In AMD, HRF overlying drusen are associated with the development of macular neovascularization, while parafoveal drusen and HRF predispose to macular atrophy. Thus, HRF can be considered a key biomarker in several common retinal diseases. Their recognition and critical interpretation via multimodal imaging are vital to support clinical strategies and management.Hyperreflective foci (HRF) is a term coined to depict hyperreflective dots or roundish lesions within retinal layers visualized through optical coherence tomography (OCT). Histopathological correlates of HRF are not univocal, spacing from migrating retinal pigment epithelium cells, lipid-laden macrophages, microglial cells, and extravasated proteinaceous or lipid material. Despite this, HRF can be considered OCT biomarkers for disease progression, treatment response, and prognosis in several retinal diseases, including diabetic macular edema, age-related macular degeneration (AMD), retinal vascular occlusions, and inherited retinal dystrophies. The structural features and topographic location of HRF guide the interpretation of their significance in different pathological conditions. The presence of HRF less than 30  The terin vivo . Howeverin vivo , migratiin vivo –5, and din vivo .The presence of HRF has revealed prognostic and clinical implications in several retinal diseases –12 and hThe present study aims to provide an overview of the existing literature on HRF as OCT biomarkers associated with disease progression, treatment response, and prognosis of several retinal disorders, including DME, AMD retinal vein occlusion, retinal dystrophies, and uveitis.th December 2020. The articles selected described the clinical and prognostic implications of intraretinal and choroidal HRF detected in retinal diseases. Of 212 publications, 119 manuscripts published between 2005 and 2020 are reported in this narrative literature review. Reference lists of the selected manuscripts were also analyzed to retrieve other relevant studies.A literature search of the Medline database was performed using the term “hyperreflective foci” for articles published in English, last accessed on 9The presence of HRF in treatment-naïve DME was first described by Bolz et al.  as hyperAnother theory hypothesized that HRF were lipid-laden macrophages migrating into cystoid spaces as a consequence of blood-retinal barrier (BRB) breakdown ,22. HoweSuspended scattering particles in motion (SSPiM) is a novel OCTA feature characterized by a flow artifact produced by moving material within cystic spaces possibly due to large molecules such as serum proteins and albumin permeated through the retinal interstitium . SSPiM iCombined multimodal analysis showed that HRF mainly occupy the outer nuclear layer (ONL) and outer plexiform layer (OPL) with distribution of the smallest foci in the inner nuclear layer (INL) and inner plexiform layer (IPL) and posterior shadowing caused by larger foci . The ideHRF cannot be identified with clinical examination because of their small size and axial thickness, and appropriate imaging resolution is necessary for their recognition. It was hypothesized that the foci gradually tend to grow and coalescence into visible lesions as hard exudates . On nearInterestingly, Lee et al.  demonstrμm, absence of posterior shadowing, and reflectivity similar to the retinal nerve fiber layer  on OCT B-scans include location within the inner retina, size ≤30 er layer  [15,32,3The amount of HRF reflects disease severity, exhibiting direct associations with HbA1c values and high levels of total cholesterol, triglycerides, and low-density lipoprotein –37. The In eyes with DME, HRF located in the outer retinal layers have been strongly associated with worse visual prognosis, disruption of the ELM, photoreceptor loss, and worse prognosis after vitrectomy ,29,40,41The number of HRF in the outer retinal layers, as a predictor of final visual acuity, was associated with different patterns of DME including diffuse macular edema, cystoid macular edema, and serous retinal detachment . The detChanges in intraretinal HRF distribution during DME resorption after anti-vascular growth factor (VEGF) treatment included descending migration toward outer retinal layers, supporting the role of the osmotic gradient in fluid and macromolecule clearance . DME witβ and HRF (>10) in refractory DME [While the role of HRF in predicting visual outcome of DME treated with anti-VEGF agents did not reach univocal conclusions ,45,51,52tory DME ; likewistory DME ,58. Patitory DME .Evidence of HRF in the foveal region influenced postoperative visual recovery in eyes with vitreous hemorrhage due to proliferative diabetic retinopathy . NeverthRecently, multiple (more than 30 in number) and diffuse HRF were considered integrant criteria of severity in the OCT grading proposed for diabetic maculopathy by an international panel of retinal experts .Khanifer et al. first reported HRF in AMD in 2008  and analIt was generally believed that HRF represent anteriorly migrating RPE cells and possible disaggregated photoreceptors, as supported by the corresponding pigmentary changes visible on color photographic images ,64,65. Hnascent type 3 [HRF located above the external limiting membrane and ONL/OPL junction, often co-localized with a drusenoid pigment epithelial detachment (PED), can also represent the antecedents of type 3 macular neovascularization (MNV), or the so-called t type 3 –73. Nasct type 3 .  Figuret type 3 ,74.Intraretinal HRF from a possible RPE source have been characterized on clinicopathological correlations as isolated or grouped pigmented, nucleated RPE cells that shadow posteriorly on OCT B-scans often associated with hypertransmission areas reflecting the atrophic and dissociated RPE cells ,75,76. DHRF can be detected in intermediate to advanced AMD, demonstrating a predictive role for AMD progression and prognostic value when macular complications occur –80. HRF More interestingly, the increasing number of HRF was associated with RPE atrophy and considered a precursor of geographic atrophy ,77,79. SSimilarly, in eyes with drusenoid PED, the presence of HRF at baseline and their migration throughout retinal layers were directly associated with new-onset atrophy . ChangesThe prognostic role of HRF has been proven for predicting neovascular conversion. Both the presence and HRF count represented strong predictive biomarkers of neovascular progression . PrecursIn eyes with MNV, HRF were diffusely distributed in the neurosensory retina and their presence was associated with a poor visual outcome despite anti-VEGF treatment ,98. AntiThe role of HRF has been investigated in other retinal vascular diseases, including branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). In this regard, two distinct HRF populations have been identified, including fine scattered HRF probably related to extravasation of blood constituents and confluent HRF mainly located in the unaffected areas spared by the retinal occlusion. Confluent HRF were thought to be associated with the absorption of water and other molecules . While fAmong degenerative retinal diseases, retinitis pigmentosa (RP) revealed HRF with specific topographic distribution and association with disease progression. Eyes with HRF distributed in the INL denote an early stage of RP with spared RPE-Bruch's membrane complex. However, eyes with HRF in the ONL designate a more advanced disease characterized by photoreceptor loss and RPE cell migration and degeneration . RPE cel2, hypothesizing that HRF tended to fade with atrophy enlargement [In Stargardt disease, the evidence of choroidal HRF primarily located in the choriocapillaris and Sattler's layer was considered a biomarker of disease severity in terms of atrophic changes and visual function ,113. FurIn pathologic myopia, the HRF role has been investigated in myopic choroidal neovascularization and myopic macular hole ,115. HRFHRF were recognized in uveitis and intraocular inflammatory disorders and were likely presumed to represent intraretinal exudates, lymphocytic cellular or clumping of photoreceptors or intraretinal RPE cells when related to photoreceptor loss –119. In μm without posterior shadowing and reflectivity similar to the retinal nerve fiber layer configures the inflammatory phenotype in DME that usually responds better to early intravitreal steroid implant.Hyperreflective foci represent a univocal OCT feature revealing several possible histopathological correlates, including migrating RPE cells, microglia, precursors of exudates, or intraretinal neovascularization in the setting of AMD. HRF represent an important OCT biomarker with significant clinical and prognostic implications embracing several common macular diseases. The detection of HRF of size ≤30 Relevance as a biomarker is also observed in AMD, where the number and distribution of HRF may be predictors for progression to advanced stages of disease. The co-localization of HRF overlying drusen associated with drusen growth in the foveal center is believed to be a predictor of neovascular progression. In contrast, a high concentration of HRF distributed at 0.5 mm of eccentricity edging the foveal pit, in the absence of drusen occupying the foveal center, tends to predispose to macular atrophy. Moreover, the presence of HRF influences anti-VEGF treatment response and visual prognosis of MNV. In conclusion, HRF can be considered a critical OCT feature with substantial predictive value for disease progression and treatment response in the principal macular disorders encountered in routine clinical practice. Their prompt recognition and critical interpretation may guide clinical and therapeutic strategies.


