A) receptor availability following traumatic brain injury have remained uncharacterized and may reflect changes in neuronal structure and function linked to cognitive recovery. We measured GABAA receptor availability using the tracer [11C]flumazenil in nine adults with traumatic brain injury  and in 20 non-brain-injured individuals. A subset of subjects with traumatic brain injury (n = 7) were scanned at a second chronic time-point, 7–13 months after their first scan; controls (n = 9) were scanned for a second time, 5–11 months after the first scan. After accounting for atrophy in subjects with traumatic brain injury, we find broad decreases in GABAA receptor availability predominantly within the frontal lobes, striatum, and posterior-medial thalami; focal reductions were most pronounced in the right insula and anterior cingulate cortex (p < 0.05). Greater relative increase, compared to controls, in global GABAA receptor availability appeared between subacute and chronic scans. At chronic scan (>1 year post-injury), we find increased pallidal receptor availability compared to controls. Conversely, receptor availability remained depressed across the frontal cortices. Longitudinal improvement in executive attention correlated with increases in receptor availability across bilateral fronto-parietal cortical regions and the anterior-lateral aspects of the thalami. The specific observations of persistent bi-frontal lobe reductions and bilateral pallidal elevation are consistent with the anterior forebrain mesocircuit hypothesis for recovery of consciousness following a wide range of brain injuries; our results provide novel correlative data in support of specific cellular mechanisms underlying persistent cognitive deficits. Collectively, these measurements support the use of [11C]flumazenil to track recovery of large-scale network function following brain injuries and measure response to therapeutics.Longitudinal alterations of gamma-aminobutyric acid (GABA et al. report that following traumatic brain injury, decreased GABAA receptor availability is seen in the anterior forebrain mesocircuit. Recovery during the ∼1 year post is marked by widespread increases, especially in the pallidum, but remains depressed across the frontal cortices possibly contributing to enduring cognitive impairments.Kang   However, these correlations with structural damage11 and electrophysiological responses,9 alone, do not provide insight into the underlying neuronal substrate associated with executive attention deficits. Most importantly, these measurements are incapable of directly measuring the alterations and dynamics of neuronal integrity within cortical and subcortical structures.Traumatic brain injury (TBI) is a leading cause of death and long-term disability in the United States, as well as world-wide,15 imaging can isolate changes in neurotransmitter availability, neuronal metabolism, and molecular structural features within the central nervous system (e.g. quantification of amyloid or tau proteins utilizing molecular probes). A few PET neuroimaging studies have related regional alterations in metabolism, measured using fluorodeoxyglucose PET (FDG) and binding of a benzodiazepine/γ-aminobutyric acid (GABA) receptor ligand ([11C]-flumazenil (FMZ)), to behavioural outcomes in cross-sectional studies of subjects with TBI. These studies suggest that behavioural outcomes grade with overall recovery of cerebral metabolic rate17 and degree of gamma-aminobutyric acid (GABAA) binding.18 Specifically, they showed that reduction of GABAA binding, measured using [11C]FMZ-PET, within the medial frontal cortices, anterior cingulate, and central thalamus correlates with executive dysfunction.18 A primary role for these regions in supporting recovery of consciousness and cognitive function following varying aetiologies of brain injury is proposed by the anterior forebrain mesocircuit (AFM) hypothesis.19 This hypothesis isolates the contribution of the central thalamus and its reciprocal connections with the frontal cortex and striatum  to impaired arousal regulation and cognitive dysfunction following structural brain injuries. Prior studies support this hypothesis and several have related alteration of function within these same regions with levels of recovery up to near baseline performance of cognitive functions .Positron emission tomography (PET)A receptor is widely distributed throughout the brain and is in particularly high concentration within the cerebral cortex because of the numerous GABA-ergic inhibitory synapses.23 A reduction of GABAA receptor binding measured by FMZ-PET has also been suggested as an in vivo marker of neuronal cell death.24–31 Decreased GABAA receptor binding, as a measure of neuronal loss, has been verified with autoradiographic,32 direct 33–35 and indirect histopathological findings,36 and MRI imaging36–38 However, beyond neuronal loss, alterations in GABAA receptor binding could also result from receptor dysfunction/reduced affinity as has been suggested by studies of isoflurane39 and tiagabine,40 both of which induced elevations in [11C]FMZ non-displaceable binding potential (BPND). In rodents, an increased availability of GABAA receptors41 has been associated with recovery following TBI.42 FMZ-PET binding alterations have also been correlated with cognitive deficits in ALS,43 multiple sclerosis,31 memory performance in Alzheimer’s disease36 and executive dysfunction following carotid artery disease.38The GABAA receptors in the remaining neurones 45 indicating a recruitable reserve for potential recovery. While prior studies suggest a relationship between FMZ-PET binding and cognitive function, they have not been tracked longitudinally during clinical recovery post-TBI. Changes in GABA availability can be expected to arise with shifts in large-scale network function and behavioural recovery that continue to evolve over long time periods following TBI.47 Here, we explore the use of FMZ-PET to measure and track changes in GABAA availability following TBI, systematically, across brain regions and with a special emphasis on substructures identified as components of the AFM.19In this context, FMZ-PET could serve as an in-vivo marker of both permanent neuronal damage and/or functional recovery, especially as it relates to cognitive impairments as they change over time since injury. Preserved or mild reductions in binding might be an indication of intact structure, or of increased expression of GABAA receptor availability in adults with TBI to control individuals without TBI. We measured brain GABAA receptor binding using PET imaging with the tracer [11C]FMZ. We included data from 9  adults with TBI and 20  adult controls. TBI participants underwent study activities at two timepoints: 3–6 months after injury  and 11–20 months after injury . Because the goal of the current study is to relate enduring cognitive impairments to the biological substrate changes following TBI, we focused on the sub-acute period for the first scan, to allow for sufficient time for acute medical issues to resolve. A subset of control individuals without TBI (n = 9) underwent a second scan 5–11 months after the initial visit.The study was designed to compare GABATBI participants were recruited through inpatient rehabilitation units and trauma departments at large, urban academic medical centres. Control individuals were recruited through local advertisements. All study activities were approved by Weill Cornell Medicine’s Institutional Review Board.All participants were required to meet the following criteria: (i) 18 years of age or above; (ii) English-speaking; (iii) capable of providing informed consent or a proxy/authorized agent available to provide informed consent; (iv) physically healthy and able to safely undergo PET imaging; (v) not currently taking any psychoactive or benzodiazepine drugs; (vi) not currently taking any medication for attention-deficit/hyperactivity disorder; (vii) no history of schizophrenia, drug, or alcohol abuse; (viii) no history of epilepsy, stroke, dementia, or serious medical illness by self-report; and (iv) not pregnant .48 score of 13–15 with evidence of intracranial lesion as verified on acute neuroimaging) or moderate-severe TBI  within the last 6 months.Participants in the TBI group were required to have sustained a complicated mild  in anhydrous Dimethyl sulfoxide (0.35 mL) was added into the vial containing NaOH solution , and the vial was subjected to vortex to allow for well-mixing of the reaction mixture. After the collection of 11C-MeI, the vial was heated at 60°C for 1 min. It was then mixed and injected into reverse phase semi-prep high-pressure liquid chromatography for purification . The radioactive peak corresponding to 11C-FMZ was collected, diluted with H2O (60 mL), and passed through a pre-activated C18 plus cartridge (waters). The retained activity was eluted with ethanol (1 mL) and 0.9% saline (14 mL) through a 0.22 μ Millex GV filter into a sterile vial as final drug product. 