substantially improve the accuracy of modeling the temperature profile within a DAC loaded with He or Ar. The P-T dependences of the thermal conductivity of He are important to better model and constrain the structural and thermal evolution of gas giant planets containing He.Helium (He) and argon (Ar) are important rare gases and pressure media used in diamond-anvil cell (DAC) experiments. Their thermal conductivity at high pressure–temperature ( Combined with previous temperature-dependence measurements at ambient and lower pressures [To understand how the thermal conductivity of He changes with temperature, we have also performed simultaneous high ing line ,18. Suching line  and crysing line  and Ar bressures ,18, the P) of Ar at room temperature up to 49 GPa (solid circles). Here, we focus on the solid phase where its Λ = 0.6 W m−1 K−1 at 2.1 GPa, typical of the relatively low thermal conductivity of molecular solids at similar pressures, see, e.g., CO2 [4 [−1 K−1 at 49 GPa, with a pressure slope of α = 1.25(±0.025) in the lnΛ–lnP plot. Our data for the values of Λ(P) at room temperature and the pressure slope (1.25) are both in good agreement with previous theoretical calculations based on Green-Kubo molecular dynamics simulations (α = 1.29) [α = 1.39) [P) are ~50–60% smaller over the pressure range we studied than those calculated by kinetic theory [P-T measurements to obtain the Λ(T) of Ar, see β = −1.26(±0.01) and −1.37(±0.005) in the lnΛ–lnT plot, well in line with the temperature dependence reported in literature (β ranges from −1.31 to −1.4) [T−1 has been experimentally observed in solid Ar at ambient [The thermal conductivity of the Ar, on the other hand, shows distinct pressure and temperature dependences compared to the He. .g., CO2  and CH4 , CO2 [4 . The Λ i = 1.29)  and the  = 1.39) . Neverthc theory  and measto −1.4) ,25,30. TNote that the opposite temperature dependence of thermal conductivity for liquid He and crystalline Ar originates from different physical mechanisms. The positive temperature dependence for the liquid He is due to the fact that, in liquids, the thermal energy is typically transported by the diffusion of heat from atom to atom, based on the so-called minimum thermal conductivity model, see  and refeρ and temperature T:g = 3γ + 2q − 1/3 [T, ν is the phonon vibrational frequency, and q = −(∂lnγ/∂lnρ)T. Based on our experimental results, n= −0.45 and about 1.3 for liquid He and solid Ar, respectively,  − ln(ρ/ρ0) relations, where the g = 2.33(±0.15) for the solid He, slightly smaller than that of the liquid He, g = 2.57(±0.15). By contrast, the solid Ar has a g value of 5.49(±0.2), which is in reasonable agreement with that obtained by molecular dynamics calculations [A number of phenomenological models have been proposed to describe how the thermal conductivity of a material changes upon compression at variable temperatures. For instance, under the Debye approximation ,51, ther2q − 1/3 ,51, wherctively, b. As shouctivity a and denulations  and compulations .A is a normalization constant, V the volume, T the temperature. The LS equation is a simple physical model originally formulated for pure, isotropic dielectric crystals. It assumes that heat is predominantly transported by acoustic phonons via the anharmonic three phonon scattering mechanism. Prior studies have shown that the LS equation adequately describes the pressure dependence of Λ for H2O ice VII [P) of solid He and solid Ar  can be simplified to P) predicted by the LS equation at room temperature for solid He as the dashed line in P) of solid He and solid Ar suggests that besides the three phonon anharmonic scattering between acoustic modes, as pressure increases, additional scattering mechanisms that suppress the phonon transport may play an influential role in heat conduction in these materials. Future, more sophisticated computational studies are required to identify their detailed physics of phonon transport.Alternatively, the effects of pressure and temperature on the thermal conductivity Λ of a dielectric is often described by the Leibfried-Schlömann (LS) equation ,53:(2)Λ= ice VII , MgO [51 ice VII , and NaC ice VII , at room that in ). As des that in ,42, for  that in ,23. As sP-T conditions. The effects of the density (pressure) and temperature on their thermal conductivity not only shed light on the physical mechanisms of heat transport in these materials, but also enable modelling of their thermal conductivity at further extreme conditions. Our results for liquid He offer critical information to better simulate the thermal conductivity of gas giant planets over a depth range where liquid He is present, such as Jupiter and Saturn which could contain ~20–25 wt.% He and ~75–80 wt.% H2 in their interiors. Future studies on the high P-T thermal conductivity of H2 will significantly improve our understanding of the fundamental physics of heat transport in such simple, quantum systems as well as the thermal evolution of the aforementioned gas giant planets. In addition to He and Ar, knowledge about the thermal conductivity of Ne will also be required. A comprehensive documentation of the thermal conductivity of these important, common pressure media used in high P-T DAC experiments will substantially advance research in Earth and planetary sciences, as well as materials physics and chemistry under extreme conditions.We have coupled the ultrafast TDTR and EHDAC to precisely determine the thermal conductivity of He and Ar at high


Time-varying caloric vestibular stimulation (tvCVS) is a new form of non-invasive neuromodulation similar to, but different from, diagnostic caloric vestibular stimulation (CVS). Using a non-invasive, solid-state delivery device, tvCVS has been successfully used in a human clinical trial with Parkinson’s disease (PD) subjects. Additionally, the effects of tvCVS on brain activation have been studied in healthy human subjects using transcranial Doppler sonography (TCD) and functional magnetic resonance imaging (BOLD fMRI). A novel finding in the TCD and fMRI studies was the induction of cerebral blood flow velocity (CBFv) oscillations. How such oscillations might lead to the observed clinical effects seen in PD subjects will be discussed. Enabling studies of tvCVS with rodents is an attractive goal in support of explorations of the mechanism of action. Male Wistar rats were used in a proof-of-concept study described herein. Rats were anesthetized (isoflurane) and ventilated for the duration of the tvCVS runs. Time-varying thermal stimuli were administered using a digital temperature controller to modulate Peltier-type heater/cooler devices. Blunt ear bars conveyed the thermal stimulus to the external ear canals of the rats. Different thermal waveform combinations were evaluated for evidence of successful induction of the CVS effect. It was found that bilateral triangular thermal waveforms could induce oscillations in CBFv both during and after the application of tvCVS. These oscillations were similar to, but different from those observed in awake human subjects. The establishment of a viable animal model for the study of tvCVS will augment ongoing clinical investigations of this new form of neuromodulation in patients with neurodegenerative disease. Caloric vestibular stimulation (CVS) has been used in diagnostics for decades as a tool to study balance disorders. The diagnostic CVS units use water or air as the working fluid to irrigate the external ear canal at temperatures above and below body temperature . Ear canHere, we describe a tvCVS device adapted to a stereotactic frame where blunt ear bars were modified to convey a contact-based thermal stimulus in rodents. The temperature of the ear bars was regulated by a closed-loop control circuit driving solid-state heater/cooler elements (Peltier devices). Preliminary, proof-of-concept testing provided evidence that the tvCVS system successfully delivered thermal energy to the vestibular labyrinth. In particular, cerebral blood flow velocity (CBFv) oscillations, as measured with laser Doppler flowmetry, in response to a time-varying CVS stimulus pattern were observed. The demonstration of similar flow oscillations induced in human subjects facilitates a novel platform to study changes in brain-blood-flow associated with a range of disease processes (including neurodegenerative diseases).2/balance N2 in an induction box. Following tracheal intubation, the lungs were mechanically ventilated to maintain normocapnia . Aseptic technique was used. A tail artery catheter was placed for blood pressure monitoring. The wound was infiltrated with 0.25% bupivacaine. A 1-cm scalp incision was made, and a burr hole was drilled through the outer table of the skull (inner table left intact) 1-mm posterior to bregma and a 6-mm right lateral of midline. A laser Doppler flow probe  was temporarily placed at this site to evaluate red blood cell flow velocity as a surrogate measure for cerebral blood flow. Laser Doppler flowmetry is a convenient tool for studying real-time flow changes  were fasted from food for 8–12 h to deplete liver glycogen thereby controlling plasma glucose concentration. Rats were anesthetized with isoflurane in 50% O changes . A pericA tvCVS unit that employs Peltier devices to warm/cool the ear canals was designed and constructed so that it would fit with a stereotactic positioning system. The triangular thermal waveforms were chosen based on the thermal output capabilities of the caloric ear bar device and to avoid adaptation of vestibular hair cells. The use of a constant temperature for CVS will result in reduced responsiveness of the hair cells after several minutes  and thusFor tvCVS stimulation the rat was placed in a stereotactic head frame and the caloric ear bars were placed in the ear canals without damaging the tympanic membrane . The totThe method for delivering tvCVS was found to be effective and took advantage of good familiarity with stereotactic fixation protocols. Ensuring good registration of the ear bars was straightforward. Accommodating the need to tilt the rat so that the horizontal semicircular canal was closer to a vertical orientation required a number of tests. Initially, tilting the animal platform to about 50° above the horizontal was evaluated. This proved to be cumbersome and the platform was repositioned to be horizontal. A number of runs were completed in the horizontal orientation before another modification was evaluated with the rat’s body tilted slightly above horizontal and with an upward head flexion of about 30° . This prTwo different thermal waveform delivery approaches are described here: (1) single ear, cold triangular and (2) dual ear, warm, and cold triangular waves  the study was not statistically powered and instead used a phenomenological approach to power future research; (2) the aforementioned arousing effects of CVS can complicate the maintenance of anesthesia; (3) isoflurane may have altered normal cerebral autoregulation and altered the basal metabolic rate; (4) the low mass of the rat’s skull can lead to temperature changes in the vestibular labyrinth, which must be considered when discussion the details of CVS induction ; and (5)Home-use neuromodulation devices are under active development. The device used in previous clinical studies  has beenThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Duke University Institutional Animal Care and Use Committee, Durham, NC, USA.RB was responsible for the neurostimulation equipment and initial data analysis. EC performed all animal care and handling tasks. Both authors contributed to the writing of the manuscript.


Pulmonary rehabilitation (PR) is a core component of management people with chronic obstructive pulmonary disease (COPD); yet, people with COPD face significant barriers to attending centre-based PR programs. The emergence of new models of PR, remotely delivered directly into people’s homes, has the potential to improve rehabilitation access and completion by providing patients with a choice of rehabilitation location (centre or home). However, offering patients a choice of rehabilitation model is not usual practice. We are undertaking a 14-site cluster randomised controlled trial to determine whether offering choice of PR location improves rehabilitation completion rates resulting in reduced all-cause unplanned hospitalisation over 12 months. The aim of this paper is to describe the protocol for the process evaluation of the HomeBase2 trial.A mixed methods process evaluation, to be undertaken in real time, has been developed in accordance with UK Medical Research Council (MRC) recommendations on process evaluation of complex interventions. This protocol describes the intended use of two theoretical frameworks  and Theoretical Domains Framework (TDF)) to synthesise findings and interpret data from a combination of qualitative (semi-structured interviews) and quantitative  methodologies. Data will be collected at an intervention, patient and clinician level. Qualitative and quantitative data will be used to derive context-specific potential and actual barriers and facilitators to offering patients choice of rehabilitation location. Acceptability and sustainability of the intervention will be evaluated for future scale-up.The process evaluation described here will appraise the clinical implementation of offering a choice of rehabilitation program location for people with COPD. It will identify and evaluate key factors for future scale-up and sustainability and scale-up of offering choice of pulmonary rehabilitation program model for people.ClinicalTrials.gov NCT04217330 Registration date: January 3 2020. Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and mortality globally . In exceKey barriers to undertaking pulmonary rehabilitation include a lack of qualified staff , insuffiWhile undertaking rehabilitation at their preferred location may help improve rehabilitation completion rates, offering patients a choice of rehabilitation location is not routine clinical practice and has not previously been studied in a clinical trial. Additionally, implementation of home-based models of program delivery into clinical practice is challenging. Prior to the COVID-19 pandemic, fewer than 5% of pulmonary rehabilitation programs offered a home-based service , and theThe HomeBase2 trial is an Australian Medical Research Future Fund supported trial. It is a cluster randomised controlled trial at 14 centre-based pulmonary rehabilitation programs in Australia, with programs (clusters) randomised 1:1 to the intervention or control group. A detailed protocol for the HomeBase2 study has been published , with trAs offering a choice of rehabilitation location is a departure from usual practice, and home-based rehabilitation is not widely implemented in clinical practice , a proce1. To what extent did the clinicians or patients use the various components of the planned intervention programs (home-based or centre-based pulmonary rehabilitation)?2. Which factors are associated with effective implementation of offering choice of pulmonary rehabilitation location?3. What barriers to and facilitators exist for implementation of the intervention, from the perspectives of the clinicians delivering the program, and the patients who are offered a choice in rehabilitation location?4. Is offering choice of pulmonary rehabilitation location acceptable to clinicians and patients?5. How likely is the HomeBase2 intervention to be sustainable and what factors might ensure sustainability?The aim of the process evaluation conducted alongside the HomeBase2 trial is to support the interpretation of trial outcomes and refine processes for future implementation and scale-up into practice. Therefore, the planned process evaluation is intended to answer the following questions:A mixed method process evaluation embedded within the HomeBase2 trial, informed by recommendations of the UK Medical Research Council (MRC) on process evaluation of complex interventions , will usTranslation and