Until now, the microscopic origin of the induced superconductivity and the role of oxygen are far from clear. Here, by combining in situ scanning tunneling microscopy/spectroscopy (STM/STS) and X-ray photoemission spectroscopy (XPS) on oxygenated FeTe, we found physically adsorbed O2 molecules crystallized into c (2/3 × 2) structure as an oxygen overlayer at low temperature, which was vital for superconductivity. The O2 overlayer were not epitaxial on the FeTe lattice, which implied weak O2 –FeTe interaction but strong molecular interactions. The energy shift observed in the STS and XPS measurements indicated a hole doping effect from the O2 overlayer to the FeTe layer, leading to a superconducting gap of 4.5 meV opened across the Fermi level. Our direct microscopic probe clarified the role of oxygen on FeTe and emphasized the importance of charge transfer effect to induce superconductivity in iron-chalcogenide thin films.The phenomenon of oxygen incorporation-induced superconductivity in iron telluride (Fe Tc) iron-based high transition temperature (Tc) superconductors. The monolayer grown on SrTiO3 (STO) still holds the record in Tc with much-enhanced superconducting pairing [2 atmosphere [Iron-chalcogenide Fe  superconductors are an important family of . We found that O2 molecules physically adsorbed on FeTe surface under low O2 partial pressure at room temperature and crystallized into c (2/3 × 2) structure, which gradually disappeared after heating up to 100 °C in vacuum. No surface oxidation can be found. The band shift observed in STS and XPS suggests hole doping from the O2 overlayer to FeTe, which induced a superconducting gap in FeTe. It agrees with the ex situ transport measurement that long-time exposure to air can induce superconducting transition in 10UC FeTe on STO.First, we grew nearly stoichiometric 10 Unit-Cell (UC) FeTe epitaxy ultrathin films by molecular beam epitaxy (MBE) and then studied the adsorption of O3(001) by using a Unisoku ultrahigh vacuum (UHV) low-temperature STM system , equipped with an MBE chamber for film preparation. The base pressure of our MBE chamber is 1 × 10−10 mbar and does not exceed 5 × 10−10 mbar during FeTe epitaxial growth. The Nb doped-STO substrate  was firstly annealed at 1000 °C for 1 h and then kept at 280 °C during FeTe growth. High purity Fe (99.9999%) and Te (99.9999%) sources were co-evaporated onto SrTiO3(001) substrates from two standard Knudsen cells. To improve the quality of crystallization, FeTe films were annealed at 280 °C for 1 h after growth. The O2 gas (99.999%) was introduced to a small preparation chamber with a base pressure of 2 × 10−9 mbar. Then the oxygen absorption was carried out at room temperature under O2 partial pressure of 1.6 × 10−4 mbar (if not specified otherwise). After O2 absorption, the samples were in situ transferred to the STM chamber or XPS equipment for further characterizations. For electronic transport measurement, 10UC FeTe films were grown on high-resistance STO and covered with the Te protection layer.High-quality 10UC FeTe thin films were grown on SrTiOI/dV spectra were acquired by using a standard lock-in technique at a frequency of 983 Hz. The STM topographic images were processed with WSXM software  [All STM/STS measurements were performed at a temperature of 4.7 K with a bias voltage applied to the sample. Polycrystalline Pt/Ir tips were cleaned by electron bombardment and then carefully calibrated on Ag films grown on Si (111). All STM topographic images were obtained under a constant current mode. The differential conductance d, Spain) .−10 mbar, 2016, Chigasaki, Kanagawa, Japan), equipped with a monochromatic Al Kα X-ray source of 1486.7 eV. The binding energy (BE) of core-level peaks were calibrated with respect to the C-C 1s bond (BE = 284.8 eV). A monochromatized He I with an energy of 21.22 eV were used for UPS measurement. During the UPS measurement, a voltage of −5 V was applied between the sample and the spectrometer.After STM/STS measurements, the samples were transferred via a UHV interconnection pipeline in Nano-X for XPS/UPS characterization without exposure to air. XPS/UPS experiments were carried out by using a commercial analyzer , 2, respectively. After inlet O2 under a partial pressure of 1.6 × 10−4 mbar, we do not observe Te-O and Fe-O spectra signals. If exposure to O2 partial pressure of 1.5 × 10−1 mbar for 20 min, as shown in 2 partial pressure. The XPS spectra of Te 3d and Fe 2p show an obvious peak shift toward higher binding energy, which hints hole doping effect in FeTe. The overlayer would gradually desorb when heating up to 100 °C and disappeared after annealing at 200 °C for 2 h. Only a clean FeTe surface was left. The overlayer will re-adsorb after inlet O2 again. Thus, we can rule out the possibility of Fe- or Te-related compounds because there was negligible residual Fe or Te atoms after growth. In addition, we notice there are some dispersed clusters higher than the compacted islands in 2 molecules rather than stacked O atoms. The shape of O 1s core level almost remains unchanged after O2 adsorption under a partial pressure of 1.6 × 10−4 mbar, as illustrated in 2 molecules, where characteristic core-level XPS peak always cannot be found. Thus, we name the overlayer heterostructure as FeTe : O2. UPS measurements in ϕFeTe ~ 4.43 eV to ϕ2FeTe:O ~ 4.38 eV after O2 adsorption. The small difference in work function is also consistent with the nature of O2 molecules in the overlayer.To unravel the nature of adsorbed overlayer , as shown in 2 adsorption overlayer (FeTe : O2) and the FeTe surface. To locate the precise adsorption sites of O2 on FeTe, we achieved an atomically resolved image on both the FeTe : O2 island and FeTe surface in n1 direction, the adsorption sites of O2 molecules are not well-defined relative to FeTe lattice and not at high-symmetry points. It not only signifies that the van der Waals interaction between O2 molecules plays a vital role in the overlayer but also verifies the absence of chemical bonding between the O2 interlayer and the FeTe surface.2 absorption, we conducted detailed differential conductance dI/dV measurements, which are known to be proportional to the local density of state (LDOS). On as-prepared and uncovered clean 10UC FeTe surfaces, the STS remain nearly unchanged with a “V” shape across the Fermi level in 2 after O2 adsorption, which indicates hole doping effect to FeTe, agreeing well with the observation of peak shift in XPS experiments in 3Sb5 with an increased superconducting transition temperature. Additionally, hole doping effects were observed in Bi2Te3/FeTe [2Te3/FeTe [I/dV spectra in a small energy range. A clear V-shape was observed on a clean FeTe surface, similar to the one on the monolayer FeTe [2 islands two pronounced peaks with an energy gap of ~9 meV were clearly identified across the Fermi level. Considering the facts of previous observation of hole-doping-induced superconductivity in the Bi2Te3/FeTe heterostructure and the superconductivity observed in 10UC FeTe/STO sample after long-time exposure to air, we conclude that the gap on FeTe : O2 is just a superconducting gap with Δ ~4.5 meV, larger than the one on Bi2Te3/FeTe heterostructure (~2.5 meV) [xSe1-x [2 islands in I/dV curves.To explore how the electronic structure changes due to OTe3/FeTe ,33 and STe3/FeTe  heterostyer FeTe . Strikin2.5 meV) ,34. It s2.5 meV)  and mono [xSe1-x . We have2 islands is intriguing and distinct from all the previously proposed mechanisms. Physically adsorbed O2 molecules rather than interstitial oxygen or oxygen substitution are responsible for superconductivity in oxygenated FeTe. Previously, annealing under an elevated temperature or quite a long-time aging may be aimed at the formation of a uniform O2 overlayer into the FeTe layer. Our study here also emphasizes the importance of the hole doping effect and interfacial effect to induce superconductivity on FeTe. We have not observed a superconducting gap on FeTe:O2 overlayer on monolayer FeTe, which may be due to the extra electron doping from the STO substrate.The observation of enhanced superconducting gap on FeTe : O2 adsorption. Ex-situ transport measurements demonstrate long-term exposure to air could induce superconducting transition in 10UC FeTe ultrathin film, which verifies the effect of oxygen incorporation. Initially, O2 molecules physically adsorbed on the FeTe surface and formed compacted FeTe : O2 islands with c(2/3×2) structure at low temperatures. No oxygen-related defects can be detected on the uncovered clean FeTe surface. Energy shifts in STS and XPS measurements point out obvious hole doping into FeTe from the oxygen overlayer. Such hole doping results in a superconducting gap of ~ 4.5 meV opened with apparent coherent peaks. Our study here directly provides microscopical insights about the role of oxygen on FeTe thin film.In summary, we have systematically investigated the changes of morphology and electronic structure of 10UC FeTe films after O


This study aimed to assess the appropriateness of the post-operative rehabilitation of low energy hip fractures in the elderly by comparing between the rehabilitations actually provided at level one trauma center and the AAOS Appropriate Use Criteria (AUC) recommendations.A retrospective review of the medical charts of all patients who underwent surgery for hip fractures followed by post-operative rehabilitation between October 2016 and May 2018. The age, gender, fracture types, four AUC variables including; the surgical approach, pre-operative mobility/functional status, cognitive impairment, and post-operative delirium, and types of post-operative rehabilitation received were collected.The four patient variables were entered into the AUC application to generate the recommended rehabilitation procedures. Afterward, the rate of appropriateness of the treatments and the agreement between the rehabilitations actually provided and the AUC recommendation were measured.Over the study period, a consecutive series of 101 patients were included. The mean age was 75 years. Most of the patients were males (51.5%). Seventeen scenarios were observed in our patients. The most common scenario were patients with low functional/physical demands (48%), intact cognitive function (91%), non-arthroplasty approach (76%), and no post-operative delirium(97%).P = .001), maybe appropriate in 19 (3%) (P < .001), rarely appropriate in 61 (8.3%) (P = .59), and 40% of rehabilitation procedures were not provided (P < .001).The overall appropriateness rate of the provided rehabilitation treatments for our patients in comparison with AUC recommendation was appropriate in 356 (48.7%)  of three procedures , in (72.2%) of osteoporosis assessment/management, in (63.8%) of outpatient occupational/physical therapy, in (10.2%) of delirium prevention, in (33.3%) of delirium management and in (25%) of home care therapy.This study demonstrated that there is a remarkable variation in the appropriateness of the various post-operative rehabilitation procedures for elderly hip fracture. Additionally, the AUC application was easy to use and simple for identifying post-operative rehabilitation protocols for elderly hip fractures, hence, we recommend to use it in the trauma clinical practice.Level of evidence: IV Hip fracture is one of the most common fractures in the Elderly. It is usually caused by low-energy trauma. It is often associated with osteoporosis and other medical co-morbidities that may increase the prevalence of falls –3. Most Elderly patients with hip fractures are at risk for decreased level of mobility, inability to return to prior living circumstances, impaired quality of life, and increased rate of mortality –9.Hip fractures are almost always treated surgically with either internal fixation or arthroplasty depending on the fracture type, age of the patient, fracture site, and pre-injury functional status , 11. TheTo improve the quality of the management of hip fractures in the elderly, the American Academy of Orthopedic Surgeons (AAOS) published clinical practice guidelines in 2014 based on the best available evidence .Subsequently, the AAOS published the Appropriate Use Criteria (AUC) in 2015 for the Post-operative Rehabilitation of Low Energy Hip Fractures in the Elderly (PORHFE) based on the relevant evidence and experts from different fields of musculoskeletal care. The AAOS made the free web-based AUC application widely available to help orthopedic surgeons to select the most appropriate post-operative rehabilitation protocols .Four clinical variables for a specific patient clinical scenario are entered into the AUC application: a surgical approach for arthroplasty (or non-arthroplasty); pre-operative mobility/functional status; cognitive impairment; and post-operative delirium. The application then provides a listing of upto 10 different rehabilitation procedure recommendations. Each procedure is rated into one of three categories: appropriate, may be appropriate, and rarely appropriate , 17.This study aimed to assess the appropriateness of the post-operative rehabilitation of low energy hip fractures in the elderly by comparing between the rehabilitations actually provided at a level one trauma center and the AAOS Appropriate Use Criteria (AUC) recommendations.to determine the rate of appropriateness and agreement with AUC recommendations.The Institutional Medical Research Center approved this study with a protocol number (MRC-01-18-072), and informed consent was exempted. Retrospectively, all elderly hip fractures (≥ 60 years) who underwent surgical treatments (fixation or arthroplasty) between October 2016 and May 2018 were identified from the operating theater registry. Our institution is a level 1 trauma center accredited by Joint Commission International (JCI) and Accreditation Council of Graduate Medical Education-International (ACGME-I). Our orthopedic unit includes 14 consultant orthopedic surgeons who manage orthopedic trauma, including hip fractures in elderly patients.The eligibility criteria were according to the AUC criteria for post-operative rehabilitation of hip fracture in elderly.The inclusion criteria were patients who underwent surgery (fixation or arthroplasty) for low-energy isolated elderly hip fractures (≥ 60 years).Patients with previous surgical intervention, revision surgery, bilateral hip fractures, pathological fractures, and open fractures, poly trauma, and medical contraindications to post-operative rehabilitation therapies were excluded because those patients need special care and multidisciplinary approach which differs from the standard post-operative rehabilitation procedure.The data for patient age, gender, the surgical approach for arthroplasty or non-arthroplasty, pre-operative mobility/functional status, cognitive impairment, post-operative delirium, and post-operative rehabilitation treatment procedures were collected from the patients’ medical charts and radiographs.The AUC for post-operative rehabilitation of low energy hip fractures in the elderly requires four patients’ variables to generate appropriateness ratings for ten post-operative rehabilitation procedures. These variables include 1. Surgical approach for arthroplasty, which was retrieved from surgeon operative note and could be either Posterior, Anterior/Anterolateral, or Non-arthroplasty procedure. 