11C-FMZ was prepared with an average radiochemical yield of 68.1 ± 12.5%  and the average molar activity at the end of bombardment was 2016 ± 633 GBq/μmol (54.5 ± 17.1 Ci/μmoL), and the synthesis took 44 ± 3 min.The radioligand ethyl 8-fluoro-5,6-dihydro-5-[11C]methyl-6-oxo-4H-imidazo   benzodiazepine-3-carboxylate, known as 11C-FMZ, was prepared by modifying previously described procedures.3 using a zoom of 2.0 and an iterative + time of flight list-mode reconstruction algorithm provided by the manufacturer.50 FMZ-PET images were reconstructed into 22 frames (4 frames of 15 seconds (s) each, then 4 × 30 s, 3 × 60 s, 2 × 120 s, 8 × 300 s and 1 × 600 s).A dose of 407–595 MBq (11–16mCi) of 11C-FMZ was administered intravenously to each subject. Tracer dosing is reported in 51 was used to calculate non-displaceable binding potential (BPND) for FMZ-PET with pons acting as reference region . The simplified reference tissue modele region . Summed 52 to generate gray-matter regions of interest for subsequent PET analysis, as well as to estimate variability in gray-matter volume across the study population.To maximize signal-to-noise ratio and simplify statistical comparisons while preserving regional variation within the anterior forebrain mesocircuit (AFM), we combined the FreeSurfer gyral and subcortical ROIs and thalamic nuclei into larger groups. The six-lobe-based gyral groups were frontal, insular, polymodal, posteromedial cortex (PMC), temporal, and occipital groups. The five AFM cortical regions were anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), lateral parietal, and medial parietal. The seven subcortical groups were caudate, pallidum, putamen, anterior thalamus, ventral thalamus, posterior thalamus, and medial thalamus. See A 3T Siemens Prisma scanner with a 32-channel head coil was used to collect 3D T1-weighted sagittal MPRAGE anatomical images. All T1 volumes were processed using FreeSurfer 6.05 a computer-administered measure designed to examine the alerting, orienting, and executive attention networks. See Subjects with TBI and uninjured control participants performed the Attention Network Test (ANT) paradigm,ND, region of interest (ROI) size, and attention-network scores were normalized and age-adjusted based on the control population. For each metric and each ROI, we computes the least squares linear effect of age for the uninjured population and then applied that slope and offset to remove the effect of age within the TBI group. This age-adjusted residual is then normalized by the mean and standard deviation of the age-adjusted residual from the uninjured population to produce an age-adjusted z-score. BPND measurements were simultaneously adjusted for both age and ROI size in this manner. For longitudinal changes, we computed the unadjusted difference across the two sessions before adjusting and normalizing. Group means were compared via an unpaired, two-tailed t test. Inter-metric relationships were examined using Pearson correlation, followed by a Student's t-test. For all analyses, α was set at 0.05, and two-tailed tests were used. All p-values reported are uncorrected for multiple comparisons. Data were analyzed and visualized using custom scripts in Matlab .BPThe study protocol will be available on request to the principal investigator. Data from this study are available from the corresponding author upon reasonable request.11C]FMZ tracer for PET imaging, we found reductions in estimated [11C]FMZ binding potential (BPND) in adults with TBI (n = 9) during the subacute phase of recovery compared to uninjured control individuals (n = 20) at their baseline assessment. In ND reductions in the medial frontal regions and thalamus.Using the FMZ studies.55–57 Similarly, our findings of inter-individual variability in the BPND are consistent with previous reports.55 The notable differences between our study and these previous reports are as follows. Our sample spans a fuller range of TBI injury severity from complicated mild to severe compared to previous studies,18 and patients in our study were not selected a priori by degree of cognitive impairment or cortical damage. We restricted our first scan to 3–6 months post injury and our second scan to 11–20 months post injury. In contrast, the single scans, in the previous cross-sectional studies, varied widely in time since injury: 2–17 months,55 > 6 months,57 >1 year30 and 12–228 months.18 Our healthy control sample  also differed from previous studies which limited enrolment to those under age 3018 or 4030 years old. Thus, the effect of age on BPND in healthy controls was not explored in these prior studies, nor, adjusted for in the TBI findings. Our findings of an effect of age on BPND in healthy controls has, however, been reported before in [11C]FMZ PET studies of epilepsy.58 The other studies also did not account for atrophy changes following TBI, as we have done for all our BPND findings. Despite these various methodological differences with prior studies, our confirmation of a dominant depression of GABAA receptor availability following TBI and marked loss of signal within the medial frontal lobes and thalamus supports the generalizability of this result seen across prior FMZ PET studies in TBI.The observations of focal reductions in BPND suggest a mix of underlying factors. Reductions in GABAA receptor availability has been proposed as a marker of neuronal cell death as the GABAA receptor is the most abundantly occurring neuronal receptor.36 However, reduced binding could also reflect a reduced population of GABAA receptors secondary to changes in synaptic activity .62The broad reductions in BP63–65 Nakayama et al.63 found that diffuse traumatic brain injuries showed a consistent hypometabolism in medial bifrontal, cingulate gyrus and thalamus that graded with severity of behavioural impairment across patients with moderate cognitive disability through vegetative state outcomes. Garcia-Panach et al.17 found similar changes in FDG-PET patterns of cerebral metabolism and TBI outcomes but specifically identified decreased medial frontal and thalamic metabolism in patients who emerged from post-traumatic amnesia and controls, similar to our observations. Nakashima et al.65 reported on hypometabolism within the cingulate gyrus in subjects with TBI with neuropsychologic deficits. Other studies have isolated reduced thalamic metabolism with TBI in early66 and, more comparably, late time points after initial TBI.64 One study specifically correlated reductions in the anterior cingulate FDG-PET metabolic signal with neuropsychological deficits following diffuse axonal injuries.16 These prior findings of selectively reduced cerebral metabolism in the same regions in which BPND is reduced suggest an important functional component to the loss of GABAA receptor availability particularly within medial frontal and thalamic regions as seen in Our FMZ-PET results are also comparable to prior cross-sectional [18F] fluorodeoxyglucose PET studies of TBI patients which demonstrate graded thalamic and medial frontal hypometabolism that correlates with behavioural outcomes.ND between the sub-acute time point and ∼1 year time-point that exceed the measured longitudinal variability in our controls across a similar time interval. No prior studies of subjects with TBI have evaluated interval changes in [11C]FMZ PET measured GABAA receptor availability; thus, these findings provide the first evidence that FMZ PET is sensitive to evolving changes in the expression of the GABAA receptor on neurones across the cerebrum following TBI. Notably, while frontal cortical regions showed persistent and significant loss of GABAA receptor availability, a specific pattern of subcortical changes within the striatum and pallidum emerged. In the striatum, marked increases from initially decreased BPND, are observed  alterations in expression and affinity of GABAA within preserved or remaining neuronal structure,45 and/or (ii) evidence of receptor plasticity.42 Previous studies have reported a return to baseline67 in glutamate signalling by 6 months post concussions and suggested chronic excitatory-inhibitory signalling imbalances (glutamate-GABA) following mild TBI.69 However, no studies provide comparable timelines and methodologies to directly compare our findings.Longitudinal measurements revealed significant changes in the BPobserved . ChangesA receptor availability with improved ANT executive attention score. The ANT executive score is a measure of inhibition and conflict resolution.9 These findings can be compared to a previous study18 of eight severe TBI patients—preselected by behavioural impairment and limited cortical damage; in this group, a graded FMZ binding reduction in the right thalamus and left medial frontal gyrus, during the chronic phase of recovery (12–228 months), was associated with lower general cognitive function . Another study57 reported that the majority of patients with memory impairment (n = 6 of 9) had low binding potential in the temporal lobe. In our results, we show an overall global increase in BPND within cortical structures and thalami relates to an improvement in executive attention behaviour. The relationship between GABA receptor availability and executive attention is particularly relevant to recovery given the strong correlation between executive functions and daily activities.71We demonstrate a significant correlation of increased GABAA binding reflected in the [11C]FMZ PET BPND are strongly consistent with the AFM model of recovery of consciousness and brain function following varying aetiologies of brain injury.72 The mesocircuit model begins with a single assumption that multi-focal brain injuries result in a broad reduction of background synaptic activity across the corticothalamic system. This emerges as a consequence of widespread deafferentation and is amplified by the disfacilitation of central thalamic regions which act as a critical hub in the forebrain arousal regulation system.72 The model proposes that marked reduction in frontal cortical and striatal function arise via functional and structural deafferentation of central thalamic projections to these structures. These changes are proposed to be secondary to: (i) the strong central thalamic anatomical projections to these structures73 and (ii) the effects of chained inhibition within the cortico-striato-pallidal-thalamocortical loop systems.74 Down-regulation of striatal activity is predicted to arise as a consequence of reduced thalamostriatal/thalamocortical and cortico-striatal outflow in turn leading to disinhibition of the globus pallidus interna that results in additional direct inhibition of thalamic efferent activity. Thus, the mesocircuit model predicts the specific pattern seen in the subacute period here of reduced GABAA binding across the frontal lobes and striatum . Our findings can specifically be compared to a