behaviour change success in intervention clusters will be evaluated using the RE-AIM framework which aims to improve the sustainable adoption and implementation of effective, generalisable, evidence-based interventions . OutcomeA mixed methods study design, with formative evaluation, will be undertaken in real time.Reach); program completion (≥ 70% sessions attended) and clinical outcomes (Effectiveness); number of staff trained to deliver home-based pulmonary rehabilitation and number of home-visits and MI calls completed (Adoption); program components delivered (e.g. exercise training/progression) (Implementation); and intent to continue delivery of a home-based program and modifications required for local context (Maintenance). Clinical outcomes and site characteristics will also be compared between sites that achieved an average participant rehabilitation completion rate ≥ 70% versus those that did not.Process data will be described quantitatively to determine the fidelity of the intervention (aim 1). All intervention sites will be provided with resources and training by the research team, including a script for describing the rehabilitation programs on offer to inform participant choice, resources and equipment to conduct an initial home-visit for exercise training prescription, specialised training in motivational interviewing to enable delivery of the telephone modules of the home-based rehabilitation program and ongoing support and training from an expert motivational interviewing practitioner. The degree to which the interventions are delivered in accordance with the study protocols will be evaluated and described according to the RE-AIM framework. Outcomes will include the following: proportion of eligible PR referrals offered program choice and intervention participation rates (proportion who choose home-based and centre-based rehabilitation)  clusters will be invited to participate in a guided discussion after the conclusion of their 8-week rehabilitation period and completion of their end-rehabilitation assessment. Discussion will be undertaken to gain an in-depth understanding of patient’s perceptions and experience of the rehabilitation program and the opportunity to choose their rehabilitation location. Qualitative interviews will be led by an experienced researcher who is not involved in providing either pulmonary rehabilitation model for the intervention (‘choice’) clusters nor in providing usual care for participants. Interviews will be conducted via telephone, at a time of the participants’ choosing. See online supplementary material for interview guideline addressing study aims 2–4. A sampling framework will be employed to ensure that data from patient participants reflect all sites  as well as key features of individuals commonly referred to centre-based pulmonary rehabilitation . Clinician participants will be invited to complete an online survey  prior to recruitment of each site’s first participant to understand clinicians’ perspectives of the barriers and facilitators to offering choice of pulmonary rehabilitation location. Clinicians at sites randomised to intervention clusters will be invited to complete a follow-up survey at the conclusion of participant recruitment at their site. Survey responses will be coded so that baseline responses can be paired with later survey responses. The questionnaire comprises 41 questions, based on the TDF , to be a–5. CliniBarriers and facilitators to successful implementation will also be explored through qualitative interviews with clinicians from intervention clusters. Clinicians at sites randomised to intervention clusters will be invited to participate in 1:1 qualitative interviews at a time corresponding to approximately 50% of their site recruitment and at the completion of their site recruitment. The interview discussion guide is designed to understand the clinician experience of offering a choice of pulmonary rehabilitation model, and the experience of delivering an alternative model of pulmonary rehabilitation (if applicable). By seeking clinician experiences at two time points, we will be able to describe perceived and actual barriers to and facilitators for offering/implementing more than one model of pulmonary rehabilitation in the context of any adaptations made as the trial progresses. In addition, we will be able to describe the expectations of the clinicians with respect to offering a choice of pulmonary rehabilitation location, whether these expectations were met by the conclusion of the trial, and perceived acceptability of the intervention (aim 4). Insights from the second clinician data collection time point will additionally be drawn together with recruitment data and survey feedback at the end of the trial to determine factors which might ensure sustainability of the HomeBase2 intervention at trial completion (aim 5).In keeping with UK MRC guidance , a logicThe design of this process evaluation is covered within the ethics application and overall protocol of the HomeBase2 trial approved by the Alfred Health Human Research Ethics Committee . Local governance approvals were obtained from all participating sites. Written informed consent will be obtained from all participants (patient and clinician). The results of this process evaluation will be submitted for publication in peer-reviewed journals, presented at conferences and described in lay communications.Patient and public involvement in the HomeBase2 trial has been from trial inception, including study design and trial oversight. Full details are described elsewhere .reverted back to traditional, centre-based, in-person delivery models as soon as this was possible [In response to restrictions associated with the COVID-19 pandemic, there was a rapid shift from centre-based pulmonary rehabilitation services to those that could be delivered remotely . Howeverpossible . This supossible , and up possible , 30. ThiRecruitment for the HomeBase2 trial commenced in March 2021 and remains ongoing. Trial recruitment is anticipated to be completed by April 2024.


The Atmospheric River (AR) Tracking Method Intercomparison Project (ARTMIP) is a community effort to systematically assess how the uncertainties from AR detectors (ARDTs) impact our scientific understanding of ARs. This study describes the ARTMIP Tier 2 experimental design and initial results using the Coupled Model Intercomparison Project (CMIP) Phases 5 and 6 multi‐model ensembles. We show that AR statistics from a given ARDT in CMIP5/6 historical simulations compare remarkably well with the MERRA‐2 reanalysis. In CMIP5/6 future simulations, most ARDTs project a global increase in AR frequency, counts, and sizes, especially along the western coastlines of the Pacific and Atlantic oceans. We find that the choice of ARDT is the dominant contributor to the uncertainty in projected AR frequency when compared with model choice. These results imply that new projects investigating future changes in ARs should explicitly consider ARDT uncertainty as a core part of the experimental design. Uncertainty associated with atmospheric river (AR) definition dominates model uncertainty for projections of Pacific and Atlantic landfalling ARsMost AR detection algorithms show an increase in AR frequency in future simulationsAR statistics in CMIP 5‐and‐6 models compare remarkably well with reanalysis We chose to focus on models providing data on the native model vertical grid (either sigma or hybrid‐sigma) because this facilitates an accurate calculation of vertical integrals without having to handle below‐ground levels as would be necessary if dealing with model output on isobaric surfaces; this choice simplifies interpretation of inter‐ARDT differences in continental interiors, where such below‐ground levels are common. At the time that the Tier 1 input data set was constructed (in Summer 2019), we were able to access 6 models from CMIP5  and 3 models from CMIP6  by end‐of‐century.For the Tier 2 input data set for ARDTs, we derive integrated water