2. Pre-operative Mobility/function status graded in four levels from high functioning to non-ambulatory. It was retrieved from admitting physician and physiotherapist notes. 3. Cognitive impairment was retrieved from an emergency physician triage or attending physician assessment notes. It was assessed using Mini-mental state examination (MMSE) and graded into three levels; intact, mild, and moderate or severe. 4. Post-operative delirium was collected from the post-operative attending physician or anesthetist assessment notes.Thus, the four parameters according to the criteria of the AUC were retrieved by two authors for 101 consecutive patients included in this study and entered into the AUC application to generate the post-operative rehabilitation protocols.To assess the appropriateness of post-operative rehabilitation, first, the four parameters of each patient were input into the AUC to generate the appropriateness rating of the ten provided rehabilitation procedures for each patient.Each of the ten rehabilitation procedures is rated as appropriate, may be appropriate, or rarely appropriate according to the AUC application Fig. .Fig. 1WeAfterward, the appropriateness rate and agreement with the AUC recommendations were then compared between the treatments actually provided and the AUC recommendations.Delirium management was removed in scenarios with no post-operative delirium.Delirium prevention was removed in patients with post-operative delirium.Outpatient Rehabilitation was removed in the patient scenarios with the inability to leave the house (low function patient).Outpatient Rehabilitation was removed in scenarios with non-ambulatory/bed dependent.Interdisciplinary management at Inpatient Rehabilitation or Skilled Nursing Facility (IRF or SNF) was provided only if the patient unable to return home.Home care therapy was provided if able to return home but unable to transport to a local rehab facility.Thus, according to the above-mentioned amendments; two hundred seventy-eight rehabilitation procedures for 101 patients were removed. Hence, 732 rehabilitation procedures should be provided for our patients.The AAOS panels made amendments to remove the below treatment options from specific patient scenarios due to clinical irrelevance:T test and Chi-squared test, respectively. A p value < 0.05 was considered statistically significant. All data were analyzed using statistical software .Descriptive statistics such as means, ranges, ± standard deviation, and frequency were used to describe the continuous variables such as the patient characteristics and patient scenarios. Whereas discrete variables were described as frequency  such as appropriateness rating for each rehabilitation procedure and the agreement of the treatments implemented at our institution with the AUC recommendations. Continuous and discrete variables were analyzed via No sample size calculations were performed before conducting this study because all patients who met the inclusion criteria were included. A post hoc power analysis revealed a power of greater than 80%, which indicated that the sample size was adequate for analysis. The calculation was based on using post-hoc calculator with a one sample proportion test and a 5% level of significant to evaluate the power of existing study to detect a difference by comparing our appropriateness rate (48.7%) of 101 cases versus the AAOS AUC appropriateness rate of 75% that was published in previous literature.A total of 210 cases were identified in our theater registry with a diagnosis of hip fractures. One hundred and nine cases were excluded; the reasons for exclusion were < 60 years in 80 patients, medical contraindication to post-operative rehabilitation in 13 cases, revision surgery in five patients, three cases were polytrauma, pathological fractures in seven patients and one patient with bilateral hip fractures. Thus, 101 patients with elderly hip fractures met the inclusion criteria and eligible for analysis , and 51.5% were males. Forty-one case (40.6%) sustained stable intertrochanteric, 23 (22.8%) unstable intertrochanteric fractures, 7 (6.9%) subtrochanteric, 26 (25.8%) displaced neck of femur, 4 (3.9%) nondisplaced neck of femur fractures.Seventeen out of 72 AUC scenarios were observed in our study. With predominance of low function/low physical demands (48%), intact cognitive function (91%), non-arthroplasty approach (76%) (stable intertrochanteric fracture (40.5%) fixed by DHS (44.5%)) with no post-operative delirium (97%). (Table P < 0.001).In comparison with AUC recommendation, four hundred thirty-six (60%) rehabilitation procedures were provided, and 296 (40%) of rehabilitation procedures were not provided for our patients (P = 0.001), maybe appropriate in 19 (3%) (P < 0.001), and rarely appropriate in 61 (8.3%) (P = 0.59) of rehabilitation procedures.The overall appropriateness rate of the provided rehabilitation treatments for our patients in comparison with AUC recommendation was appropriate in 356 (48.7%) (P < 0.01), in (63.8%) of outpatient occupational and physical therapy (P = 0.01), in (25%) of home care therapy (P < 0.001), in (10.2%) of delirium prevention (P < 0.001), and in (33.3%) of delirium management (P = 0.25). Table The actual treatment was appropriate and in agreement with the AUC recommendations in (100%) of three procedures (Deep venous thrombosis (DVT) prophylaxis, pain management, and Inpatient Rehabilitation Facility (IRF) or Skilled Nursing Facility (SNF)), in (72.2%) of osteoporosis and assessment management (01), in 6.8% of ou01), in 6.8% of ouThe most important finding of this study was that the appropriateness rate in our patients was significantly lower than the AUC recommendations for the appropriate and maybe appropriate treatments; however, the rarely appropriate treatment was not statistically different compared with the AUC recommendation.Furthermore, this study demonstrated a remarkable variation in the appropriateness of post-operative rehabilitation procedures for elderly hip fractures at our center. It was appropriate and in agreement with AUC recommendations only in a few procedures and, to a lesser extent, in the other rehabilitation procedures.It is concerning that some rehabilitation procedures were not provided in a high percentage of patients at our institution, like home care therapy, delirium prevention, delirium management. The reasons might be due to the lack of evidence-based post-operative rehabilitation protocols for hip fractures in elderly patients at our institute, underestimation of the importance of these procedures by some surgeons, and/or the lack of the orthogeriatric service at our center. Consequently, implementation of AUC for post-operative rehabilitation of hip fractures in elderly could allow surgeons to explore all available and evidence-based rehabilitation options. It is a known fact from the literature and AUC guidelines that the post-operative rehabilitation procedures should be provided for any elderly patients with hip fractures to improve the quality of patient care by guiding the treating physicians in selecting an appropriate rehabilitation procedure. Hence, the variation in the post-operative rehabilitation for elderly patients with hip fractures should be decreased, and the patient care should be improved , 15, 16.Several authors have investigated the importance of the evidence-based post-operative rehabilitation protocols, and the orthogeriatric settings for the management of the elderly hip fracture –22.Mark et al. demonstrated that hip fractures should be treated according to the most up-to-date evidence to achieve the best possible outcomes and optimal use of limited resources .Beaupre et al. reported that the implementation of an evidence-based clinical pathway reduced the post-operative morbidity and did not affect in-hospital mortality or overall costs of inpatient care after hip fractures .Adunsky et al. reported that the functional outcome of elderly hip fracture patients is better for those treated in the orthogeriatric setting, as compared with the common two-steps model of orthopedic surgery followed by transfer to a geriatric rehabilitation facility .Siddiqi et al. emphasized that a proactive geriatric consultation may reduce delirium incidence and severity in patients undergoing surgery for hip fracture .We also found that the application of patients’ data into the free web-based AUC application made post-operative rehabilitation options for each case is relatively easy and simple to use. Most of the AUC rehabilitation therapies were provided at our center; however, not all the AUC scenarios were observed in our patients.The availability of the AUC as a free web-based application is a valuable tool that can help the orthopedic surgeons to build their practice on a solid evidence-based data to improve the quality of care in such group of patients.The AUC for the surgical treatment of knee osteoarthritis (OA) was recently evaluated, and concluded that AUC for the surgical treatment of knee OA can be applied easily in a clinical setting with 99% agreement was observed between the actual treatment of 100 patients and the AUC recommendations of appropriate treatment .This study also has shown that the hip fractures were more common in male patients with a low prevalence of cognitive impairment and post-operative delirium.The previous studies reported that the elderly hip fractures most commonly occurred in women with a higher prevalence of cognitive impairment and post-operative delirium –27.These variations might be attributed to the health, cultural, and demographic variation across the countries and/or the global geographic variations in hip fractures and cognitive impairment , 29.In Qatar, the population characteristics are male predominance with a ratio of 2.6:1 because it is a newly growing country and depends mainly on male laborers from other countries and constitutes about 72% of the total population . AdditioThere were some drawbacks of AAOS published AUC for PORHFE: The appropriateness was not clearly defined for each recommendation of AUC, such as what is the alternative to the appropriateness ratings if the recommended procedure was not provided. For example, the range of motion restriction and weight-bearing restriction was always graded as maybe or rarely appropriate in all AUC scenarios; however, they did not specify how it graded the appropriateness if there were no restrictions.Sherrington et al. reported in a randomized clinical trial that weight-bearing and non-weight-bearing exercise programs produce similar effects on strength, balance, gait, and functional performance among inpatients after hip fracture .Home care therapy is a treatment that still controversial, where not all patients or hospitals could afford such treatment after the AUC amendment.This study has several limitations: the retrospective design of study, lack of comparative group, and patient outcome. The lack of sample size calculation, low level of evidence, and the cultural difference across the countries might affect the appropriateness ratings are other limitations of this study.This study demonstrated that there is a remarkable variation in the appropriateness of the various post-operative rehabilitation procedures for elderly hip fracture. Additionally, the AUC application was easy to use and simple for identifying post-operative rehabilitation protocols for elderly hip fractures in the trauma setting, hence, we recommend to use it in the clinical practice.