recent study75 in which secondary thalamic pathology was strongly correlated with outcomes following moderate to severe brain injury patients following TBI. In addition, a correlation of recovery of executive function with broad increases in [11C]FMZ PET BPND across cerebral structures  in a cross-sectional study of patients with varying levels of recovery from severe brain injury. The GP/CT ratio showed an inverse correlation with increasing recovery of consciousness and restoration of higher-brain brain function. These observations are consistent with the findings here of chronically reduced frontal lobe and elevated GP [11C]FMZ PET BPND as reduced cortico-striatal and thalamo-striatal activity would be predicted to correlate with release of local pallidal neuronal firing.74 The increase in pallidal GABAA binding likely reflects local circuit inhibitory activity; prior studies have demonstrated that microinfusion of zolpidem  within the pallidum can suppress such activity.76 Moreover, human globus pallidus interna is enriched with the GABAA alpha-1 subunit.77 Targeting of overactive pallidal GABAA activity in the setting of marked functional deafferentation of the frontal cortex and striatum has been proposed as a key component of paradoxical behavioural improvements seen in a minority78 of patients with disorders of consciousness following structural brain injuries with administration of zolpidem.79Fridman 80 and is thus positioned to integrate loss of activity and connectivity across these structures. In the context of the role of the projections from the central thalamus to the fronto-striatal regions,73 these anatomical specialization can be envisioned to act as a ‘repeater circuit’ and amplify effects of arousal regulation through pre-frontal and frontal regions. Underactivation of these regions at baseline might provide the anatomical basis for reduced readiness to deploy executive attention observed in TBI patients with moderate to severe brain injuries.9 In this context, recent observations that patients with chronic cognitive impairments  show improvement with central thalamic deep brain stimulation (DBS) with driving of the central thalamus into frontal cortex and striatum particularly in the Trail Making Test-B performance82 suggest that the reduced frontal GABAA activity may provide a marker of a recruitable reserve.While limited by multiple comparisons made in a small sample, our findings that right ACC showed significant change are also notable in the context of the mesocircuit model. The ACC has widespread projections across Layer 1 of frontal and pre-frontal cortices84 Within neocortical neurons, increased arousal is dominated by inhibitory currents86 and controlled by increased overall excitatory neurotransmission via long-range projections across the cerebrum. Increased arousal levels are associated with increased resting metabolism87 and would be predicted to increase the number of GABA receptors on neocortical neurons over time. GABAA receptors mediate fast responsive changes in cortical tone88 and play a key role in the strong background inhibitory currents associated with awake ‘activated’ states of the cortex.85 Thus, we propose that the increases observed across all brain regions between the subacute and chronic (∼1 year) time points of measurement here  electrodes in magnetic resonance based techniques and with the use of additional ligands92 allows a detailed molecular neuroimaging of either spontaneous recovery or therapeutic responses. The primary limitation of this study, similar to other existing [11C]FMZ PET studies57 of subjects with TBI, is its small sample size along with the heterogeneity of injury severity and wide range of ages. The range of cognitive impairments, though not selected for apriori, is relatively comparable. These constraints limit the generalizability of our results; nonetheless, we find a strong inter consistency of changes across cortical regions and subcortical structure comparable with those obtained using entirely independent methods in subjects with TBI as noted above. While we have detailed cognitive assessments in our subjects with TBI, statistical considerations of a small sample prevent finer stratification of our BPND results by cognitive impairment. We cannot draw strong conclusions about individual recovery trajectories and changes in GABAA receptor availability as we have very few longitudinally repeated measurements. The limited GABAA increases in the frontal cortex may be influenced by heterogeneity of injury severity and recovery in our sample. In a larger sample, we might expect to relate these factors to specific patterns of changes in GABAA. A larger cohort of healthy controls across a wider age range, and with test-retests across multiple timelines, would help to establish more precise quantitative expectations in control subjects. Moreover, GABAA receptors are highly dynamic over time and recent studies have shown marked alteration of subunit types can arise in response to activity changes in network state  and instead chose to adjust for region size, as traditional PVC methods like geometric transfer matrix94 correction may increase noise and assume homogeneous values across regions. Our approach, however, does not take account of the spatially and temporally variant contrast in radioactivity concentration that induces the partial volume error. Future studies will compare PVC methods. Lastly, the use of a single ligand, specific to GABAA receptors (and largely sensitive to the ɑ1 subunit given its 10-fold increased concentration95) limits our ability to assess the full range of changes in GABA receptor availability in our subjects and possible functional and structural alterations signalled by changes in this receptor type following TBI.In the aggregate, our observations suggest the future use of [fcac159_Supplementary_DataClick here for additional data file.


Currently, no standardized methods exist to assess the geriatric skills and training needs of internal medicine trainees to enable them to become confident in caring for older patients. This study aimed to describe the self-reported confidence and training requirements in core geriatric skills amongst internal medicine residents in Toronto, Ontario using a standardized assessment tool.This study used a novel self-rating instrument, known as the Geriatric Skills Assessment Tool (GSAT), among incoming and current internal medicine residents at the University of Toronto, to describe self-reported confidence in performing, teaching and interest in further training with regard to 15 core geriatric skills previously identified by the American Board of Internal Medicine.P < 0.001 to P = 0.04) and in teaching 9/15 GSAT skills (P < 0.001 to P = 0.04). Overall, the residents surveyed identified their highest confidence in administering the Mini-Mental Status Examination and lowest confidence in assessing fall risk using a gait and balance tool, and in evaluating and managing chronic pain.190 (75.1%) out of 253 eligible incoming (Year 0) and current internal medicine residents (Years 1–3) completed the GSAT. Year 1–3 internal medicine residents who had completed a geriatric rotation reported being significantly more confident in performing 13/15 (A structured needs assessment like the GSAT can be valuable in identifying the geriatric training needs of internal medicine trainees based on their reported levels of self-confidence. Residents in internal medicine could further benefit from completing a mandatory geriatric rotation early in their training, since this may improve their overall confidence in providing care for the mostly older patients they will work with during their residency and beyond.The online version contains supplementary material available at 10.1186/s12909-022-03934-2. The rapid growth in the number of persons aged 65 years and older has been well documented, as have concerns of how global healthcare systems will respond to meet the complex medical needs of growing aging populations –3. OlderWith a rapidly aging population, it is reasonable to expect that all internal medicine specialists graduating from residency training programs acquire an appropriate amount of knowledge, skill and exposure to caring for older adults, so they can be confident in providing care for them. Despite this, current literature suggests that internal medicine physicians may not feel comfortable in some areas of geriatric medicine, such as deprescribing guideline-recommended therapies to avoid polypharmacy , addressThis study examined the use of a self-rating instrument, known as the Geriatric Skills Assessment Tool (GSAT) Fig. , among aThis study aimed to describe the self-reported confidence and training needs of internal medicine residents with regard to core geriatric skills, using the GSAT. The specific objectives were to: 1) identify the self-reported confidence of internal medicine residents in performing core geriatric skills; and 2) identify the self-reported geriatric medicine training needs of internal medicine residents. A quantitative study using a non-experimental design was utilized. A novel survey (GSAT) was implemented to answer the research objectives.This study was approved by the Mount Sinai Hospital Research Ethics Board and was conducted in accordance with all regulations (REB #11–0124-E). All participants provided informed consent by completing the survey.This study explored patterns of confidence and training needs amongst internal medicine residents at the University of Toronto (UT). UT is a world-leading educational institution and the sole medical school for numerous major hospitals in Toronto, Canada’s most populous city. It runs the largest internal medicine residency program in Canada and is in the minority of programs mandating the completion of a rotation in geriatrics, which occurs between years 1 to 3 at a time of the trainees’ choosing , 38. DurAll incoming (Year 0) and current (Years 1–3) core internal medicine residents at UT were invited to complete an anonymous, electronic SurveyMonkey® or paper-based structured survey from February to June 2012. This captured existing internal medicine residents towards the end of their current training year, as well as the newly selected group of incoming internal medicine residents who were final-year medical students at the time of survey distribution. The survey assessed core geriatric skills competencies using the GSAT and collected baseline demographic and training history information.Survey invitations were delivered via personalized email and an in-person presentation during an internal medicine academic teaching session. Response rates were optimized through five follow-up email invitations. Participants were incentivized in the form of a random draw for gift cards offered to all who submitted a completed survey. Consent was implied if participants proceeded with survey submission.The American Board of Internal Medicine (ABIM) certifies general internists and medical subspecialists who demonstrate the necessary knowledge, skills and attitudes essential for patient care according to their standards of examination. The GSAT is a cross-sectional educational needs assessment tool developed to assess a general internist’s confidence in performing and teaching, as well as their interest in further training, with regard to 15 ABIM-identified core geriatric clinical skills , 36. WhiFreely available on the Portal of Geriatrics Online Education, the GSAT is the first self-rating instrument designed to assess geriatric skills in postgraduate internal medicine trainees and specialists. It has been used to assess the skills of internal medicine teaching faculty and residents at academic teaching hospitals in both Canada and the US , 40. TheThe GSAT uses a modified 4-level (low to high) Likert scale , throughp-value < 0.05 was considered statistically significant for our analyses [The GSAT data were analyzed with SAS software® using descriptive statistical methodologies to evaluate the trainees’ responses . For theanalyses .190 (75.1%) out of the 253 eligible incoming (Year 0) and current internal medicine residents (Years 1–3) completed the survey and are further characterized in Table P = 0.03). Additional file There was no gender variation other than the observation that female respondents showed a higher interest in acquiring further training about situations where diagnosis and treatment in older adults should be modified , administering the Mini-Mental Status Examination (MMSE) [P = 0.004) and conducting discussions regarding goals of care , compared with respondents who completed medical school outside of Canada. They were also significantly more confident in teaching 5/15 GSAT Skills (P < 0.001 to P = 0.03).Significant GSAT score differences were found in several selected domains for the respondents’ place of medical school training, prior completion of a geriatric training rotation, number of postgraduate training years, and identified future subspecialty area of interest. Respondents who attended a medical school in Canada were significantly more confident in assessing functional capacity   (GSAT SkP < 0.001 to P = 0.04) and in teaching 9/15 GSAT Skills (P < 0.001 to P = 0.04), compared to those who had not completed a geriatrics rotation.Year 1–3 respondents who had completed a formal rotation in geriatrics during their residency reported a significantly higher degree of confidence in performing 13/15 GSAT Skills (P = 0.05), assessing an older patient’s fall risk using a gait and balance assessment tool , knowing the indications of and risks associated with antipsychotic medications  and evaluating and managing chronic pain in older adults . Tables The number of postgraduate years in residency training significantly impacted respondents’ confidence in performing and teaching geriatric skills. Incoming residents (Year 0) were more confident in performing 8/15 and teaching 6/15 GSAT Skills when compared with Year 1 residents. Year 2 and Year 3 residents showed higher levels of confidence in performing and teaching 11/15 and 12/15 GSAT Skills respectively compared with lower year residents. There were 4/15 GSAT skills in which Year 1 or 2 residents who had completed a formal rotation in geriatrics showed significantly greater confidence in performing compared to Year 3 residents who had not completed a geriatric rotation. These included identifying medications that should be used with caution in older adults  and recognizing an older person’s risk of falls . However, these internal medicine residents were less confident in teaching the evaluation and management of chronic pain in older adults when compared with all other residents . Our results did not show that residents interested in geriatrics expressed a significantly greater interest to pursue further training in core geriatric skills, compared with other residents. Residents who were undecided about their future subspecialty were less confident in differentiating normal from abnormal aging  and identifying situations where standard diagnosis and treatment in older adults should be modified .Differences were noted in the collective self-rating scores between residents interested in general internal medicine as a future subspecialty versus residents who were reportedly undecided or interested in other subspecialties across all years of training. Those interested in general internal medicine expressed greater confidence in performing 5/15 GSAT Skills  and in evaluating and managing chronic pain in older adults . The two GSAT skills with the reported highest interest in acquiring further training were knowing indications and risks associated with antipsychotic medications  and managing chronic pain in older adults  , suggesting that further education in this area is not required. Additionally, a topic that third-year residents expressed great interest in receiving further training in, was evaluating and managing chronic pain in older adults (GSAT Skill 12). This was the same geriatric skill in which first and second-year residents who had completed a rotation in geriatrics were significantly more confident in managing than third-year residents who had not completed a geriatrics rotation. This type of information may prompt educators to incorporate training on chronic pain earlier in residency to more proactively and adequately address this training gap. Identifying residents’ learning interests and knowledge gaps, as evidenced by low self-reported confidence levels, can also be used to make improvements to internal medicine residency program curricula.As a cross-sectional, single-site study providing a descriptive snapshot of UT internal medicine residents, our findings have training- and location-specific implications that may not be transferable to other programs that vary in size, geographical location, curriculum orientation, and culture. However, it is important to note that our survey achieved a 75% overall response rate and was conducted in one of the largest internal medicine resident cohorts in North America, with trainees who had completed undergraduate training in over 38 medical schools across 14 countries around the world. Further research is needed to develop a broader understanding of the geriatric training needs and applicability of the GSAT in determining these amongst internal medicine residents in other settings. A further limitation is that the GSAT is currently not a validated tool, despite being used in previous research , and altThis study emphasizes the value of a needs assessment, such as the GSAT, in the improvement of postgraduate medical curricula. Using the GSAT amongst all UT internal medicine residents, our findings suggest that the inclusion of a formal rotation in geriatrics, particularly early on in training, significantly improves residents’ confidence in performing and teaching multiple core geriatric skills. Medical curricula designers should consider incorporating a mandatory geriatric rotation for all internal medicine residents. Future research is encouraged to consider the applicability of the GSAT in determining training needs amongst internal medicine residents in other settings, such that this information can be used to further refine recommendations for internal medicine training.Additional file 1.Additional file 2.Additional file 3.


Population patterns of immunosenescence are not well described. We characterized markers of immunosenescence and assessed sociodemographic differences in a population of individuals ages 56 years and older using newly released venous blood data from the nationally representative U.S. Health and Retirement Study (HRS) . Median values of the CD8+:CD4+, effector memory (em)RA:naïve CD4+ and emRA:naïve CD8+ T cell ratios were higher among older participants (more aged immune profile) and were lower among those with additional educational attainment (less aged immune profile). Racialized minority populations had immune markers suggestive of a more aged immune profile: Hispanics had a CD8+:CD4+ median value of 0.37  compared to Whites . Blacks had the highest median value of the emRA:naive CD4+ ratio  compared to Whites . Our regression analyses showed that race/ethnicity and education were associated with large differences in T-cell markers of aging, which were orders of magnitude greater than age. By standardizing regression coefficients to estimate years of immunological aging, we found that each additional level of education was associated with roughly an additional decade of immunological age, and racialized minorities had on average an immunological age two to four decades higher than Whites. As one of the first large-scale population-based investigations of immunosenescence, our study advances understanding of the immune mechanisms underlying age-related disease, with implications for risks such as vulnerability to novel pathogens .