vapor (IWV), and the components of the integrated vapor transport (IVT) vector from outputs from atmosphere‐ocean general circulation models associated with the Coupled Model Intercomparison Project (CMIP) Phases 5  and water vapor transport (ρu⃗q) are calculated from all native model levels in the CMIP5/6 output as:k corresponds to model levels going from the surface (k = 1) to the top of the model atmosphere (k = N), and Δpk is the difference in level pressures, estimated at level k. The total vapor transport is calculated as the vector magnitude: IVT=IVT→.The mass‐weighted vertical integrals of water vapor  and algorithms designed for specific regions ; see Table S1 in the Supporting Information 2.1IVT→ described in Section All Tier 2 CMIP5/6 ARDT contributions use the common data set of IWV, IVT, and absolute , fixed relative , and relative (Tempest and TECA‐BARD v1.0.1). The categorizations are described and justified in Text S2 in the Supporting Information Grouping algorithms by the type of criteria applied (relative vs. absolute thresholds) and degree of restrictiveness  can reduce the spread associated with ARDTs  experiments for the 6 global ARDT algorithms in the top row of Figure Simulated ARs in the Tier 2 CMIP5/6 experiment are remarkably consistent with those in the Tier 1 MERRA‐2 experiment. Results from an arbitrary model–MRI‐ESM‐2‐0 from the CMIP6 multimodel ensemble–are shown in the second row of Figure Each ARDT has idiosyncratic spatial patterns that are expressed in both Tier 1 and Tier 2. This suggests that the spatial pattern maps are an emergent property of each ARDT, and that these spatial patterns are relatively insensitive to significant changes in the representation of the underlying atmospheric dynamics. For example, the diffuse spatial pattern associated with the Guan_Waliser_v2 (GW) algorithm is evident in Tier 1 and in all Tier 2 simulations , and the ratio of spatial standard deviations of AR frequency (Tier 2 divided by Tier 1) is between 0.75 and 1.25 for 40 out of 52 ARDT‐model pairs. The Taylor skill scores ; likewise, one combination (ARCONNECT_v2 and CMIP5 IPSL‐CM5A‐LR) has variability that is too low by approximately 25%, and one combination (Tempest and CMIP5 IPSL‐CM5B‐LR) has variability that is about 50% too high. Overall, this emphasizes the high degree of similarity between simulated ARs and ARs in MERRA‐2, when comparing results using a single ARDT.Figure  Taylor,  are abovAltogether, the various ARDTs portray a similar assessment of model skill, with essentially all of the models analyzed appearing to be ‘fit for purpose’. This is true even for the lowest resolution simulations , and AR location. Two ARDTs (TECA‐BARD v1.0.1 and to a lesser extent Tempest) suggest poleward shifts in AR location Figure , whereasA and AR count N; Figure A⊕ percentage . These show that algorithms typically detect ARs such that approximately 5% of the Earth's surface is covered in AR objects in the historical simulations. Therefore, we can interpret the relative location of ARDTs in Figure We decompose the changes in AR frequency by changes in AR area Figure There is an indication that the resolution of the underlying model may affect the characteristics of detected ARs for some ARDTs. The CMIP6 BCC‐CSM2‐MR, CMIP6 MRI‐ESM2‐0, and CMIP5 CCSM4 simulations–which are the three highest resolution simulations analyzed  and the variance across the bottommost row in Figure S3 in the Supporting Information σA2), . As shown in Figures The spread in the number of detected ARs accounts for some of the spread in trends. If the trends in Figures 4While there have been studies examining future changes in ARs  and time‐independent relative thresholds (fixed relative ARDTs) tend to produce increases in AR frequency, whereas use of time‐dependent relative thresholds (relative ARDTs) tend to produce patterns more indicative of a poleward shift. Absolute ARDTs and fixed relative ARDTs, with thresholds that do not change in time, would be expected to increase the frequency of exceedance of regions above the historical thresholds: more detected AR days in a warmer climate. Such ARDTs are designed to detect increases in occurrence of regions with high IVT, which are important for AR impacts. In contrast, relative ARDTs  are designed to only account for dynamical–rather than thermodynamical–changes in ARs.These results further show that future changes in AR frequency can qualitatively differ depending on the type of ARDT used. We aggregate trends by AR classification . The model spread in these trends are shown in Figures To illustrate the thermodynamic and dynamic changes in IVT, Figures The similarity of the IVT and IWV trend magnitudes implies that most of the trend in IVT is due to the thermodynamic component: the increase in atmospheric water vapor content due to Clausius‐Clapeyron (CC) scaling. In contrast, the dynamic change is more indicative of a poleward shift in the magnitude of moisture‐transporting winds. It is worth noting that the results presented in Figure absolute ARDTs and fixed relative ARDTs are more sensitive to thermodynamic changes than relative ARDTs. The strongest increase in the absolute and fixed relative ARDTs compared to relative ARDTs explains the sensitivity to ARDT choice especially approaching colder and drier polar regions. The future, much stronger, increase in high latitude temperature associated with polar amplification, compared to other regions, together with hydrological cycle intensification will be more evident in the absolute and fixed relative ARDTs compared to the relative ARDTs.The literature documents two major modes of AR change associated with climate change: (a) A quasi‐global increase in IVT associated with CC scaling , and we encourage current and future ARDT designers to likewise enter their codes into the public domain in order to facilitate such uncertainty exploration in future studies.These results suggest that new projects investigating future changes in the statistics and characteristics of ARs should explicitly consider ARDT uncertainty as a core part of the experimental design. This study makes it clear that ARDT design choices can have a major impact on the results of climate change studies, and with dozens of ARDTs in use (Rutz et al., Ralph et al.  provide This study focuses on a bulk, global perspective of uncertainty associated with ARDTs and simulations in the Tier 2 CMIP5/6 experiment. There are many other types of more detailed analyses that others could take on. For example, this study has not considered the temporal characteristics of ARs, since relatively few existing ARDTs track ARs as they propagate in time; a recent study by Zhou et al.  uses a cAre some ARDTs simply missing ARs that other ARDTs are identifying, or is there more than one type of dynamical phenomenon that produces AR‐like objects; are some ARDTs more sensitive to one dynamical phenomenon and others are more sensitive to another; and if there are multiple dynamical causes of ARs, do they have different spatiotemporal responses to climate change? These questions are likely answerable with the datasets that have been produced by the ARTMIP project.Prior to ARTMIP, it was assumed that the various ARDTs in the literature were simply different methods of looking at the same dynamical phenomenon. Recent papers associated with ARTMIP show that that is true for strong ARs (with high IVT, e.g., Rutz et al., In summary, this initial analysis of the Tier 2 CMIP5/6 experiment shows that most ARDTs and simulations indicate an increasing trend in AR frequency, size, and number in future simulations with strong radiative forcing. It also shows the critical importance of understanding the implications of uncertainty for AR‐related research. Finally, this paper introduces the publicly available Tier 2 CMIP5/6 data set, which may be a valuable resource for answering fundamental questions about ARs and about ARs and climate change.Supporting Information S1Click here for additional data file.