There is great need for development of feasible rehabilitation for older people with dementia. Increased understanding of this population’s experiences of rehabilitation participation is therefore important. The aim of this study was to explore the experiences of community-dwelling older people with dementia participating in a person-centred multidimensional interdisciplinary rehabilitation program.Sixteen older people with dementia were interviewed about their experiences of participation in a person-centred multidimensional interdisciplinary rehabilitation program. The program comprised assessments by a comprehensive team of rehabilitation professionals followed by a rehabilitation period of 16 weeks, including interventions based on individualized rehabilitation goals conducted with the support of the rehabilitation team. The rehabilitation was performed in the participants’ homes, in the community and at an outpatient clinic, including exercise with social interaction in small groups offered twice a week to all participants. The interviews were conducted at the end of the rehabilitation period and analysed with qualitative content analysis.Empowered through participation and togetherness and four sub-themes: Being strengthened through challenges; Gaining insights, motives, and raising concerns about the future; Being seen makes participation worthwhile; and Feelings of togetherness in prosperity and adversity. The participants increased their self-esteem by daring and coping in the rehabilitation. The insights about themselves and their condition motivated them to continue with their prioritized activities, but also raised concerns about how the future would play out. Collaboration in the group and being seen and acknowledged by staff strengthened their own motivation and self-efficacy.The analysis resulted in one overarching theme: According to community-dwelling older people with dementia, a person-centred multidimensional interdisciplinary rehabilitation program was experienced as viable and beneficial. The participants seemed empowered through the rehabilitation and expressed mostly positive experiences and perceived improvements. Providers of interdisciplinary rehabilitation programs for this group should consider aspects raised by the participants e.g. the positive experience of being challenged in both exercise and daily activities; the importance of being seen and feeling secure; the benefits and challenges of collaboration with others in the same situation; and the generation of new perspectives of current and future situation.The online version contains supplementary material available at 10.1186/s12877-021-02282-y. Dementia significantly influences all aspects of life for affected individuals, as well as for family members and friends in their immediate networks . DementiRehabilitation is a set of interventions designed to optimize functioning and reduce disability among individuals with health conditions in interaction with their environment . As rehaAlthough studies have evaluated different aspects of rehabilitation for people with dementia, few studies have evaluated rehabilitation provided by interdisciplinary teams comprised of many different professionals who collaborate to conduct assessments, set common goals, and perform continuous follow-ups  in an ouhttp://www.isrctn.com/ISRCTN59155421. . Participants in the MIDRED study were recruited through local health centers and the outpatient unit of the Geriatric Center, University Hospital of Umeå. The study inclusion criteria were: diagnosis of dementia according to the 10th revision of the International Statistical Classification of Diseases and Related Health Problems in medical records, age ≥ 60 years, Mini-Mental State Examination (MMSE) score ≥ 10  you feel that they are used to dementia, so you relax…When we sat and talked, it felt like things were normal” (Bridget). According to the participants, the staff were able to see each person’s progress, and had the ability to adapt treatment to personal needs. “Yes, they are nice people [the team staff]...they have been attentive...if you ask, you get answers to everything you ask about...helpful in every way…I think that is a suitable team size anyway when doing something like this” (Adam). The participants appreciated being greeted by staff at the entrance of the rehabilitation unit, which made them feel safe and welcomed. The assistant nurse support with practical things, including coffee breaks, was very much appreciated. Participants described the support with travel as a privilege that solved the logistical problem of getting to and from the day rehabilitation unit, and thus reduced potential feelings of anxiety before leaving home.The participants appreciated that the staff had appropriate skills, and characteristics, and commended them for their qualities, which contributed to their well-being. The staff’s support and care were sensitive to their individual problems, which created security. The participants emphasized that the rehabilitation team provided great overall service and that the staff had been handpicked for the purpose: “We are not alike and have not all progressed as far in our illness, this should be the least you think of there” (Eva). They also had different expectations about the content of the rehabilitation and what it would lead to. One expectation mentioned was to take part in lectures given to informal caregivers instead of being in the exercise session. The different focus between participants and their informal caregivers was also mentioned. One woman had wanted to find a friend during the rehabilitation, but this did not happen. Some described difficulties in adapting to the logistics of traveling between their homes and the day rehabilitation unit and that travel could cause stress and uncertainty.Some participants stated that they had needs that were not met by the rehabilitation program. For example, wishes for more information about dementia, more help from the doctor, and more strength training were voiced. One woman expressed that she did not feel she was seen as a capable individual, and that the focus of the rehabilitation was on the informal caregivers. There were constructive suggestions for changes of the rehabilitation, such as group allocation based on functional level and stage of the disease. “In the future I think it is important for such activities, that it is a slightly smaller group that stimulates each other, because it is not every day you think positively, there are days that you are negative and you feel down…You play off each other” (Adam). The coffee break after the exercise was highlighted. Having coffee together and conversing was described as a pleasant experience. Participants felt positive about the conversations during the break, and expressed that everyone felt included and involved in the dialog. They felt able to talk like ordinary people and to discuss current topics. However, when talking about all of these positive aspects, sad feelings emerged that the rehabilitation program would end soon. They expressed that they would miss the activities, the staff and the other participants in the group: “I will miss the others in the group…I will do that…well I think it has been good…better than when you were alone” (Bridget).The participants described having fun and forming friendships in the group at the day rehabilitation unit. The atmosphere was described as relaxed, supportive, and spirit-boosting. They characterized the group as stimulating, which implied a sense of being comfortable. This comfort, in turn, led them to dare to contribute to the group. “We sit together around this table, but then...it can be fun if you find a topic of conversation, but it always dies away...it is not possible for these people to respond, but the staff try to keep it going further so we get some views on what we are talking about and so on, but no one comes with their own point of view connected with the topic... if so, it is something entirely different…so the conversation stops from its own lack of…fuel, so to say” (Betty).The participants also perceived obstacles to interaction in the group setting, and described the group situation as complex given the variation in participants’ abilities and personalities, which meant that it was not always easy to interpret others. The importance of contributing and communicating with each other in the group was emphasized. Some also mentioned feeling sad because they had not gotten to know each other well during the rehabilitation period. Others also described grief about being unable to communicate actively with everyone in the group, or to keep conversations going, as some in the group could not actively engage in the dialogue. Empowered through participation and togetherness. Participants described that they were strengthened by facing individualized challenges during the rehabilitation. Mediated by the rehabilitation program, they gained insights about themselves and their condition, which motivated them to continue engagement in prioritized activities, but they also became concerned about how the future would turn out. Participation was experienced as a privilege and being seen made participation worthwhile. They described their experience of being part of the exercise group as togetherness in prosperity and adversity.This is to our knowledge the first study exploring experiences of community-dwelling older people with dementia taking part in a person-centred multidimensional interdisciplinary rehabilitation program. The interpretation of the interviews was expressed as the overarching theme Although it was demanding, both cognitively and physically in exercise and daily activities, the participants in our study described the combination of being challenged while supported by the staff as positive. This is in line with positive experiences of being challenged during exercise among people with dementia in nursing homes , 48. Bei, a social arena, being included in enjoyable and meaningful activities, and feeling supported have been expressed as important for the ability to cope with dementia [Despite the progressive disease, the participants realized that they were able to influence their situation and improve their physical capacity and ability in daily activities. Like in another study, engaging in regular activities affected the mood positively and being part of a rehabilitation group led to feelings of belonging . The condementia , 56–58, dementia , 56, 59.dementia , and reldementia .While some of them were hesitant to participate at first, our participants gradually changed their minds and became positive to participation, which is a similar pattern as the increased motivation seen during exercise over time in nursing home residents . People Participants in our study praised the professionals, whose sensitivity created security and support along with a welcoming atmosphere. This is in accordance with an activity center study, whose participants valued having the staff seeing them and treating them as normal people , and as . Based on the interviews, it was concluded that person-centred care was not always accomplished. This further indicates the importance of sensitivity and effort among staff to increase awareness of each human being and their wishes. There is a need to further evaluate the experience of the composition of different groups when offering activities to people with dementia.Although there were mostly positive experiences about the group setting and fellow participants, some perceived obstacles to interaction in the groups due to their diverse needs. It seems therefore important that the professionals are supportive and apply their expertise to facilitate the communication in the group settings . The perThe results show that people with