B) and boron mono vacancies with oxygen atoms (VBO2) respectively, which can enhance the successful implementation of the efficient QKD. We also examine the tunability of the other defects viz. nitrogen mono vacancies, nitrogen mono vacancy with self-interstitials, nitrogen mono vacancy with carbon interstitials, carbon dimers and boron dangling bonds, which revealed the tunable quantum emission in the visible, other UV and IR spectrum ranges and such customized quantum emission can enhance the birth of other quantum photonic devices.This study presents extending the tunability of 2D hBN Quantum emitters towards telecom (C-band − 1530 to 1560 nm) and UV-C (solar blind − 100 to 280 nm) optical bands using external strain inducements, for long- and short-range quantum communication (Quantum key distribution (QKD)) applications, respectively. Quantum emitters are the basic building blocks of this QKD (quantum communication or information) technologies, which need to emit single photons over room temperature and capable of tuning the emission wavelength to the above necessary range. Recent literature revealed that quantum emitters in 2D hBN only has the ability to withstand at elevated temperatures and aggressive annealing treatments, but density functional theory (DFT) predictions stated that hBN can only emit the single photons from around 290 to 900 nm (UV to near-IR regions) range. So, there is a need to engineer and further tune the emission wavelength of hBN quantum emitters to the above said bands (necessary for efficient QKD implementation). One of the solutions to tune the emission wavelength is by inducing external strain. In this work, we examine the tunability of quantum emission in hBN with point defects by inducing three different normal strains using DFT computations. We obtained the tunability range up to 255 nm and 1589.5 nm, for the point defects viz boron mono vacancies (V Quantum communication in UV-region is also another alternative approach to short-range distances [under non-line of sight (NLOS) condition], which requires quantum emission in solar-blind (UV-C) region of 100–280 nm range8.Photo-luminescent quantum emitters which are close enough to ideal single photon emission characteristics, capable of holding the emissive properties at higher operating temperatures, various harsh environments and possibility to tune the emission spectrum to the wide range (higher to shorter wavelength range) are the central elements for implementing successful quantum information technologies and integrated quantum photonics. In particular, robust quantum communications demand quantum emitters that provide efficient quantum emission in the telecom (C-band) range of 1530–1560 nm for longer and short-range distances12. However, to-date quantum emitters developed in 2D hBN (white graphene) are found to sustain their high emission characteristics at elevated operating temperatures13 and vigorous annealing treatments14, but exhibits the emission spectrum only from UV to near-IR region i.e., around 290–900 nm range16. As an alternative technique, carbon nanotubes exhibit the quantum emission around 1500 nm17, but faces the drawback of narrow emission range and their low operating temperatures. On the other hand, quantum dots can achieve broad emission spectrum19. However, the specific wavelength emission in quantum dots requires distinct quantum arrangements and dissimilar doping. Hence, it is difficult to achieve complete wide-range emission spectrum on a single host material using quantum dots.The state-of-the-art research revealed that, implementing such ideal quantum emitters using layered materials is one of the most promising solutions20 of 2D materials supports to strain engineer the electronic band gap of quantum emitters and promotes the tunability of single photon emission. Here, we illustrate the optical tunability of precise quantum emitters (Luminescent point defects) in 2D hBN by inducing strain gradients, using density functional theory (DFT) calculations.One of the most promising solutions to fulfil the quantum communication requirement is by tuning the quantum emission in 2D hBN through defects to the necessary range. As hBN is the first known natural hyperbolic material, i.e., in-plane bonds are stronger than out-of-plane bonds in its crystal structure, external strain can be applied to modify the electronic energy levels of luminescent point defect states and tune their emission spectrum. The high stretchability feature21. In order to identify potential quantum emission candidates (luminescent point defects), to employ for our strain inducements simulations, earlier published DFT simulations without strain inducements has taken into consideration24. Our DFT simulated results of quantum emitters without external strain inducement also consistent with the earlier published experimental observations. From our work with various types of strain inducements, it is observed that the emitters exhibit greater tunability and the broad emission spectrum from solar blind region (UV-C) of 255 nm to beyond telecom wavelength range of 1589.5 nm, respectively. The schematic illustration of tuned near-IR single photon emission from the quantum emitters subjected to external strain under optical excitation is shown in Fig. In this work, we simulated three different types of normal strain inducements in 2D hBN with point defects by approximating an experimental situation such as inducing strain on 2D hBN layer with point defects using a bendable polycarbonate (PCB) substrate25 and computational works21 and here we projected the emission tunability of different luminescent point defects for different normal strains induced. Inducing shear strain is out of our research interest.In this article, we majorly concentrate to surveil the broader tunability of quantum emitters in 2D hBN under different normal strains induced. Figure V) defines that along with strain induced , there will also be another small deformation of the material, which is perpendicular to the load direction (applied strain direction). This small deformation will be in negative ratio as shown in Fig. One important phenomenon needs to be considered while computing this strain inducements, particularly, while inducing transverse or longitudinal strains is the Poisson’s ratio. The Poisson’s ratio  and the other two are one-sided lateral and one-sided longitudinal strains. This kind of one-sided lateral or longitudinal strain can be applied to the material, by placing it on a bendable polycarbonate (PC) beam  as observed in reference21. Hence, by computing these three strain types, we examine the quantum emission tunability of different luminescent point defects in 2D hBN and project their tunability.As per earlier literature (strain induced quantum tuning), we found three major types of normal strains, studied in references26 and bending all the edges upwards (downwards) simultaneously, as shown in Fig. We computed the effect of biaxial strain to the hBN quantum emitters using DFT simulations by considering experimental conditions. In practise, a negative (positive) biaxial strain can be applied by depositing the hBN film on the core of PC beams, arranged in cruciform structure as observed in Ref.3.By using target-stress tensor section present in geometrical optimizer in DFT computations, we simulated the effect of negative (positive) biaxial strains to various luminescent point defects in 2D hBN. All the stress error tolerance values were set to 0.0005 eV/AThe target-stress tensor section, targets the internal stress of the material, where negative strain values along xx and yy components results in compression force along the xx and yy (tensor) directions of 2D hBN as shown in Fig. 21. This kind of normal strain  was induced experimentally, by transferring the hBN film on to a 1.5-mm thick bendable polycarbonate (PC) beam, which allows to induce controllable strain. One edge  of the PC beam will be fixed and the other side will be bent downward (upward) to produce tensile (compressive) effects as shown in Fig. We also computed the effect of one-sided lateral and one-sided longitudinal strains to hBN quantum emitters using DFT simulations, to examine the quantum tunability. This approach of inducing constrained normal strains  in order to efficiently tune the quantum emission, was considered from earlier experimental and DFT observations as shown in referenceWhile simulating this kind of one-sided lateral or one-sided longitudinal strains inducement as similar to experimental approximation, the Poisson’s ratio effect as shown in Fig. According to Poisson’s ratio, when a tensile (stretching) effect is induced towards one-sided lateral  [or longitudinal ] direction, it creates an expansion of material  and also produces a small compressive deformation. This compressive deformation will be orthogonal to applied strain (tensile effect) direction.Similarly, when a compression (shrinking) effect is induced towards one-sided lateral  [or longitudinal ] direction, it creates shrinking of material  and also produces a small expansive deformation. This expansive deformation will be orthogonal to applied strain (compressive effect) direction.21. The Poisson’s ratio relation for inducing one-sided lateral and one-sided longitudinal strain to the hBN point defects, using a bendable polycarbonate (PC) beam is represented in Fig. Hence, to compute these effects in a realistic way, we considered the Poisson’s ratio of polycarbonate (PC) beam = 0.37, by which strain is induced to 2D hBN quantum emitters as observed in reference21.This strategy of assigning these two orthogonal strain directions, to compute one-sided lateral and one-sided longitudinal strain inducement to the point defects in 2D hBN and considering experimental approximations such as Poisson’s ratio of PC beam were acquired from earlier DFT computations as in reference3.We simulated these two orthogonal strain inducements (due to Poisson’s effect) in mutually exclusive method with the help of atomic constraint editor using geometry optimizer in DFT computations, by setting the stress error tolerance to 0.0005 eV/ABVN), using plane-wave calculations.Initially, a few DFT computations for performing volumetric strain inducements, like biaxial strains, were carried out for the luminescent point defect (C27. The nucleus–electron interaction is represented by projector augmented wave (PAW) pseudopotentials. A Gaussian smearing occupation is employed for numerical accuracy, with a broadening of 0.05 eV and to an energy tolerance of 0.01 eV.All plane-wave calculations are spin-polarized. A plane-wave cut-off of 450 eV was used for the calculations and by using Generalized Gradient Approximation (GGA) to the exchange correlation functional proposed by Perdew, Burke and Ernzerhof (PBE)Pristine single-layer hBN was first geometry-optimized using a 21 × 21 × 1 Monkhurst–Pack reciprocal space grid. The defective hBN monolayer was created using a 7 × 7 supercell and the defective structures were re-optimized with the reciprocal space grid reduced to 3 × 3 × 1.BVN), by employing Linear combination of atomic orbitals (LCAO) calculations. In LCAO, all the parameters and approximations were similar to the above plane-wave calculations and the only difference is projector augmented wave (PAW) pseudopotentials is replaced with Fritz-Haber Institute (FHI) pseudopotentials, which computed according to the procedure reported by Troullier and Martins28 and the Double-zeta plus polarization (DZP) basis set was employed for the calculations.Next, we re-performed the same