Prostate cancer is one of the leading causes of cancer death and affects millions of men in the world. The American Cancer Society estimated about 34,500 deaths from prostate cancer in the United States in year 2022. The Androgen receptor (AR) signaling is a major pathway that sustains local and metastatic prostate tumor growth. Androgen-deprivation therapy (ADT) is the standard of care for metastatic prostate cancer patient and can suppress the tumor growth for a median of 2–3 years. Unfortunately, the malignancy inevitably progresses to castration-resistant prostate cancer (CRPC) which is more aggressive and no longer responsive to ADT. Surprisingly, for most of the CPRC patients, cancer growth still depends on androgen receptor signaling. Accumulating evidence suggests that CRPC cells have rewired their transcriptional program to retain AR signaling in the absence of androgens. Besides AR, other transcription factors also contribute to the resistance mechanism through multiple pathways including enhancing AR signaling pathway and activating other complementary signaling pathways for the favor of AR downstream genes expression. More recent studies have shown the role of transcription factors in reconfiguring chromatin 3D structure and regulating topologically associating domains (TADs). Pioneer factors, transcription factors and coactivators form liquid-liquid phase separation compartment that can modulate transcriptional events along with configuring TADs. The role of AR and other transcription factors on chromatin structure change and formation of condensate compartment in prostate cancer cells has only been recently investigated and appreciated. This review intends to provide an overview of transcription factors that contribute to AR signaling through activation of gene expression, governing 3D chromatin structure and establishing phase to phase separation. A more detailed understanding of the spatial role of transcription factors in CRPC might provide novel therapeutic targets for the treatment of CRPC. Prostate cancer is one of the most frequently diagnosed cancers in America. It is the second most common cause of cancer death in American men. During the progression of prostate cancer, androgen receptor (AR) functions as a critical regulator that governs cancer development through transcriptional regulation of its targets gene expression . AndrogeThere is growing evidence that CRPC cells have rewired their transcriptional program to recover and maintain AR signaling in the absence of androgens. The alteration of transcription factors and their associated chromatin modifiers contribute to the resistance mechanism through multiple pathways. These changes also shape the higher order of chromatin structure, affect gene expression, and consequently allow the progression of CRPC and therapy resistance. This review is focused on androgen receptor, AR-related transcription factors, and their associated spatial organization of genome in CRPC. A more comprehensive review on clinical and molecular alterations during development of CRPC has been summarized in another review .2-terminal transcription activation domain (NTD), the central DNA binding domain (DBD), and a carboxyl-terminal ligand binding domain (LBD). The AR DBD specifically recognizes the androgen response elements (ARE) that contain a palindromic dihexameric motif with 5′-AGAACA-3′ core sequence (The Androgen receptor (AR) is the receptor protein mediating the androgen action and essential for prostate cancer development. It is encoded by the AR gene located on X chromosome with eight exons. AR contains three distinct functional domains and one hinge region. The functional domains include an NHsequence . DBD is sequence . The binBy classical transient transfection/luciferase-based transcriptional assays, two transactivation regions were identified in AR, namely Activation Function 1 (AF1) and Activation Function 2 (AF2). The ligand-independent AF1 is located in the AR NTD, and the ligand-dependent AF2 is located in the AR LBD. In contrast to many other nuclear receptors that AF2 regions are responsible for the dominant transactivation activity, the AR AF1, rather than AF2, plays a major role in determining the transactivation activity of AR , 10. ThiAndrogen receptor can be activated by its natural agonists testosterone and dihydrotestosterone and is the major target for prostate cancer therapy , 13. EarTo adapt to the minimal levels of androgens after castration, malignant cells have undergone various genetic alterations to preserve the AR signaling pathway. As a central player for the AR signaling, AR gene expression level is frequently augmented in CRPC. This can be achieved by several molecular alterations, including amplification of AR gene and a distant enhancer, change of chromatin interactions, translational regulation of AR mRNA, and increase of AR protein stability. AR gene amplification and copy number alterations are detected in up to 60% of metastatic CRPC patients but not in untreated primary prostate tumors –30. Mattin vivo , ERα and ERβ, that are encoded by different genes on chromosome 6 and 14, respectively. They share similar protein structure but ERβ is the prevalent ER expressed in human prostate tissue . It is gMR is ubiquitously expressed in various tissues. The expression of MR is low in prostate cancer cells, but studies have showed that MR might be also involved in enzalutamide resistance in CRPC , 67. Minin vivo . Within TADs, the embedded genes can share similar transcription factors and coregulators. Different gene elements, including enhancers, promoters, or gene bodies, have more frequent interactions with each other. TADs are separated by TAD boundaries, which are the regions enriched with insulator proteins, such as the CCCTC-biding factor (CTCF) protein. As it was named, CTCF binds to the core sequence CCCTC and was first identified as a transcriptional repressor of chicken c-myc gene . Later Cin vivo , 76.In 2016, Susan Clark and her colleagues  reportedin situ Hi-C and ChIP-seq experiments in prostate cancer cells to determine how three-dimensional chromatin structure is correlated to prostate cancer transcriptome. This study generated chromatin interaction map in high resolution and identified more than a thousand of TADs with altered boundaries in prostate cancer cells . Mo. Moin sier cells .Recently, Rachel Patton McCord’s group analyzed the genome organization of nine cell lines that mimic different stages of prostate cancer progression by Hi-C. CRPC cell lines 22Rv1 and C4-2B were included in the study. Across prostate cancer progression, 386 genes were found switching from transcriptionally silenced compartments to transcriptionally active compartments along with TAD rearrangement. In addition, they further defined several “genomic architecture hotspots,” where the chromatin alterations were highly similar among all metastatic models. Some important genes in prostate tumorigenesis, including AR, WNT5A, and CDK14, were located in these hotspots. This study suggested that the changes of 3D genome structure are critical for prostate cancer progression .Liquid-liquid phase separation (LLPS) represents a dynamic phenomenon that two distinct liquid phases are demixed . LLPS isSimilar to many other biological processes, gene expression also takes advantage of LLPS to maximize the output of gene transcription. To achieve high density of biomolecules in LLPS, transcription factor binding sites frequently form clusters on gene regulatory regions including enhancers and promoters. In AR-regulated genes, the response elements of pioneer transcription factors of AR, such as Forkhead Box A1 (FOXA1) and GATA-binding protein 2 (GATA2), were often found in close proximity to ARE –94. The 2-terminal domains of steroid hormone receptors all contain IDRs, it is conceivable that these NTDs play a role in forming phase separation . IDR refers to a protein region that does not form a fixed three-dimensional structure, but rather adopts flexible conformation . The dynparation , 106. Inparation . Interesparation . Althougto occur .A very recent study showed that AR formed transcriptionally active condensates with coactivator MED1 in androgen-responsive prostate cancer cells such as VCaP and LAPC4 cells, but not in RWPE1, a normal prostate epithelial cell line. Interestingly, these condensates were only observed with full-length AR upon DHT stimulation, but not with truncated AR mutants such as AR-V7 . This stAside from being involved in gene transcription, LLPS is implicated in other regulatory pathways in prostate cancer. In a subset of advanced CRPC where the AR protein level was low or absent, DEAD-box helicase 3 X-linked (DDX3) was reported to directly repress AR protein translation by physical association with AR mRNA in cytoplasmic liquid condensates. The upregulated DDX3 might contribute to the castration resistance in these tumors . MoreoveStudies have shown that CTCF not only functions as an insulator to establish the topological structure of TADs, but also is involved in sub-TAD chromatin loop formation within the TADs , 119–121Contrariwise, it appears that LLPS could also influence TAD assembly. One study applied a new CRISPR-Cas9-based optogenetic technology named CasDrop, which could induce microscope-visible liquid condensates to form at specific genomic loci. It was found that nuclear condensates, while they were forming, were able to gather the distal targeted genomic elements and expand to euchromatic regions . AnotherWith the advancement of next generation genome analysis technologies such as Hi-C, DNase-seq, FAIRE-seq, and ATAC-seq, we have learned that when hormone-sensitive prostate cancer progresses to castration-resistant prostate cancer, many genomic alterations at chromatin level have occurred. These genomic alternations underlie transcriptional reprogramming during the establishment of castration resistance. Recent advances in Hi-C and super resolution microscopes allow researchers to further characterize the chromatin conformation and transcriptional condensates in a spatial and dynamic view. The studies discussed in this review represent early steps toward understanding how the higher order of genomic organization affects the development of CRPC, yet more questions need to be addressed in future studies. It is hoped that these mechanistic studies could promote the development of new therapeutic interventions for the treatment of CRPC, a currently incurable disease.TZ and QF conceived and wrote the manuscript. Both authors contributed to the article and approved the submitted version.