dementia may be empowered through rehabilitation. According to the World Health Organization, patient empowerment is “a process through which people gain greater control over decisions and actions affecting their health”  buildingSome limitations of the study needs to be considered. When interviewing people with dementia, their impaired memory and limited awareness of their disability might influence responses. However, efforts were made to facilitate participants’ recall as the interviews were conducted in close conjunction with the rehabilitation visits, together with the use of recall cues. The sample was selected in the sense that all had agreed to participate in the study. However, none of the participants in this qualitative study had MMSE score of less than 15, which diminishes the transferability to people with more severe dementia.The interviewers were all observant to the participants’ feelings and whishes during the interviews. The depth and richness of the conversations showed that the participants were able to reflect on and describe participation in the rehabilitation program. Considering participants’ experiences is of great importance when evaluating rehabilitation in general and for people with dementia in particular.According to community-dwelling older people with dementia, a person-centred multidimensional interdisciplinary rehabilitation program was experienced as viable and beneficial. The participants seemed empowered through the rehabilitation and expressed mostly positive experiences and perceived improvements. Providers of interdisciplinary rehabilitation programs for this group should consider aspects raised by participants e.g. the positive experience of being challenged in both exercise and daily activities; the importance of being seen and feel secure; the benefits and challenges of collaboration with others in the same situation; and the generation of new perspectives on current and future situation. The findings could furthermore have a positive impact on staff attitudes regarding the ability of this group to participate in rehabilitation. However, more research is needed to explore and evaluate interdisciplinary rehabilitation for people with dementia in various settings, explore experiences of rehabilitation among informal primary caregivers, as well as to determine how to adjust rehabilitation to individual courses of the dementia condition.Additional file 1. Interview Guide


Aldose reductase (AR) is an aldo-keto reductase that catalyzes the first step in the polyol pathway which converts glucose to sorbitol. Under normal glucose homeostasis the pathway represents a minor route of glucose metabolism that operates in parallel with glycolysis. However, during hyperglycemia the flux of glucose via the polyol pathway increases significantly, leading to excessive formation of sorbitol. The polyol pathway-driven accumulation of osmotically active sorbitol has been implicated in the development of secondary diabetic complications such as retinopathy, nephropathy, and neuropathy. Based on the notion that inhibition of AR could prevent these complications a range of AR inhibitors have been developed and tested; however, their clinical efficacy has been found to be marginal at best. Moreover, recent work has shown that AR participates in the detoxification of aldehydes that are derived from lipid peroxidation and their glutathione conjugates. Although in some contexts this antioxidant function of AR helps protect against tissue injury and dysfunction, the metabolic transformation of the glutathione conjugates of lipid peroxidation-derived aldehydes could also lead to the generation of reactive metabolites that can stimulate mitogenic or inflammatory signaling events. Thus, inhibition of AR could have both salutary and injurious outcomes. Nevertheless, accumulating evidence suggests that inhibition of AR could modify the effects of cardiovascular disease, asthma, neuropathy, sepsis, and cancer; therefore, additional work is required to selectively target AR inhibitors to specific disease states. Despite past challenges, we opine that a more gainful consideration of therapeutic modulation of AR activity awaits clearer identification of the specific role(s) of the AR enzyme in health and disease.  Based on sequence identity, aldo-keto reductases (AKRs) have been grouped into distinct families, AKR1to AKR15; each family contains multiple subfamilies. The AKR1 family has been divided into five subfamilies, A to E. Of these, AKR1B is the most studied subfamily because of the potential role of its founding member, aldose reductase (AKR1B1), in the development of diabetic complications . Aldose Several studies have demonstrated a role for hyperglycemia in the pathogenesis of diabetic microvascular complications such as retinopathy, nephropathy, neuropathy, and cognitive disorders ,3. In adThe generation of superoxide and other ROS are believed to underlie many of the oxidative changes in hyperglycemic conditions. However, despite strong evidence that oxidative stress is associated with diabetic complications, clinical trials with several antioxidants  such as trans-retinaldehyde. Residues that interact with all-trans-retinaldehyde and differ between AKR1B1 and AKR1B10 are Leu125Lys and Val131Ala (loop A), Leu301Val, Ser303Gln, and Cys304Ser (loop C). Recently, the importance of Lys125 as a determinant of AKR1B10 specificity for retinoids was demonstrated. Residues 301 and 304 are also involved in interactions with substrates or inhibitors. When members of the rodent AKR1B subfamily AKR1B3 (AR), AKR1B7 (mouse vas deferens protein), AKR1B8 (fibroblast-growth factor 1-regulated protein), and AKR1B9 (Chinese hamster ovary reductase) were tested against all-trans isomers of retinaldehyde, and retinol, the enzymes were active with retinaldehyde, but with kcat values (0.02–0.52 min−1) much lower than that of AKR1B10 (27 min−1) ) have been shown to be substantially increased . Thus, iIt has been reported that ROS and ROS-derived lipid peroxidation products like HNE and malondialdehyde (MDA) are involved in asthma pathogenesis, and that the reduced products of GS-lipid aldehydes such as GS-lipid-alcohols are important inducers of signaling cascades. AR inhibition has been shown to interfere in the formation of GS-lipid alcohol species as ROS-mediated activation of inflammatory signals that are blocked by AR inhibition . Also, sA detailed examination of OVA sensitization and challenge showed a clear and marked perivascular and peri-bronchial infiltration of eosinophils into the lungs of the mice. Such infiltration of inflammatory cells into the airways of OVA-challenged mice was reduced with an AR inhibitor. More importantly, protective effect of the AR inhibitor against OVA-induced airway inflammation coincided with a significant reduction in the levels of Th2 cytokines, including IL-4, IL-5, and IL-6 and chemokines such as keratinocyte-derived chemokine, as well as granulocyte colony stimulating factor (G-CSF) and MCP-1 in broncho-alveolar lavage fluid , indicatDiabetic retinopathy (DR) is one of the common microvascular disorders, and the most severe of diabetic ocular complications. DR has been shown to be significantly associated with impending risk of cerebrovascular accident (CVA), myocardial infarction (MI), congestive heart failure (CHF), and all-cause mortality in patients with type 2 diabetes mellitus, suggesting that patients exhibiting higher degrees of retinopathy appear to carry a heightened risk for each of the above mentioned outcomes; thus retinal information may provide valuable insights into patients’ risk of future vascular disease including death . In the In another study, in vivo evaluation of the potency of fidarestat in STZ treated diabetic rats was conducted for diabetes-associated cataract formation, retinal oxidative nitrosative stress levels, glial activation, and apoptosis. Fidarestat treatment prevented diabetic cataract formation and successfully counteracted retinal nitrosative stress and poly (ADP-ribose) polymerase activation as well as glial activation. It also prevented nitrotyrosine, poly (ADP-ribose) accumulation, and apoptosis. These findings supported an important role for AR in diabetes-associated cataract formation, as well as retinal oxidative-nitrosative stress, glial activation, and apoptosis. These results provide a strong rationale for the development of AR inhibitors such as fidarestat for the prevention and treatment of diabetic ocular complications . Paradoxically, not all patients with diabetes develop ocular complications. Some diabetics with poor metabolic control appear to be protected against retinopathy, while others with a history of excellent metabolic control develop severe complications. These observations indicate that some risk factor(s) may influence the likelihood that an individual with diabetes will develop cataract and/or retinopathy. It seems that an elevated level of AR gene expression could confer higher risk for the development of diabetic eye disease. A transgenic mouse strain harboring human AR was examined for the onset and severity of diabetes-induced cataract. AR-TG mice homozygous for the transgene demonstrated a conditional cataract phenotype whereby they developed lens vacuoles and cataract-associated structural changes only after induction of experimental diabetes; no such changes were observed in AR-TG heterozygotes or non-transgenic mice with or without experimental diabetes induction. The nondiabetic AR-TG mice did not show structural changes in the lens even though they had lenticular sorbitol levels almost as high as the diabetic AR-TG lenses that showed early signs of cataract. However, overexpression of AR led to increase in the ratio of activated to total levels of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal (JNK1/2), which are known to be involved in cell growth and apoptosis, respectively ,38,80. AMore recently, advances in molecular genetics are enabling studies to discern the influence of individual genes among patients with similar risk factors for the development and progression of DR because of the substantial variability in the progression of disease and its severity. Polymorphism in the promoter of the AR gene has been suggested in changing the expression of its gene in certain ethnic groups. In a limited number of type 2 diabetic patients categorized for the presence or absence of diabetic microangiopathy, AR genotyping revealed a C-106T polymorphism that turned out to be a risk factor for the development of retinal complications in those patients . A few oApart from its association with the etiology of DR, AR has also been linked to the causation of autoimmune-mediated uveitis. Earlier studies suggested that inhibition of AR prevented cytokine, growth factor, and LPS-induced oxidative stress signals, leading to production of prostaglandin E (PGE) 2, cytokines, and activation of cycloxygenase-2 (Cox-2) and iNOS; activation of these inflammatory markers is known to be the major mediator of ocular inflammation. Srivastava and colleagues investigated the effect of AR inhibition on endotoxin-induced uveitis (EIU) in rats . InhibitAdministration of AR inhibitor also prevented the activation of NF-kB in the ciliary body, corneal epithelium and retinal wall of LPS-treated rat eyes, suggesting that inhibition of AR prevents EIU in rats . Thus, ADiabetic nephropathy (DN) is the principal cause of end-stage renal disease in Western society, affecting a substantial proportion (25–40%) of patients . The patIn the past, treatment of DN has focused on controlling the hyperglycemia and interrupting RAS with anti-hypertensive agents. Novel targets, some of which are linked to glucose dependent pathways targeting the AR, appear to be a major focus of new therapies