biaxial strain inducement simulations to the same luminescent point defect (CBVN), using plane-wave and LCAO calculations, we observed no major difference in the obtained optical spectrum results as shown in Fig. BVN defect, using plane-wave and LCAO calculations, respectively.By comparing the biaxial strain inducement simulations of the point defect 35. These defects’ single photon emission with GW approximations  are beyond the scope of our work.The precise luminescent point defects, which we employed for strain inducing simulations were earlier demonstrated (with published experiments) as the reliable single photon emitters as listed in Table 136, initially we cross-examined the optical emission spectrums and the corresponding projected density of states (PDOS) of precise luminescent point defects  with earlier published literature44, without inducing any external strain inducement. We have selected these precise luminescent point defects, based on their consistence of experimental observations with DFT approximations and simple fabrication possibilities as shown in Table By performing constrained DFT simulations39. When this occupied ground state electron is excited with enough energy, it transmits to un-occupied excited state. As this ground and excited state transition is based on single electron, it emits a single photon of specific wavelength while relaxing back to ground state. The DFT studies acknowledges this single photon emission by a Lorentzian shape peak (sharp emission peak), which is a signature of quantum emission and this Lorentzian shaped sharp emission peak is also considered as zero-phonon line (ZPL), by quantum studies.These luminescent point defects create intermediate energy levels (an electron occupied ground state and un-occupied excited state) between valence and conduction bands of 2D hBN as shown in referenceThe DFT computed optical emission spectrums of luminescent point defects under no external strain inducement  formed due to the point defects and energy difference between these occupied and un-occupied states is found to be consistent with ZPL energies of corresponding luminescent point defects, which further strongly confirms the quantum emission signature of point defects. The complete DFT computed information related to various point defects, their schematics, computed ZPL quantum emission energies and corresponding PDOS information are listed in Table As from the simulated data observed from Table Hence, in order to fulfil the QKD (quantum communication) requirement for long distances and as well as to still enhance the short-range UV communications, we attempted the possible emission tunability of precise quantum emitters by inducing external strain.BO2 defect exhibits emission in near-IR region, whose DFT approximations were found to be consistent with experimental observations as listed in Table The first and foremost consideration while tuning the quantum emission towards IR region is, selecting luminescent point defects whose quantum emission (ZPL) energy is around the frontier of near-IR region, which makes it easier to efficiently tune the quantum emission towards deep IR region. In such a way, among all the luminescent point defects in 2D hBN only VBO2 (boron vacancy with oxygen atoms passivated) defect, as shown in Fig. The schematic of VBO2 defect under no external strain is shown in Fig. The graphically represented PDOS of VBO2 defect and the disclose of Lorentzian shaped ZPL peak at its respective energy (1.26 eV), whose value consistent with energy difference of intermediate states under no external strain inducement , confirms that VBO2 is intrinsically a potential quantum emitter at near IR region.These intermediate energy states are formed due to VBO2 exhibits giant tunability towards lower and higher energy regions for one-sided longitudinal strain inducement. The defect tunability range and responsible strain details are listed in Tables Out of all the three different normal strain inducements which are considered for simulation as discussed in methodology section, VBO2 defect exhibits greater tunability up to 0.78 eV (mid IR region) for tensile (stretching) effect produced at one-sided longitudinal strain inducement and tunability up to 1.44 eV (near IR region) for compressive (shrinking) effect produced at one-sided longitudinal strain inducement and the complete tunability is shown in Fig. BO2 defect and we observed modulating the bandgap of inter energy states. For the tensile effect produced in one-sided longitudinal strain inducement, the energy gap between these intermediate states is found to be reduced  as shown in Fig. BO2 defect towards mid IR region and this reduced energy gap value also consistent with tuned emission energy . These complete details related to PDOS of strained defects and their maximum tunable emission are listed in Table VBO2 defect engineered and this increased energy difference is also consistent with tuned emission energy as shown in Table Similarly, for the compressive effect produced in one-sided longitudinal strain, the energy gap between these intermediate states is found to be increased  as shown in Fig. BO2 defect.Hence, this consistence of un-strained and one sided longitudinal strained engineered intermediated states energy gap (observed from PDOS representation), along with un-tuned and tuned emission spectrums confirms the quantum emission tunability (Mid IR to near IR) from VB, VN and VBN), which are consistent with experimental declarations as listed in Table Only mono and di-vacancy defects (VB (boron mono vacancy), VN (nitrogen mono vacancy) and VBN (boron and nitrogen di-vacancy) defects as shown in Figs. The schematics of VB, VN and VBN defects under no external strain is shown in Fig. The graphically represented PDOS of VThis consistence of PDOS energy gaps of this mono and di-vacancy defects with their Lorentzian shaped ZPL energies confirms their intrinsic potential quantum emission at different shades of UV region.All these mono and di-vacancy defects exhibit greater and linear tunability towards lower and higher energy regions, only with biaxial strain inducements and these defects tunability range and type of biaxial strains responsible for tuning are listed in Tables B and VBN defects exhibit tunability towards lower energy region up to 4.4 eV and 3.24 eV respectively as shown in Figs. N defect exhibits tunability towards higher energy region up to 3.9 eV, as shown in Fig. B and VBN defects exhibits tunability towards higher energy region up to 4.86 eV and 4.08 eV respectively as shown in Figs. N defect exhibits tunability towards lower energy region up to 3.3 eV as shown in Fig. VB, VN and VBN defects. For the defects VB and VBN, energy gap between inter energy states found to be reduced  as shown in Fig. N defect energy gap found to be increased  as shown in Fig. We also investigated the PDOS of strain induced  2D hBN layers containing VB and VBN as shown in Fig. N defect energy gap found to be decreased  as shown in Fig. As in contrast, energy gap between inter energy states found to be increased  for VB, VN and VBN defects also consistent with their tuned emission energies  and these complete details related to PDOS of strained defects and their maximum tunable emissions are listed in Table Thus, the modulated energy gap values for VB, VN and VBN defects were consistent with un-tuned and tuned emission spectrums.Hence, the un-strained (no strain applied) and biaxially strained engineered intermediated states energy gap (observed from PDOS representation) of layered hBN containing VN and VBN defects and tunable quantum emission from UV-B to UV-C region from VB defect.This consistency confirms the tunable quantum emission in UV-A region from VBVN defect (which is mostly referred luminescent point defect to date).Out of all the point defects ) as shown in Fig. The schematics of NBVN defect under no external strain is shown in Figs. BVN defect.The graphically represented PDOS of NBVN defect responds linearly for all the three different kinds of strains . Thus, the defect tunability range for different type of strain inducements and other details are listed in Tables The NBVN defect exhibits giant tunability towards lower energy region up to 1.74 eV for positive biaxial and 1.38 eV for the compressive effect produced in one-sided longitudinal strain inducements respectively as shown in Fig. The NBVN defect exhibits giant tunability towards higher energy region up to 2.21 eV for negative biaxial strain and 2.57 eV for tensile effect produced in on-sided lateral strain inducements respectively as shown in Fig. Besides, the NBVN defect and we observed giant modulation (strain engineering) of the bandgap of inter energy states. For the positive biaxial strain and for the compressive effect produced in one-sided longitudinal strain inducement, the energy gap between these intermediate states is found to be reduced  as shown in Figs. BVN defect.We also examined the PDOS of all three types of strains induced  in 2D hBN layers containing NBVN defect is blue-shifted.Contrastingly, for the negative biaxial strain and for the tensile effect produced in one-sided lateral strain inducements, the energy gap between these intermediate states is found to be increased  as shown in Figs. BVN defect  also consistent with their tuned emission energies . These complete details related to PDOS of strained defects and their maximum tunable emissions are listed in Table Thus, the modulated energy gap values of PDOS for NBVN defectHence, this consistence of un-strained and three different types of strain induced engineered intermediated states energy gaps (observed from PDOS representation), along with un-tuned and tuned emission spectrums confirms the tuning of quantum emission (visible region) from NBO2, UV region—VB, VN and VBN and visible region—NBVN) of electromagnetic spectrum. Moreover, we also found that these three  point defects can be able to tune the quantum emission, which can cover from near-IR to visible regions and visible to UV (UV-A) regions, respectively.Through-out the discussion of quantum emission tunability till now, all the five different luminescent point defects exhibited their complete possible tunability through a single region  as shown in Fig. The schematics of CBVN defect under no external strain is shown in Figs. The graphically represented PDOS of CBVN defect, CBVN defect also responds linearly for all the three different kinds of strains . Thus, the defect tunability range for different type of strain inducements and other details are listed in Tables As similar to NBVN defect also exhibits giant tunability towards lower energy region up to 1.22 eV and 1.3 eV respectively as shown in Figs. CBVN defect and we observed greater modulation (strain engineering) of the bandgap of inter energy states. For the positive biaxial strain and for the compressive effect produced in one-sided longitudinal strain inducement, the energy gap between these intermediate states is found to be reduced  as shown in Figs. BVN defect.We also examined the PDOS of all three types strains induced  2D hBN layers containing CBVN defect is blue-shifted.On the other hand, for the negative biaxial strain and for the tensile effect produced in one-sided lateral strain inducements, the energy gap between these intermediate states is found to be increased  as shown in Figs. BVN defect  also consistent with their tuned emission energies  and these complete details related to PDOS of strained defects and their maximum tunable emissions are listed in Table Thus, the modulated energy