Bell's palsy in pregnancy is not frequently seen. The association of preeclampsia with Bell's palsy is reported in the research, however, the exact link between Bell's palsy and preeclampsia is unknown. The treatment of Bell's palsy during the pregnancy is difficult and controversial. We report two cases of Bell's palsy with preeclampsia diagnosed during the third trimester of the pregnancy. The first case was diagnosed with Bell's palsy with severe preeclampsia with placental abruption with fetal distress; the pregnancy was terminated by cesarean section. Another case was diagnosed with Bell's palsy with mild preeclampsia. She had a spontaneous vaginal delivery at term. Both the cases achieved complete recovery from Bell's palsy after treatment with corticosteroid and antiviral drugs. Every obstetrician should be able to recognize Bell's palsy in pregnancy and initiate early treatment with corticosteroid and mount surveillance for preeclampsia. There is likely an association of Bell's palsy with preeclampsia during pregnancy. It is imperative to initiate screening for preeclampsia in pregnant women with Bell's palsy to detect and treat it early to improve the maternal and perinatal outcomes. It is also known as idiopathic facial palsy. The seventh cranial nerve  supplies muscles of the face, eye, tear glands, salivary glands, and muscles of the small bones in the middle ear, and it transmits taste sensation from the tongue. The dysfunction of this seventh cranial nerve  results in Bell's palsy.A high extracellular fluid content as part of physiological changes, hypercoagulable states, hormonal changes, and relative immunosuppression in pregnancy, the edema in preeclampsia, viral inflammation, and edema are thought to be predisposing factors for the development of Bell's palsy.The incidence of Bell's palsy is around 40 persons per 100,000 women in pregnancy which is high as compared to non‐pregnant women and it is seen more frequently during the third trimester and the immediate postpartum period.In general, Bell's palsy is a unilateral facial paralysis affecting only one side of the face, and in rare instances, it can affect both sides.The treatment of Bell's palsy in pregnancy remains controversial. The American Academy of Neurology and the other literature recommend treatment with corticosteroids alone.This write‐up is to describe the cases of Bell's palsy with preeclampsia in pregnancy diagnosed during the third trimester and treated with combined therapy.22.1+4 weeks gestation was admitted to the maternity ward on August 19, 2020 with complaints of sudden onset of left‐sided facial weakness, difficulty in closing the eye on the left side for 2 days, and mild abdominal pain for a 1‐day duration. She does not gave a history of trauma, ear pain, ear discharge, fever, or loss of taste sensation. She was complaining of a mild headache, however, no blurring of vision or chest pain. This was a planned pregnancy and her antenatal care (ANC) follow‐up was uneventful until the development of the above symptoms. Her neurological examination of the face revealed a loss of creases on the left side of the forehead, inability to close her left eye, wide palpebral fissure, weakness of muscle on the left side of the face, deviation of the angle of mouth on the right side, and loss of left nasolabial fold  and MgSO4 IV 1 g/h (maintenance dose) were administered for dual purposes; prevention of eclampsia and fetal neuroprotection. After the stabilization of the mother, the pregnancy was terminated by emergency cesarean section under spinal anesthesia on August 21, 2020. Per‐operatively there was a massive retroplacental blood clot with an umbilical cord double around the neck of the baby found. A live male baby weighing 1600 g was delivered with an Apgar score of 9 in 1 min and 10 in 5 min. After the cesarean section, the patient was treated with Tab. Prednisolone 40 mg daily for 7 days, then tapered doses over the next 12 days. Tab. Acyclovir 400 mg 5 times daily for 10 days was given with prednisolone along with daily physiotherapy for Bell's palsy. Her blood pressure was within normal range after the delivery. Mother was discharged on postoperative day 8. The baby was suspected to have retinopathy of prematurity and was referred to Jige Dorji Wangchuk National Referral Hospital, Thimphu for further evaluation and management. Follow‐up after 10 months showed the patient is still feeling slight weakness on the left side of the face, however, on clinical examination, the finding was unremarkable  unit. Her BP was under control and there was an obvious clinical improvement in Bell's palsy during the follow‐up visits. She had a spontaneous vaginal delivery at term on October 22, 2020 and delivered a healthy female baby weighing 3900 g. The patient had achieved full recovery of Bell's palsy after 6 weeks of the treatment.A 29‐year primigravida at 323Among the cranial nerves, the facial nerve is a special one as it has to travel a long distance through a tiny narrow bony tunnel with little room for swelling.In the present cases, both the pregnant mothers developed Bell's palsy in their third trimesters of the pregnancy. In the literature, Bell's palsy was reported in the third trimesters and early postpartum period.The treatment of Bell's palsy during the pregnancy is controversial and challenging. There is no standard recommendations or guideline on the treatment of Bell's palsy during the pregnancy. The concern of adverse effects of drug use during pregnancy on the fetus makes the treatment decision more difficult. The multicentric clinical trials have shown corticosteroid, prednisolone alone showed superiority over the combined therapy of prednisolone with antiviral, acyclovir, or use of acyclovir alone.4Every obstetrician should be aware of the unexpected neurological complications and be able to recognize Bell's palsy and initiate treatment with steroids and perform surveillance for preeclampsia.YD is involved in the conception, consent, data collection, manuscript writing, and submission for publication.The author does not have a conflict of interest to declare.The informed written consent has been obtained from the patient to collect the case history, collect the data, take the pictures, and write a case report for publication in the medical journals.