directed against the development and progression of renal damage. It is likely that resolution of DN will require synergistic therapies to target multiple mediators . GeneticA meta-analysis of studies on this association concluded that Z-2 allele appeared to be a genetic risk factor for DN . ARIs maIt has been hypothesized that ARI treatment lowers plasma VEGF in diabetic rats, and this may contribute to ARIs’ anti-microalbuminuric effects . DespiteDiabetic peripheral neuropathy (DPN) is a common yet painful and severely debilitating complication that currently has no effective treatments other than diabetes control and management. The recognition of the difficulty in reversing established DPN has focused efforts primarily on slowing its progression . ARIs haIn one study of patients with symptomatic neuropathy, a sustained improvement in motor nerve conduction velocity and paresthesia was seen in 28 percent of patients treated with tolrestat, versus five percent in the placebo group. There was no benefit in neuropathic pain, which improved to an equivalent degree in both groups. A multicenter double-blind trial involving 549 patients with sensorimotor polyneuropathy who were assigned to treatment with placebo or ranirestat 10, 20, or 40 mg/day for 52 weeks found no significant change in nerve conduction studies, or in quantitative sensory tests of bilateral sural plus proximal median sensory nerve conduction velocity . There wAt present, there is decreased enthusiasm for ARIs to prevent or treat diabetic complications, since the large sorbinil retinopathy trial showed a lack of important benefits . AlthougOne positive clinical application has been reported in a Japanese trial of the AR inhibitor epalrestat ,231. In Clinical end points for improvement in diabetic neuropathy are difficult to quantitate, and caution is appropriate in accepting a positive conclusion from those studies reported to date . Except Although AR was initially studied for its role in the pathogenesis of diabetic complications, but it has also gained attention for its role in several inflammatory conditions . One of Lipid peroxidation derived carbonyls generated by oxidative stress are catalyzed to their glutathione adducts by AR . These aMoreover, it has been shown that inhibition of AR prevents LPS-induced secretion of cytokines in serum, liver, kidney, spleen, and heart along with a concomitant decrease in mouse cardiac muscle contractility that leads to cardiomyopathy and lethality in a mouse model of sepsis . SimilarRecent studies suggest that AR is a key regulator of ROS signals induced by cytokines and growth factors (GF) leading to cell growth and differentiation in vascular cells and colorectal cancer (CRC) cells ,127,128.AR inhibition prevented the azoxymethane (AOM)-induced aberrant crypt foci (ACF) formation and premalignant lesions in mice. These studies indicated that AR null mice are resistant to AOM-induced ACF formation, and expression of inflammatory and carcinogenic markers ,241. SevAR is an important enzyme that has been the focus of active research for more than four decades. It is a rate-limiting enzyme in the polyol pathway and has been consistently implicated in the pathogenesis of diabetic complications. The enzyme catalyzes the reduction of glucose to sorbitol. So far, outcomes from clinical studies targeting its inhibition have not led to robust and convincing evidence of significant benefits, except in some patients with diabetic neuropathy. It is possible that doses employed for various ARIs were low (in anticipation of possible toxicity at higher doses), or that studies were not done for long enough  7]. Mic. Mic7]. As the molecular basis for the pathogenesis of diabetic complications is further unraveled, an increasingly promising therapy would be to administer two or more synergistic metabolic blockers. As an example, expression of retinal VEGF and development of proliferative retinopathy in galactosemic rats may be prevented by either aminoguanidine or ARIs. Since both drugs impede immunocytochemical expression of VGEF, their combined therapy may ultimately prevent diabetic retinopathy ,245. TheAlthough AR was initially thought to be involved in secondary diabetic complications because of its glucose reducing potential, evidence from recent studies indicates that AR is an excellent catalyst for the reduction of a number of lipid peroxidation-derived aldehydes as well as their glutathione conjugates, which regulate inflammatory signals initiated by oxidants such as cytokines, growth factors, and bacterial endotoxins, and thus revealing the potential use of AR inhibition as an approach to prevent inflammatory complication . NonetheThere are obvious challenges associated with in vivo studies, as AR-like enzymes such as AKR1B10, AKR1B7, and AKR1B8 are highly related isoforms and share up to 65% protein identity, and are often co-expressed along with AR, making functional analysis a difficult task. They can reduce many redundant substrates  . Based oApart from its role as a detoxifying enzyme of toxic aldehydes , AR is aPast research indicates that AR is involved in the pathogenesis of secondary diabetic complications. As a result, several ARIs were developed and tested in the setting of diabetic complications . These iRecently, several groups have suggested that besides reducing glucose, AR also efficiently reduces oxidative stress-generated lipid peroxidation derived-aldehydes and their glutathione conjugates. Since lipid aldehydes alter cellular signals  by regul


Cases of Bell's palsy following COVID-19 vaccination were reported disproportionately in the vaccine group during phase 3 clinical trials and have now been reported multiple times post-licensure. The U.S. Food and Drug Administration has stated the frequency of Bell's palsy in the vaccine group is consistent with the expected background rate of Bell's palsy in the population but recommends “surveillance for cases of Bell's palsy with deployment of the vaccine into larger populations.“A 60-year-old male with HIV presented to the emergency department for evaluation of left facial droop. He had received the first dose of Pfizer/BioNTech BNT162b2 vaccination approximately 42 hours prior to symptom onset. Physical examination in the ED revealed left-sided facial weakness with involvement of the forehead, inability to raise left eyebrow, and inability to close left eye with sensation and strength intact in bilateral upper and lower extremities. Physical examination in our outpatient ophthalmology clinic on day 2 following symptom onset was revealing for mild exposure keratopathy, 5 mm lagophthalmos and very poor Bell's reflex in the left eye with otherwise normal exam findings. These findings were judged to be consistent with uncomplicated Bell's palsy. He was provided ophthalmic lubricating ointment to use hourly, artificial tears as needed, moisture goggles and suggested to tape eyelids nightly in addition to standard systemic glucocorticoid and antiviral therapy. The patient's facial weakness and exposure keratopathy were completely resolved at approximately 90 days following symptom onset.Though there is insufficient evidence at this time to support any causal association between COVID-19 vaccines and Bell's palsy, the temporal relationship between vaccination and classic clinical features of Bell's palsy in our patient certainly raises suspicion for association with Pfizer/BioNTech BNT162b2 COVID-19 vaccination. It will be important to monitor for cases of Bell's palsy following COVID-19 immunization as an increasing percentage of the global population receives vaccination. It is the most common form of facial paralysis, estimated to occur in the general population at a rate of approximately 15–25 per 100,000 person-years.2A 60-year-old male presented to the emergency department for evaluation of left facial droop. He reported spilling water from his mouth during dinner the night before and woke up with persistent left facial weakness and inability to close his left eye. He denied any vision or hearing changes, headache, palpitations, gait disturbance, facial pain, or any other muscular weakness. His past medical history was significant for HIV diagnosed twenty years prior with long-term compliant use of highly active antiretroviral therapy Genvoya , stage 3 chronic kidney disease, and pre-diabetes. He had received the first dose of Pfizer/BioNTech BNT162b2 vaccination approximately 42 hours prior to symptom onset. Physical examination in the ED revealed left-sided facial weakness with involvement of the forehead, inability to raise left eyebrow, and inability to close left eye with sensation and strength intact in bilateral upper and lower extremities. There were no gait abnormalities, no vesicular skin lesions or other focal neurologic deficits . ElectroThe patient was evaluated in our outpatient ophthalmology clinic on day 2 following symptom onset. He complained of left eye irritation and burning sensation, with inability to fully close his left eye. Physical exam was revealing for mild exposure keratopathy, 5 mm lagophthalmos and very poor Bell's reflex in the left eye with otherwise normal exam findings. He was provided ophthalmic lubricating ointment to use hourly, artificial tears as needed, moisture goggles and suggested to tape eyelids nightly. The patient returned to our clinic for follow up at days 5 and 15 following symptom onset and showed marked improvement in his left-sided keratopathy on this treatment regimen, obviating the need for further intervention . At appr3,,,Prior to evaluation of potential association between COVID-19 vaccination and Bell's palsy, the diagnostic certainty of Bell's palsy in our case is important to discuss.,Our patient's clinical presentation was consistent with the above characteristics of Bell's palsy. HIV infection has been linked to increased risk of facial nerve palsy, but this occurs during acute infection and often is accompanied by additional polyneuropathies which was not the case in our patient.In prior scientific literature, an intranasal inactivated influenza vaccine licensed and administered in Switzerland during 2000–2001 has been linked to causation of Bell's palsy. Bell's palsy occurred most commonly during days 31–60 after vaccine administration, with more than three-quarters of cases occurring within 60 days. The relative risk of Bell's palsy following vaccination was roughly 19 times that of control patients. The vaccine is no longer in use.,,,,Seven cases of Bell's palsy occurred during the phase 3 clinical trials of COVID-19 vaccinations conducted in the United States; 4 following administration of Pfizer/BioNTech BNT162b2 and 3 cases following administration of Moderna mRNA-1273 compared to 0 in each control group.Per FDA recommendations and existing evidence, it will undoubtedly remain important to monitor for development of Bell's palsy symptoms during the 60 days following COVID-19 vaccination.4Though there is insufficient evidence at this time to support a causal association between COVID-19 vaccines and Bell's palsy, the temporal relationship between vaccination and classic clinical features of Bell's palsy in our patient certainly raises suspicion for association with Pfizer/BioNTech BNT162b2 COVID-19 vaccination. We present this case of Bell's palsy in an HIV-positive patient as an adverse event potentially associated with BNT162b2 COVID-19 vaccination. It will be important to monitor for cases of Bell's palsy following COVID-19 immunization as an increasing percentage of the global population receives vaccination.The patient provided written consent for publication of this case.No funding or grant support.All authors attest that they meet the current ICMJE criteria for authorship.The authors have no conflicts of interest to disclose.