gap values of PDOS for CBVN defect.Hence, this consistence of un-strained and three different types of strain inducing engineered intermediated states energy gaps (observed from PDOS representation), along with un-tuned and tuned emission spectrums confirms the tuning of quantum emission (from near-IR to visible region) from CBCN defect and boron dangling bonds found to exhibit tunable quantum emission from visible to UV (UV-A) region.From the herd of luminescent point defects till date,  and boron dangling bonds defects as shown in Figs. The schematics of CBCN and boron dangling bonds defects under no external strain is shown in Figs. The graphically represented PDOS of CBCN and boron dangling bonds defects exhibits greater and linear tunability towards lower and higher energy regions, only for biaxial strain inducements and these defects tunability range and type of biaxial strains responsible for tuning are listed in Tables This CBCN and boron dangling bonds defects exhibits tunability towards lower energy region up to 2.8 eV and 2.7 eV respectively for positive biaxial strain inducement as shown in Figs. The CBCN and boron dangling bonds defects, whose energy gaps between inter energy states found to be reduced  as shown in Figs. We also investigated the PDOS of strain induced  2D hBN layers containing CBCN and boron dangling bonds defects also consistent with their tuned emission energies . These complete details related to PDOS of strained defects and their maximum tunable emissions are listed in Table Thus, the modulated energy gap values of PDOS for CBCN and boron dangling bonds defects.Hence, this consistence of un-strained and biaxially strained engineered intermediated states energy gap (observed from PDOS representation), along with un-tuned and tuned emission spectrums confirms the tunable quantum emission (from visible to UV (UV-A) region) from CBO2 defect is found to be potential candidate to tune the quantum emission at telecom wavelength range (C-band) around 1589.5 nm (0.78 eV) as shown in Fig. B defect), exhibit the emission tunability deep into solar bind (UV-C) region around 255 nm (4.86 eV) as shown in Fig. According to the simulated data obtained, only the VBVN defect), UV–visible region (boron dangling bonds and CBCN defects) and around the parts of UV-A region (VN and VBN defects) as shown in Figs. Rest of the defects exhibit their tunable emission at visible-IR region  than compared to mono vacancy defects (VB and VN). For all the defects as listed Table BN and CBVN defects which exhibited greater tunability towards higher energy region compared to lower energy region as observed in Tables From the simulated data, it was observed that wide range of tunability is observed for all the defects (VBVN and CBVN) defects exhibits giant tunability for all the three different strains . In particular, greater order of tunability is observed for NBVN and CBVN defects for one-sided lateral and one-sided longitudinal strains than compared to biaxial strains as observed in Refs.25.In particular, we observed only nitrogen mono vacancy with self or carbon interstitial (NThe quantum emitters found to hold its ZPL Lorentzian shape (signature of quantum emission) without deforming, throughout the possible tunability range from lower to higher energy region, for all the strains induced.Different luminescent point defects exhibit different tunability range and different respondence for different strain values, which further confirms that each luminescent point defect has its own unique characteristics such as different fabrication processes and defect structure orientations, different energy gaps between intermediate energy states (created due to point defects), etc.21.While tuning the quantum emission towards lower and higher energy regions by inducing various external strains, we observed that, all of the defects exhibit either increase or decrease in intensities of Lorentzian shaped ZPL peaks in the optical emission spectrums. This increase or decrease in intensities while tuning the quantum emission was also observed in earlier experiments and DFT computational works39 and this increase or decrease in intensity will convey the increase or decrease in emission rate, while quantum tuning by external strain inducement.Conventionally, this ZPL intensity represents the emission rate (photons emitted per second)In elucidation at atomic level, the significant reason behind this shifting and tuning of emission spectrum from luminescent point defects is due to its alter and deformation of crystal structure due to external strain inducements.Predominantly, we have observed the deformation in atomic bond lengths of luminescent point defects for different strain inducements. In this article, we present some of the point defects whose bond lengths are deformed due to external strain inducements, which are responsible for their tuning their emission spectrum towards lower and higher energy regions.B point defect, due to biaxial strain inducements. Figure B defect and their corresponding bond lengths, under zero strain condition .Figure B point defect crystal bond lengths due to positive biaxial strain inducements. Figure B point defect crystal bond lengths due to negative biaxial strain inducements.Figure As the change in bond lengths were clearly observed, we can find that for positive biaxial strain inducements the crystal bond lengths were found to increase than compared to bond lengths of point defects (under no strain conditions). This increase in bond lengths can be significant reason for point defects bandgap modulation (decrement in bandgap) and corresponding shift of emission spectrum towards lower energy region.Similarly, for negative biaxial strain inducements the crystal bond lengths were found to decrease than compared to bond lengths of point defects (under no strain conditions). This decrease in bond lengths can be significant reason for point defects bandgap modulation (increment in bandgap) and corresponding shift of emission spectrum towards higher energy region.BVN and CBVN) for positive and negative biaxial strain inducements and the variation in bond length schematics was presented in Figs. We also examined the crystal bond length deformation of point defects , we have observed the increment in bond lengths for positive biaxial strain and decrement in bond lengths for negative biaxial strain, same as the behaviour observed for VB point defect as shown in Fig. For the point defects  due to positive biaxial strain and blue-shifted quantum emission for decrease in all bond lengths of point defects due to negative biaxial strain inducements was observed.As per our surveillance, the symmetrical relation of red-shifted quantum emission for increase in all bond lengths of point defects  of 2D hBN as shown in Ref.This spin type can be either spin-up ↑ or spin-down ↓ and all luminescent point defects  and other recent methods could accurately characterize the properties of luminescent point defects such as excited states structures, spin–orbit and hyperfine couplings, which is beyond the ability of DFT studies46, whose transitions resemble single photon emission possibilities. As per our DFT simulations, VB defect exhibits greater tunability towards deep solar blind (UV-C) region and their corresponding hyperfine coupling of degenerate states were also computed using GW-BSE calculations also estimated recently as in Refs.48.Mono and di-vacancy defects whose emissions are found to be around 4 eV, revealed the presence of electron fully occupied, half-filled and un-occupied energy states in excited state’s structure calculations using GW approximations as shown in Ref.49 and in such process spin–orbit and hyperfine coupling of CBVN defect were also examined as in Ref.49. Contemporary findings from GW approximations were that, as similar to other 2D materials and their corresponding defects, the optical transitions associated to the defects in hBN are also dominated by excitonic effects50. Among the pool of defects, only NBVN defect exhibits highest likelihood in correlating their atomic structure with photophysical characteristics as per GW-BSE approximations50. These deep calculations revealed, the strong dependence of its radiative properties on the small perturbations of the atomic structure of NBVN defect.The accuracy of defect levels was examined by calibrating the individual levels against ab-initio CCSD(T), EOMCCSD, CASPT2, and MRCI calculationsWe re-performed the strain inducement simulations by setting all the DFT simulation parameters to same, but assigning the spin to un-polarized conditions and we obtain all most similar tunability of quantum emitters with small variations in emission energies and their tunable quantum emission were shown in Fig. B defect)51, is also an efficient UV quantum emitter. Hence, we also examined the tunability of CB defect through external strain, and as predicted CB defect exhibits greater tunability towards lower energy region compared to its tunability towards higher energy region as shown in Fig. Earlier literatures reported that boron replaced by carbon  was observed for un-polarized spin calculations than compared to spin polarized DFT computations. In order to examine the stretchability property of 2D materials, we also simulated positive and negative biaxial strain inducement simulations (under spin un-polarised conditions) on NALVN defect52 formed in 2D AlN  material and we obtained the tunability as observed in Fig. For CBO2 and VB defects found to exhibit the quantum emission tunability for the external strain, to the wavelength range of 1589.5 nm and 255 nm respectively, which strengthens the successful implementation of quantum key distribution for longer and short-range distances via optical fibers and free-space channels, respectively. Rest of significant quantum emitters  reveal the quantum emission tunability from UV-A to near-IR region and solitarily NBVN defect projects quantum emission tuning through the core of visible region, which enhances the implementation of quantum photonic devices. The corresponding PDOS graphs of unstrained and strained luminescent point defects gives a back support to confirm the quantum emission tunability through external strain inducement. And to the great extent, irrespective of its time-consuming, a more complex GW calculations approximation of all luminescent point defects is necessary to more accurately characterize the properties such as excited state’s structure, spin–orbit and hyperfine couplings etc. Further, experimental validation is needed to practically assess this quantum emission tunability and inspect their single photon purity and the properties as mentioned above. Our outcomes may advise the experimentalists the practical implementation of quantum emitters with customized emission wavelength or hammer out absolute UV-C to telecom (C-band) wavelength emission on a single host material, which enhances to establish the robust QKD based quantum information technologies.To summarize, we confirm that quantum emitters in layered hBN are the potential candidates to cover the single photon emission from telecom (C-band) wavelength range to solar blind (UV-C) region. The natural hyperbolic and high stretchability properties of 2D hBN, allows to induce controllable external strain to high orders and customize the quantum emission wavelength. By constrained DFT computations, we simulated inducement of biaxial and constrained normal strains  to the quantum emitters, which are considered as promising single photon sources. Particularly, VSupplementary Information.