The attitude category was significantly associated with age (p = 0.003), marital status (p = 0.004), and type of allergic patients (p < 0.001), and the practice category was significantly associated with education (p = 0.027), type of allergic patients (p = 0.008), and follow-up facilities (p = 0.030). Smoking status was significantly associated with all three categories. Furthermore, we found a positive correlation between knowledge and practice scores . We recommend improving AR patients’ knowledge of the proper practices of INCS through health education programs. Furthermore, we recommend an exploratory mixed-method survey on the INCS usage among AR patients that involves other provinces in the KSA.Intranasal corticosteroids (INCS) are generally safe and effective treatments for allergic rhinitis (AR). The improper use of INCS may not alleviate AR symptoms, and it could lead to complications and an impaired quality of life. We evaluated the knowledge of, attitudes towards, and practices of INCS usage and associated factors among AR patients using a pretested Arabic questionnaire. Of the 400 participating AR patients, 39.3%, 29.0%, and 36.5% had poor scores for knowledge, attitude, and practice, respectively. We found a significant association between knowledge and education ( Allergic rhinitis (AR) is an atopic disease characterized by sneezing, runny nose, itchy nose, nasal congestion, and post-nasal drip ,2. Even The treatments for AR include antihistamines, nasal decongestants, intranasal corticosteroids (INCS), cromoglicic acid , leukotriene receptor blockers, avoidance of allergens, and nasal anti-cholinergic, immunotherapy, or combination therapy ,15. The In the KSA, AR patients are diagnosed and treated by ENT specialists at specialist hospitals, as well as at primary health centers by primary care physicians. Continuous and accurate assessment of knowledge, attitudes, and practices towards INCS usage is essential for planning care services for AR patients. However, limited data are available on this subject, especially in the Aljouf region of the KSA. Considering the region-specific required data, the present study assessed the knowledge, attitudes, and practices towards INCS usage and associated factors among AR patients in the northern KSA to find correlations between knowledge, attitude, and practice scores.n = z2pq/e2) for estimating sample size. The following values were considered while calculating the sample size: n = minimum required sample size, z = 1.96 at s confidence level of 95%, p = expected proportion of 50%, q = 1 − p, and e = margin of error at 5%. Considering all the specified values, the minimum required sample size was 377, and it was rounded to 400. A consecutive sampling method was applied to select the study participants (the AR patients). In this method, all the registered AR patients were selected. We began with the newest registered and follow-up patients to the last until the required sample size was achieved.The present analytical cross-sectional study was conducted from June to November 2022. It included the AR patients registered in the ENT clinics of specialist hospitals and primary health centers in the Aljouf region. This region is situated in the northern part of the Kingdom of Saudi Arabia (KSA) and has a population of 500,000. There are 75 primary health centers and 4 specialist hospitals in this region. This study’s sample size was estimated using the Raosoft online sample size calculator. The Raosoft online calculator uses Cochran’s formula , and unwilling to participate in the survey. Furthermore, we excluded the AR patients who had registered for the first time at the selected healthcare facilities. We invited every fifth patient during their follow-up visit during the data collection period.After obtaining ethical clearance  and the necessary permissions from the Ministry of Health, Jouf Affairs, the data collectors in the present study began the data collection by using a self-administered, validated Arabic version of the knowledge, attitude, and practice–intranasal corticosteroid questionnaire (KAP-INCS). This questionnaire was adapted from an open-source, valid, and reliable tool used to evaluate an AR patient’s KAP regarding INCS treatment . We folln, %). The data were tested for normality assumptions, and we applied Spearman’s rank correlation test to find the correlations between the KAP scores. Furthermore, we performed the chi-square test to find the relationships between the sociodemographic characteristics and the KAP categories. A p-value of less than 0.05 was set as a statistically significant value for all two-tailed statistical tests.The statistical package for social sciences (SPSS) version 21.0 was used for exporting, coding, and analyzing the data. We depicted the descriptive analysis as frequencies and proportions  of them were females, 25 to 40 years old (39.5%), married (58%), educated at the university level and above (60.7%), and non-smokers (79.3%). Regarding AR status, nearly one-third (34.7%) of the patients were suffering from mild or intermittent AR, and most of them (49.3%) were receiving treatment at a specialty hospital .p = 0.004), education (p < 0.001), smoking status (p = 0.006), and follow-up facilities (p = 0.036). The attitude category is significantly associated with age (p = 0.003), marital status (p = 0.004), smoking status (p = 0.006), and type of allergic patient (p < 0.001), and the practice category is significantly associated with current married status (p = 0.029), educational qualification (p = 0.027), smoking status (p = 0.038), type of allergic patient (p = 0.008), and follow-up facilities (p = 0.030)  .p = 0.015), knowledge and practice , and attitude and practice .The present study assessed the knowledge, attitudes, and practices regarding INCS treatment among AR patients of the Aljouf region of northern Saudi Arabia. Of the 400 studied AR patients, 34.7% suffered from mild forms of AR. The present study’s participant characteristics were similar to a nationwide study conducted by Almehezia et al. in 2019. In their research, nearly one-third of the patients presented with milder forms of AR, and a significantly higher proportion of the patients that presented milder forms of AR were female .p < 0.001), smoking status (p = 0.007), and follow-up facilities (p = 0.036). Similarly, a recent study on INCS usage found a significant association between smoking status and knowledge [Sufficient knowledge of the disease and its management are essential for patients suffering from a chronic disease, and poor knowledge can lead to improper adherence to the prescribed treatments and their associated complications ,32. The nowledge . It is wnowledge ,36. Furtnowledge ,37. Our p < 0.001) and smokers (p = 0.006). Firstly, the poor attitude toward INCS treatment among the participants could be due to the improvement in symptoms after the initial dosage among mild cases and non-adherence to the prescribed regimen. The present survey’s findings are supported by the findings of Manjit et al. (2022). Their survey found that the absence of symptoms and taking medications intermittently were significant factors for non-adherence [Patients’ attitudes and beliefs are critical for compliance with prescribed INCS treatment and other healthcare services ,26,38. Wdherence .p = 0.03). The possible factors for the poor practices among smokers could be less sensitization and effectiveness of steroids compared to non-smokers [p = 0.000), attitude and practice (p = 0.009), and knowledge and practice (p = 0.000) [Similar to knowledge and attitude, we found that a low proportion (18.5%) of AR patients had excellent practices with INCS treatment for their AR. In contrast, a recent survey by Mohammed et al. in 2022 showed that only approximately 5% of the participants had a poor level of practice . The str-smokers . Similar-smokers . It was -smokers . Further= 0.000) . The simThe researchers used the best possible and systematic methods to conduct the present research. Nonetheless, a few limitations must addressed. Firstly, as an important limitation of the cross-sectional study method that concurrently evaluated the risk factors and outcomes, we could not identify the direction of either association or causation. Secondly, self-reported and recall biases cannot be ignored as the current survey is questionnaire-based. Thirdly, the present study was conducted in healthcare facilities; thus, the results of the study cannot be generalized to the general population. Fourthly, the present study was limited to the northern region of the KSA. Considering the vast differences in sociocultural characteristics among different regions of the KSA, the present study’s findings may not be generalized to all provinces of the KSA and middle eastern countries.The present study explored the suboptimal knowledge, attitudes, and practices of INCS usage among AR patients. Smoking, education level, milder forms of AR, and follow-up facilities were the significant factors associated with the KAP categories. A positive correlation between the knowledge scores and the attitudes and practices indicated that improving a patient’s knowledge of INCS usage is essential to managing AR patients. Furthermore, we noted that poor practices were significantly higher among the AR patients receiving follow-up INCS treatment using over the counter products from a pharmacy. Hence, we recommend improving the knowledge of AR patients through awareness-raising programs that are primarily target-oriented. Furthermore, community pharmacists require that a focused training program on the protocols be followed when distributing INCS treatments. Finally, we recommend an exploratory prospective mixed-method KAP study to evaluate the qualitative components involving the other provinces of the KSA.