Androgen receptor (AR) exerts important roles in exercise-induced alterations of muscle mass, in which the proliferation and differentiation of satellite cells or myoblasts are crucial. Our previous study in C2C12 myoblasts demonstrated that 15% (mimic appropriate exercise) and 20% (mimic excessive exercise) stretches promoted and inhibited the proliferation respectively; and AR played a crucial role in 15% stretch-induced pro-proliferation through IGF-1-modulated PI3K/Akt, p38 and ERK1/2 pathways, but AR’s role in stretches-modulated proliferation of general myoblasts, especially 20% stretch, remains unclear, and the mechanisms need to be further clarified.Firstly, the discrepancy in proliferation and the above indicators between L6 (without AR) and C2C12 (with AR) myoblasts were compared under 15% or 20% stretch. Then the influences of transfection AR or exogenous IGF-1 treatment on proliferation and these indicators were detected in stretched L6 myoblasts.(1) Under un-stretched state, the proliferation of L6 was slower than C2C12 cells. Furthermore, AR knockdown in C2C12 myoblasts repressed, while AR overexpression in L6 myoblasts promoted the proliferation. (2) 15% stretch-induced increases in the proliferation and activities of p38 and ERK1/2 were lower in L6 than C2C12 cells; AR overexpression enhanced the proliferation of 15% stretched L6 cells accompanied with the increases of p38 and ERK1/2 activities. (3) 20% stretch-induced anti-proliferation and inhibition of p38 activity were severer in L6 than C2C12 myoblasts; AR overexpression reversed the anti-proliferation of 20% stretch and enhanced p38 activity in L6 myoblasts. (4) In stretched L6 myoblasts, AR overexpression increased IGF-1R level despite no detectable IGF-1; and recombinant IGF-1 increased the proliferation, the level of IGF-1R, and the activities of p38 and ERK1/2 in 15% stretched L6 myoblasts.The study demonstrated AR's crucial roles in stretches-regulated proliferation of myoblasts, and increased AR fulfilled 15% stretch's pro-proliferation via activating IGF-1R- p38 and ERK1/2 pathways while decreased AR achieved 20% stretch's anti-proliferation via inhibiting IGF-1R- p38 pathway, which is useful to understand in depth the role and mechanisms of AR in appropriate exercise increasing while excessive exercise decreasing muscle mass. Testosterone is widely reported to affect muscle mass, with high level testosterone promoting whereas low level declining muscle mass, mainly via the mediation of androgen receptor (AR), 2. DecrIn skeletal muscle, AR is predominantly expressed in satellite cells  and myonuclei, therefore satellite cells are considered as the direct target of androgens. Androgen/AR's roles in promoting the proliferation of satellite cells or myoblasts have been well demonstrated in sedentary state in vivo and undeInsulin-like growth factor (IGF-1) is an important regulator in muscle mass and strength through promoting the proliferation of satellite cells or myoblasts, increasing protein synthesis and decreasing protein degradation. It has been demonstrated that exogenous IGF-1 could significantly induce the proliferation of myoblasts in vivo and in vitro in a dose-dependent manner. IGF-1 aFor the relationship between AR and IGF-1/IGF-1R, numerous evidence indicate the crosstalk between androgen/AR and IGF-1/IGF-1R. Firstly, IGF-1/IGF-1R are the target genes of AR, and AR's effects in modulating myoblast proliferation and muscle hypertrophy are mainly mediated by IGF-1/IGF-1R, because androgen response elements (AREs) exist in IGF-1 promoter and androgen/AR agonist-induced enhancements in satellite cell activation and muscle regeneration are associated with the increase of IGF-1; in addiTherefore, the present study firstly compared the discrepancy between L6 and C2C12 myoblasts subjected to 15% and 20% stretches in proliferation, levels of IGF-1 and IGF-1R, and activities of PI3K/Akt, p38 and ERK1/2, then measured the above indicators in L6 myoblasts again after transfection with AR overexpression plasmid or treatment with IGF-1 recombinant polypeptide, for demonstrating the roles of AR in stretches-regulated proliferation of myoblasts and further exploring the possible mechanisms: IGF-1 mediated alterations in the activations of PI3K/Akt and MAPKs (p38 and ERK1/2)?Rat-derived L6 myoblasts and mouse-derived C2C12 myoblasts were purchased from Chinese Academy of Sciences Cell Bank, and cultured in high-glucose Dulbecco’s modified Eagle medium (DMEM)  supplemented with 10% fetal bovine serum (FBS)  as well as 100 U/ml penicillin and 100 μg/ml streptomycin  at 5% CO2 and 37 ℃. All cells used in the experiments were at low passages (from passage 3 to passage 8).EcoRI and BamHI to generate pcDNA3.1-AR recombinant plasmid. All constructs used for experiments were sequenced.Full-length AR cDNA was amplified by PCR using specific primers (Forward: 5′-CTTGGTACCGAGCTCGGATCCGCCACCATGGAGGTGCAGTTAGGGC-3′ and Reverse: 5′-TGCTGGATATCTGCAGAATTCTCCACTGTGTGTGGAAATAGATGGG-3′) and inserted into pcDNA3.1 ( +) vector (Invitrogen) using restriction sites For AR overexpression, L6 cells were seeded onto 6-well plates, and pcDNA3.1-AR recombinant plasmid (2.5 μg/well) were transfected using LipoPlus™ Reagent  according to the manufacturer's instructions. The equivalent amount of pcDNA3.1 vector was transfected as control. To confirm the efficiency of transfection, the level of AR was determined by Western blot at 24 h after transfection finished.For knockdown the level of AR in C2C12 cells, siRNA targeting AR (siRNA-AR) (sc-29203) and a scrambled negative control (siRNA-ctrl) (sc-37007) were purchased from Santa Cruz Biotechnology, and transfected into C2C12 cells using Lipofectamine 2000 reagent  according to manufacturer's protocol. The cells were incubated with siRNA mixture for a period of 36 h before being subjected to other assays.5/well density and incubated for 24 h before exposing to mechanical strain. Cells were then subjected to cyclic mechanical stretch of 15% or 20% elongation at 0.5 Hz frequency for 6 h using a computer-controlled vacuum stretch apparatus . In parallel with identical experimental conditions, cells grown in flexible-bottomed 6-well plates but left un-stretched were considered as control.C2C12 and L6 myoblasts were stretched as described in our previous studies, 26. BriCell proliferation was measured by Cell Counting Kit-8 (CCK8)  following the manufacturer’s protocols. At 24 h after mechanical stretches or transfection finished, culture medium was replaced with fresh cell culture medium, appropriate CCK8 was added into the medium in proportion, then the optical density (OD) values were detected at 450 nm after incubation for 2.5 h using a microplate reader .Once stretch finished, culture medium was replaced by DMEM without FBS immediately and incubated for 24 h, then cellular supernatant was collected and centrifuged at 12,000 rpm for 5 min at 4 ℃. IGF-1 concentration in cellular supernatant was determined by mouse/rat IGF-1 Quantikine ELISA Kit  according to manufacturer’s instructions.To confirm the role of IGF-1 in the proliferation of stretched myoblasts, and its relationship with PI3K/Akt and MAPKs (p38 and ERK1/2), IGF-1 recombinant polypeptide with different concentrations , 26 wereCells after culture and treatments were collected and lysed in RIPA lysis buffer  containing protease and phosphatase inhibitor cocktail  and incubated on ice for 30 min, then centrifugated at 4 ℃, 12000 rpm for 20 min. The protein concentration in the supernatant was determined using BCA protein assay kit . ~30 μg protein were separated on SDS-PAGE gel, and subsequently transferred to the PVDF membranes . After blocking with 5% (w/v) fat-free milk at RT (~25 ℃) for 2 h, the membranes were incubated with primary antibodies at 4 ℃ overnight: AR , IGF-1R , p-PI3K , PI3K , p-Akt , Akt , p-p38 MAPK , p38 , p-p44/42 MAPK , p44/42 MAPK . Thereafter, the membranes were incubated with HRP-conjugated anti-mouse/rabbit /goat secondary antibodies at RT for 2 h, and the blots were visualized by ECL reagent  and detected by automatic chemiluminesence image analysis system .p < 0.05 was consider as statistically significant.All the experiments were repeated at least three times. Data were presented as mean ± standard deviation (SD), and statistical analysis was performed by SPSS 21.0. Statistical differences among experimental groups were determined by two-way ANOVA, and differences between two groups were analyzed by using Student’s t test. We firstly confirmed that AR expressed in C2C12 myoblasts whereas no detectable AR was examined in L6 myoblasts , respectively . In the To confirm AR’s role in the proliferation of stretched myoblasts, AR overexpression plasmid was transfected into L6 myoblasts before exposing to 15% and 20% stretches. We found AR protein could be obviously detected in L6 myoblasts after transfection with AR overexpression plasmid Fig. a, and ARTo clarify relevant signal pathways involved in AR's roles in 15% stretch-induced pro-proliferation, the increased degrees of activities of PI3K/Akt, ERK1/2 and p38 were compared between C2C12 and L6 myoblasts subjected to 15% stretch, and we found that there was no difference in PI3K activity between the two cells but the increment of ERK1/2 activity in L6 myoblasts was lower  than that in C2C12 myoblasts, and what’s more interesting was that p38 activity had no change in 15% stretched L6 cells but about 2 folds increase in 15% stretched C2C12 myoblasts , while the decreases of PI3K and ERK's activities resulted from 20% stretch were similar to that in C2C12 cells  were incubated with cells to verify the regulation of IGF-1 on the proliferation as well as PI3K/Akt, p38 and ERK1/2 signals in 15% stretch myoblasts. As shown in Fig. Satellite cells or myoblasts exert crucial roles in muscle hypertrophy, and impairments in the proliferation and differentiation of these cells lead to muscle atrophy. Exercise-induced muscle hypertrophy is also associated with the increased proliferation of satellite cells , furtherAs mentioned in the Introduction, our previous work revealed that in C2C12 myoblasts (expressed AR), 15% stretch-induced pro-proliferation was likely to be mediated by up-regulation of AR because AR specific antagonist flutamide attenuated the pro-proliferation of 15% stretch on C2C12 myoblasts in a dose-dependent manner. Meanwhile, 20% stretch-induced anti-proliferation was accompanied with the down-regulation of AR . What's In addition, under un-stretched condition, the proliferation rate of L6 myoblasts was lower than that of C2C12 myoblasts (about 80.6% and 72.5% of C2C12 myoblasts at 24 h and 48 h after seeding). And AR knockdown by siRNA inhibited the proliferation of C2C12 myoblasts, while transfection with AR overexpression plasmid increased the proliferation of L6 myoblasts, implied the important role of AR in proliferation of un-stretched myoblasts.It is well known that AR affects muscle mass through genomic and non-genomic mechanisms. Recently, non-genomic mechanism of AR has been proven to be crucial in promoting myoblast proliferation and increasing muscle mass through interactions with other signaling molecules such as IGF-1 and its downstream molecules. PI3K/AkNot only that, recent studies showed the importance of PI3K/Akt, p38 and ERK1/2 MAPKs in the anabolic action of AR, which was partly fulfilled through the crosstalk with AR–37.TestoThe above situations are involved in non-exercise conditions or un-stretched myoblasts, what about the mechanisms of AR in appropriate stretch and overstretch condition? Whether IGF-1-mediated PI3K/Akt and MAPKs (p38 and ERK1/2) pathways still play key roles in the effects of AR on the two stretches-modulated proliferation of myoblasts and does there exist difference with respect to signal pathways involving in 15% and 20% stretches-regulated proliferation of myoblasts? Our previous work in 15% stretched C2C12 myoblasts indicated that the effect of increased AR on pro-proliferation was fulfilled by IGF-1 mediated activations of PI3K/Akt, p38 and ERK1/2 using IGF-1 neutralized antibody and specific inhibitors of PI3K/Akt, p38 and ERK1/2; for 20%So in this paper the discrepancies between myoblasts L6 (without AR) and C2C12 (with AR) were compared in the proliferation, the levels of IGF-1/IGF-1R, and the levels and activations of PI3K/Akt, p38 and ERK1/2 after 15% or 20% stretch, then the above indicators in L6 myoblasts were detected again after transfection with AR overexpression plasmid or treatment with IGF-1 recombinant polypeptide. Except for similar elevated degree of PI3K activity induced by 15% stretch between L6 and C2C12 myoblasts, obvious differences were found between the two myoblasts after 15% stretch, including: (1) IGF-1: increased secretion in C2C12 myoblasts while no secretion in L6 myoblasts; (2) ERK1/2 activity: increased degree in L6 myoblasts was half of that in C2C12 myoblasts; (3) p38 activity: no change in L6 myoblasts but beyond threefold elevation in C2C12 myoblasts. Furthermore, transfection L6 myoblasts with AR overexpression plasmid and treatment with IGF-1 recombinant polypeptide both enhanced the level of IGF-1R , and the activations of p38 and ERK1/2 in 15% stretched L6 myoblasts, accompanied with the further promotion of L6 cell proliferation. These results indicated that the pro-proliferative effect of AR on 15% stretched myoblasts was mediated through increasing IGF-1R, thus activating p38 and ERK1/2, especially p38, rather than PI3K/Akt pathway.For 20% stretch, our previous studies revealed significant decreases including the secretion of IGF-1 and the activations of PI3K/Akt, p38 and ERK1/2 in 20% stretched C2C12 myoblasts. In the In combination with our another work which demonstrated the important roles of PI3K/Akt and MAPK (ERK1/2 and p38) in stretches-modulated proliferation of L6 myoblasts , the preThe present study demonstrated AR's crucial roles in stretches regulated proliferation of myoblasts, and increased AR fulfilled appropriate stretch's pro-proliferation via activating IGF-1R-p38 and ERK1/2 pathways while decreased AR achieved excessive stretch's anti-proliferation via inhibiting IGF-1R- p38 pathway.