DNA damage response pathways meet endocrine systems RT is to provide a comprehensive, state-of-the-art overview of current trends and approaches in the analysis of DNA damage in the specific context of endocrinology. DNA damage affects all major cellular processes. Investigation of the impact of DNA damage on disease has dramatically expanded over the past few decades. The DNA damage response and DNA repair pathways were predominantly examined in the framework of cancer research. Lessons learned from the biology of DNA damage generated therapeutic opportunities that were successfully implemented in clinical oncology. Besides cancer, DNA damage is being also investigated in other biological areas, including aging, reproduction and the endocrine system. Dissecting the mechanisms that are responsible for the DNA damage response in endocrine systems is an important novel area in the field of endocrinology.The aim of the Characterization of the CpG island methylator phenotype subclass in papillary thyroid carcinoma” Gu et al identified two distinct methylation subgroups among papillary thyroid carcinoma patients. Subgroups were termed: (i) the ‘CpG island methylator phenotype’ (CIMP) subgroup (elevated rates of DNA methylation); and (ii) nCIMP subgroup (reduced rates of DNA methylation). Authors investigated the impact of the different methylation patterns on patient’s prognosis, immune profiles and response to immunological therapy or chemotherapy. Authors suggest that ‘CIMP might serve as a tool for risk stratification and help to make medication guide for patients of different subtypes’.In an article entitled “Integrative analysis reveals novel associations between DNA methylation and the serum metabolome of adolescents with type 2 diabetes: A cross- sectional study” Agarwal et al conducted a cross-sectional investigation of DNA methylation in blood mononuclear cells from adolescents with type 2 diabetes with serum metabolomic data. The aim of the analysis was to explore modifications in the epigenetic landscape of white blood cells that might correlate with an affected serum metabolome. Authors identified differentially methylated regions in associations with a number of important metabolites in patients. Among others, metabolites include the upstream transcription factor-2 (USF2), free fatty acid receptor-1 (FFAR1), etc. Authors conclude that ‘data may help generate new hypotheses to investigate the mechanisms that influence the metabolomic profile of adolescents diagnosed with T2D’.In a paper entitled “A comparison of DP-TOF Mass Spectroscopy (MS) and Next Generation Sequencing (NGS) methods for detecting molecular mutations in thyroid nodules fine needle aspiration biopsies”  authors compared DP-TOF, a DNA MS platform, and NGS methods for detecting multiple gene mutations (including BRAFV600E) in aspiration fluid from 93 patients. Authors suggest that ‘the MS method can be used as an inexpensive, accurate, and dependable initial screening method to detect genes mutations and as an adjunct to clinical diagnosis’.Mutations in the B-Raf proto-oncogene (BRAF) are associated with a variety of solid tumors, including papillary thyroid carcinoma. In a paper entitled “EWS gene and one of the members of the ETS gene family. EWS is the second most common tumor of soft tissue and bone in children and adolescents and has a high propensity for metastasis. Disruption of DNA methylation patterns was shown to impact EWS etiology. In an article entitled “Novel targeting of DNA methyltransferase activity inhibits Ewing sarcoma cell proliferation and enhances tumor cell sensitivity to DNA damaging drugs by activating the DNA damage response” Cristalli et al evaluate the efficacy of MC3343, a quinoline-based DNA methyltransferase (DNMT) inhibitor with high activity against cancer cells, including EWS. Authors provide evidence that MC3343 impairs DNMT1 expression but does not influence methylation of EWS cells. Authors conclude that ‘MC3343 slowed proliferation, induced DNA damage and cell death, and acted synergistically with other DNA damaging drugs, thereby indicating its potential use as an interesting adjuvant therapeutic agent against EWS’.Ewing sarcoma (EWS) is a poorly differentiated tumor with characteristic reciprocal chromosomal translocation, involving the in vitro fertilization (IVF) by sperm cells exhibiting DNA fragmentation is reported in a paper entitled “The effect of sperm DNA fragmentation on in vitro fertilization outcomes for women with polycystic ovary syndrome” . Authors provide evidence that oocytes fertilized using sperm with a high DNA fragmentation index ‘led to a lower high-quality blastocyst formation rate but had no influence on fertilization, high-quality embryo, clinical pregnancy and miscarriage rates’.Polycystic ovary syndrome (PCOS) is a female endocrine disorder associated with poor pregnancy outcomes. It is unknown whether sperm quality affects pregnancy of PCOS patients. The consequences of oocyte Li et al evaluated the embryo quality and reproductive potential of oocytes from overweight women upon fertilization with sperm with different degrees of DNA fragmentation. The paper, entitled “Decreased DNA repair ability: A mechanism for low early embryonic development potential of oocytes from overweight patients after fertilization in IVF cycles”, is based on 1,612 patients undergoing fresh autologous IVF. Patients were divided into two categories according to their BMI . Groups were subdivided into two subgroups according to sperm DNA fragmentation index [low (LF) versus high (HF) fragmentation]. For the normal weight group, there were no differences in embryo quality and reproductive potential between the LF and HF groups. However, in the overweight group, the HF subgroup exhibited lower fertilization rates, blastocyst development rates and high-quality blastocyst rates, despite similar pregnancy rates. Authors conclude that ‘decreased DNA repair activity in oocytes may be a possible mechanism for the low early development potential of embryos from overweight patients in IVF cycles’.The impact of female body mass index (BMI) on the DNA repair ability in oocytes after fertilization is unknown. Yao et al conducted an analysis of DNA methylation and RNA array data aimed at identifying thyroid cancer-specific DNA methylation markers. The article, entitled “Integrative analysis of DNA methylation and gene expression identified follicular thyroid cancer-specific diagnostic biomarkers”, was based on 14 FTC versus 16 benign thyroid lesions. Authors identified four DNA methylation sites that probably, might be used for screening and identification of FTC patients. Authors emphasize ‘the potential use of methylation markers in FTC diagnosis’.The diagnosis of follicular thyroid carcinoma (FTC) is very complex given the fact that commonly used screening methods could not diagnose FTC preoperatively. In summary, the feedback and feedforward regulatory mechanisms linking the endocrine systems to the DNA damage response pathway play central roles in various human disorders. The collection of papers presented in this RT further advances the understanding of intricacies of this system and how cells, tissues and organs modulate their responses and preserve homeostasis in the face of ever-changing conditions. Given their importance, endocrine system/DNA damage response biology is an intensely studied field, nevertheless many fundamental questions remain unanswered. For example, how coding and non-coding RNAs responses are coordinated by the endocrine system to avoid DNA-damage stress, what underlies the tissue-specific DNA damage responses, and how do cells modify their responses during cell division. Seeking answers to these and other questions is a fundamental research field for the near future.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.