Keratins make up a major portion of epithelial intermediate filament proteins. The widely diverse keratins are found in both the small and large intestines. The human intestine mainly expresses keratins 8, 18, 19, and 20. Many of the common roles of keratins are for the integrity and stability of the epithelial cells. The keratins also protect the cells and tissue from stress and are biomarkers for some diseases in the organs. Although an increasing number of studies have been performed regarding keratins, the roles of keratin in the intestine have not yet been fully understood. This review focuses on discussing the roles of keratins in the intestine. Diverse studies utilizing mouse models and samples from patients with intestinal diseases in the search for the association of keratin in intestinal diseases have been summarized. Keratins are intermediate filament proteins that are expressed in epithelial cells. They are mainly responsible for maintaining the shape of the cell and protecting it from stress, both mechanically and nonmechanically ,2. The sHuman patients, mice models, and cell cultures have been consistently used to research the diverse functions of keratins, but the defined roles in intestine are not yet fully understood. Even though the pattern of keratin expression is slightly different in humans and mice , the finA single layer of epithelial cells is folded in a specific way to form villi and crypts, which make up the small intestine. The large intestine, however, only has crypts. In the villi, the differentiated epithelial cells are accumulated. These cells do not divide and are composed of enterocytes, goblet cells, and enteroendocrine cells . On the The main keratins found in the normal intestinal epithelial cells (IECs) are K8, K18, and K19 . These kNonetheless, the atypical expressions of K7, K8, and K20 have been found to have potential roles in abnormal intestinal cells ,24. For The expression of keratin is different in human and mouse intestines. It further differs in the small and large intestines of both species. For the keratin in normal human small intestine, the presence of K8, K18, and K19 is observed in the small intestine . K20 is As for the mice, the distribution of keratin also slightly differs between the intestine and its area. For the small intestine, K8 and K19 are evenly distributed within the crypt–villus axis . HoweverKeratins have many different functions and are found in various locations of different organs and organisms. The reasons for the differences in location of K7, K8, K18, K19, and K20 for both human and mice remain unclear, and the defined attribution of a particular function to each of the keratins is ambiguous. In addition, some studies even go further to show that K23 and K80 are also weakly expressed in the colon ,29. NoneIt is known that keratins play crucial roles in stress protection, cell integrity and structure, and protein targeting ,30,31. SDespite the well-identified associations between the crucial roles and the type of keratin in the liver, the functional roles of keratin in both the small and large intestines have not yet been fully understood. However, studies regarding mouse models have provided steps closer to finding the roles. For instance, studies regarding K8 null mouse models have provided potential roles of keratin in stress protection, inflammation, and cell proliferation ,34. NoneChemicals used to induce mouse models to colon injury usually come in two forms: dextran sulfate sodium (DSS) and azoxymethane (AOM). These animal models allow for clearer explanations on the pathogenic mechanisms of inflammatory bowel diseases and colorectal cancer. Dextran sulfate sodium (DSS) is a chemical with anticoagulant properties and is used to predispose colon injury in mouse models. The DSS model is frequently used in inflammatory bowel disease, because it is easy, straightforward, and quick . The norK-ras mutation [On the other hand, azoxymethane (AOM) is a carcinogen that is intraperitoneally administered into mouse models . With thmutation ,40. Thermutation .Most of the time, the combination of DSS and AOM is used to fully induce the mice to colon injury . This isSeveral studies of intestinal phenotypes of keratin-associated mouse models are summarized in Firmicutes and Proteobacteria and the decreased Bacteroidetes and Verrucomicrobia [Even though CRC is not spontaneously developed in K8−/− mouse models, a study that utilized both AOM and ApcMin/+ CRC murine models showed that there were higher numbers of tumors in the distal colon of the K8−/− mice compared to the controls . In a simicrobia . Notablymicrobia . OverallIn addition, a previous study using nontransgenic FVB/n mice demonstrated altered keratins in intestinal stress responses . In DSS-Along with the other keratins in the intestine, K20 is expressed and its phosphorylation at serine 13 acts as a stress intestinal goblet cell marker . The ArgThe use of transgenic mice induced with DSS is a very useful mouse model. With the knowledge gained from comparing data on the role of keratins in mouse intestines, the role of keratins in human intestines can be learned about. However, unlike the liver and pancreas, not many mouse models have been used to study the role of keratin mutants in intestine diseases. As a result, more experiments need to be conducted to find a better understanding of the key functions or associations keratins have in intestine diseases. Then, they could be useful for the improvement of therapy for patients suffering from intestine diseases.The various disorders that cause chronic inflammation in the intestines are said to be types of inflammatory bowel disease (IBD). There are two main subtypes of IBD: ulcerative colitis (UC) and Crohn’s disease (CD). While UC only occurs in the rectum and colon, CD can occur anywhere in the gastrointestinal tract . HoweverBoth UC and CDD have similar symptoms in which the patient suffers from diarrhea, fever, abdominal pain, and possible malnutrition. IBD affects over 1 million people in the United States alone and around 2.5 million people in Europe . IBD casp-value was not determined in the conducted studies, except for one which involved German patients who suffer from IBD [p-value being greater than 0.05, p = 0.46 [In from IBD . The stup = 0.46 ,55. In tOn the other hand, the K19 frequency in human patients is bigger in value than K8. In As a result, the common mutations in K8, such as Y54H, G62C, and R341H, and K19 demonstrate that they have no significant association with IBD ,55. EvenNotably, keratin levels in the mucosa in IBD patients are altered in acute inflammation that predisposes to development colitis-associated cancer (CAC) . KeratinOne of the most common cancers that Americans suffer from is colorectal cancer (CRC) . In 2017K7 and K20 are potential biomarkers in CRC ,27. WhilK18 and K19 are also prognostic indicators of CRC. The overexpression of K18 is frequently observed in many types of human cancer . In termAnalyses of keratin variants in patients with IBD provide insufficient evidence for keratin function in these diseases. It remains unclear whether the keratin mutations have significant effects on IBD, since the frequency of most mutations in K8 and K19 was not statistically significant. Although one in vitro study demonstrated that the keratin variant, such as K8 G62C found in IBD patients, altered the barrier function of intestinal cells , analyse