At present, these details are lacking for diagnostic imaging physics and nuclear medicine physics. This is probably because about 75% of medical physicists work in therapy. As we study the imaging physics workforce, it is worthwhile to step back and consider how the current workforce serves the public interest and how the profession should monitor and manage it in the future. In this column, we appeal to our colleagues to contemplate how the future workforce may evolve from its present state.Nearly every citizen depends, directly or indirectly, on the services of medical physicists to ensure high‐quality and safe medical care. Medical physicists have a large societal impact, like those of engineers and teachers. In contrast to these professions, the number of medical physicists is tiny (about 9000 in the USA) and our knowledge of the profession's characteristics is incomplete.Consider differences in financial models for radiation oncology physics and diagnostic imaging physics in the USA. Many of the clinical services provided by therapy physicists are associated with current procedural terminology codes and are eligible for reimbursement . In this direct reimbursement model, therapy physics is a revenue center and staffing models are directly linked to patient volume and revenue. In contrast, diagnostic physics services are typically treated as an overhead model. That is to say, diagnostic physics services are not eligible for direct reimbursement and are only indirectly linked directly to patient volume and revenue. With the overhead model, staffing models are largely driven by compliance with minimum requirements set by regulations and clinical accreditation programs.Thus, differences in financial models can influence physicist staffing. The financial models may or may not be sufficient to provide optimal care to every patient. Research is needed to quantify the incremental improvements in patient care that can result from additional imaging physics support once the minimum requirements are met. The literature on diagnostic errors does not directly link diagnostic medical physics effort to outcomes, but it does show that applications with exacting image quality requirements, such as mammography and other cancer detection exams, are responsible for a large proportion of errors leading to suboptimal patient outcomes. Given the frequency of errors in diagnostic radiology procedures  and the potential severity of associated outcomes (42% of claims involving high‐severity injury and patient death), it is reasonable to posit that medical physicists will play essential roles in improving patient outcomes in at least some cases.https://doi.org/10.37206/163). Ongoing efforts, including a survey completed in 2020 and the development of models and future projections, will provide a current snapshot of the workforce and marketplace for clinical imaging physics services. Some preliminary data are available that will be fully detailed in forthcoming AAPM publications.The American Association of Physicists in Medicine's (AAPM's) most recent published assessments of the diagnostic physics workforce are outdated . Accreditation bodies (such as the American College of Radiology and Joint Commission) and some state regulatory agencies grant independent practice authorization to NCMPs who meet education and experience requirements. Since these individuals qualify via a variety of pathways, there is an unknowable number of inflows that are impossible to monitor. It makes sense to assume that where allowed, any shortage of board‐certified physicists would be made up, at least in part, by NCMPs in response to the excess demand.https://doi.org/10.1002/acm2.12469) and the role of the MPA . With appropriate supervision by QMPs, MPAs can be effective to extend the workforce. To our knowledge, MPAs are not yet included in tallies of the imaging physics workforce. The formal definition of the MPA role is recent and, in the future, it will be important to take into account MPAs’ impact on the capacity of the imaging physics workforce.In addition, medical physicist assistants (MPAs) in imaging physics have existed, informally, for a long time. Medical physics practice guidelines have clarified the medical physics scope of practice , which is a type of measurement bias in workforce assessments. Taken together, these and other available data suggest that a shortage of imaging physicists may exist today.There is anecdotal evidence of a current shortage of certified diagnostic imaging physicists. For example, numerous NCMPs currently practice on a permanent basis, outnumbering those who are temporarily an NCMP between completion of training and Board certification. Employers report that imaging physicist job postings (whether they require board certification or not) take a long time to fill, elicit smaller than desired pools of applicants and that candidates typically receive multiple competitive offers. Published survey results from 2004If a true shortage exists, the profession is obligated to understand why and to take corrective measures. To this end, it must be ascertained if the shortage is real  or an artifact . When a shortage in a profession occurs, it is incumbent upon the profession to determine its own causative role, if any. Specifically, professions enjoy title protection, limited monopoly, and power to regulate who may enter the profession. These privileges, if exercised imperfectly, can cause shortages. Hence, we must determine if the apparent shortage is real, and if so, what role we played in its creation.There is always some degree of turnover in existing positions as individuals seek new opportunities for a variety of personal and professional reasons. A review of current or recent job postings will show a large number of diagnostic physics job postings, but it is difficult to determine which posts are net‐new positions and which result from a sort of “musical chairs” among current physicists. Even if all job postings clearly indicated whether they were for new or replacement positions, job vacancies are a lagging indicator for demand.First‐order demand growth results from increases in factors such as the number of machines and facilities supported, exams performed, staff trained, and compliance with regulations, accreditations, registrations, and licenses maintained. At a minimum, these increases require more Level‐1 services, in the context of the levels of service model described in AAPM Report 301. We should expect such demand changes to be roughly linear, with new growth occurring predictably with new facilities and equipment. A simple demand model based on population would likely encompass first‐order demand growth on a regional or national basis.Second‐order demand growth is more difficult to predict. Second‐order demand change results when there is a change in the number of imaging physicists needed per basis unit of service, that is, per exam, machine, or facility. This can occur when a facility with established diagnostic medical physics support seeks additional services, such as the creation and implementation of new programs or services, voluntary auditing, optimization, and accreditation programs, and so forth. Second‐order demand growth also encompasses the implementation of new mandatory requirements that were previously voluntary. Aging of the population and changing disease prevalence can increase the imaging utilization per patient in the population, in turn altering the per‐patient demand for physics support. Research is an essential activity. Research and development may impact first and/or second‐order demand; for example, it may be optional for patient care but required for an institution to be a National Cancer Institute‐designated Cancer Center.Second‐order growth is likely to result when there is increased adoption of Level‐2 and Level‐3 services. Voluntary demand for additional medical physics support  would likely increase when it can be shown to produce tangible benefits to the organization, such as improved patient outcomes or access, reduced costs, increased revenue, or elevated patient or physician satisfaction. AAPM's workforce assessment efforts are studying the current level of such voluntary demand, but anecdotally, it appears quite low.https://doi.org/10.1120/jacmp.v16i5.5661). There is a great deal of overlap with other specialties. Many diagnostic physicists support nuclear imaging, and the emerging practice of radiopharmaceutical therapy includes many therapy physicists, who provide essential support where no nuclear medicine specialist is available. The nuclear medicine physicist's expertise in the safe handling and use of radioactive material qualifies them as a radiation safety officer, but this does not drive demand for nuclear medicine physicists since most medical RSOs come from other backgrounds in medical or health physics. The recent rapid growth of imaging and therapeutic radiopharmaceutical applications may create a rapid increase in demand for nuclear medicine physicists, and it is unclear whether the current education and training pipeline would be able to fulfill such demand with QMPs.Throughout this discussion, we implicitly include nuclear medicine in diagnostic or imaging physics. As the smallest medical physics subspecialty, nuclear medicine physics comprises just a few hundred QMPs in the USA  to ensure that the needs of physicians and patients for safe and high‐quality imaging are met. Most importantly, our profession must better understand current and future needs for our services and, correspondingly, ensure that adequate numbers of imaging physics workers enter our profession.All authors contributed equally to the drafting and revision of the manuscript.All authors have no conflicts of interest to disclose.