The electronic and optical properties of single-layer (SL) tungsten disulfide (WS Since SL TMDs are semiconductors with a direct band gap4, they can be used to build transistors and optoelectronic devices. Since the band gap is in the visible regime, photodetectors and solar cells can be developed. Growth processes typically introduce defects and impurities in SL TMDs with profound effects on their electronic, optical, and magnetic properties7.Single-layer (SL) transition metal dichalcogenides (TMDs) are very attractive materials because of their special electronic and optical properties that enable lots of promising applications10, which are naturally occurring during different growth processes, such as mechanical exfoliation (ME), chemical vapor deposition (CVD), and physical vapor deposition (PVD). A central result of our papers is that group theory can be used to derive strict selection rules for the optical transitions, which are in excellent agreement with the susceptibility calculated by means of the Kubo-Greenwood formula using the Kohn–Sham orbitals.Over the past few years we have developed theoretical models based on density functional theory (DFT), tight-binding model, and 2D Dirac equation for the description of the electronic and optical properties of vacancy defects in TMDs10 we performed DFT calculations and obtained the optical spectrum of SL WS11 and wafer-scale layered Yb/Er co-doped WSe12. Similar results have been found by López-Morales et al.13. One of our motivations was to find out whether some of the LIS of Er lie within the band gap of SL WS14. By replacing YAG with the calcium tungstate CaWO15. Thus, it is advantageous to identify host materials for REAs with low concentrations or even free of paramagnetic impurities and nuclear spins. We argue here that TMDs are good candidates for such host materials.In our recent paper in Ref.10, we calculate the electronic and optical properties of Ho17. Laser systems that operate in the 2 18.Here, following Ref.The goal of this paper is to demonstrate the existence of localized Ho spin–orbit states inside the bandgap of WS19 for exchange-correlation functional. Fully relativistic noncollinear and spin polarized DFT calculations were performed as implemented in the Synopsis Atomistix Toolkit (ATK) 2021.0620. For Hon enumerates different bands. The sampling of the Brillouin zone was done for a supercell with the equivalent of a 32All Numerical calculations are carried out by using DFT and with the use of Perdew–Burke–Ernzerhof (PBE) generalized gradient (GGA) parametrization11, and Er:WeSe12.Using DFT, we obtain a cohesive energy for pristine WSGiven the difference in atomic radii of Ho (1.75 Å) and W (2.1 Å), relaxing the Ho:SL WS24. The crystal structure of SL WSd-Orbitals of the W and t and b denoting the top and bottom layers) of the S atoms give the largest contribution to the conduction and valence band structure of SL WS25. Based on the We first obtain the results for bandstructure and electric susceptibility for pristine WSmentclass2pt{minim23, it is known that valence and conduction bands are primarily made from Using first principle studiesmentclass2pt{minimThe isolated Ho atom has 11 4f electrons which are shielded by the outer 5sThe bandstructure of WSentclass1pt{minima26 it has been shown that presence of Ho26, where a long-range magnetic interaction is seen. The reason is that we consider a much larger supercell of The Kramers theorem states that for every energy eigenstate of a time-reversal symmetric system with half-integer total spin, there is at least one more eigenstate with the same energy. In other words, every energy level is at least doubly degenerate if it has half-integer spin. It can be seen that Kramers degeneracy, which is a consequence of time reversal symmetry, is broken for LIS in Ho28, the irreducible representations (IRs) of which are shown in Table The Hoentclass1pt{minimaf orbitals of Hop orbitals of the nearest neighboring S atoms and from the d orbitals of next-nearest neighboring W atoms are present. This means that in the Hilbert base spanned by 10. The resulting eigenstates, identified by their IRs of 29.A Hoentclass1pt{minimaentclass1pt{minimaf orbitals couple to both the p orbitals of nearest neighboring S atoms and d orbitals of next-nearest neighboring W atoms. The resulting MOT diagram including Ho LIS is shown in Fig. f orbitals and the W d orbitals, as can be seen in the bandstructure in Fig. Analyzing the PDOS, it becomes obvious that the Ho entclass1pt{minimaentclass1pt{minima30. We evaluate the matrix elements of the dielectric tensor in three dimensions (V the volume of the crystal, f the Fermi function, and Since the f-orbital contribution to the LIS is large, the optical spectrum exhibits narrow peaks, reminding of atom-like optical transitions. The relative dielectric functions 9, which has later been experimentally confirmed32. This difference has also been verified theoretically by means of DFT calculations with GW correction and the solution of the Bethe-Salpeter equation for in-plane and out-of-plane excitons for similar crystals33. The band structure for pristine WS35.For pristine SL WSmentclass2pt{minimmentclass2pt{minimmentclass2pt{minim18.Alternatively, it is possible to use the conservation of angular momentum to derive the optical selection rules. In pristine SL WSGiven the point group symmetry of impurities in a crystal, the LIS transform according to its IRs. In the case of the Hoentclass1pt{minimaOur results of electronic and optical properties of HoW has a weak abundance of 14% of nuclear spin (The location in the direction perpendicular to the plane of the 2D material of the rare-earth impurities is accurate on the atomic level. By contrast, in 3D materials, such as GaAs and diamond, impurities and defects are spread throughout the 3D materials. Therefore we expect enhanced quantum sensing due to accurate distance to target atoms.362D materials have clean surfaces, in stark contrast to diamond that hosts dark P1 nitrogen impurities with nuclear spins and surface spins. The spin coherence time of shallow NV centers in diamond within 30 nm of the surface degrades drastically due to increased electric and magnetic noise. Diamond surfaces are difficult to be etched and polished in a controlled way due to diamond’s hardness.Ce14. This is relatively long considering that 37. This would allow for 15. In principle, this would allow for Atom-like sharp optical transitions suggest that the decoherence time should be very long, which is one of the main criteria for a spin qubit. As mentioned in the introduction, by choosing a host material free of paramagnetic impurities and nuclear spins, it would be possible to substantially increase the spin coherence time of the impurity spin, in this case the spin of a Ho38 a six-hour coherence time for optically addressable nuclear spins in EuSince WSThese advantages suggest that REAs embedded in 2D materials made of TMDs might be vastly superior to GaAs spin qubits and NV centers in diamond and could pave the way to realizing scalable quantum networks, scalable quantum computing, and ultrasensitive remote quantum sensing.


The first wave of the COVID-19 pandemic has produced remarkable effects on the sleep quality and mental status of the general population and more dramatic effects on patients with chronic illness. Patients with obstructive sleep apnea (OSA), already suffering from disordered sleep, might be more susceptible to the effect of the pandemic on their sleep quality and mental health. We therefore performed a case–control study to compare sleep quality, depression and anxiety symptoms reported by patients with severe OSA and age-matched healthy subjects during the first wave of the COVID-19. In June–July 2020 we enrolled a total of 222 patients with severe OSA, all treated with continuous positive airway pressure, and 164 healthy controls. Self-reported sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Symptoms of depression were assessed using the Patient Health Questionnaire module 9 (PHQ-9), while the specific “Coronavirus Anxiety Scale” (CAS) evaluated the level of anxiety.2 = 0.81) and the CAS score (r2 = 0.65).Patients with OSA  and healthy controls had similar characteristics except for BMI slightly lower in controls. The perceived quality of sleep, referred to the pre-pandemic period, was significantly worse in patients with OSA than in controls. During the pandemic the rate of reported sleep disturbance increased from 54 to 66% in patients with OSA and from 29 to 40% in controls. A high percentage of patients and controls reported symptoms of depression (61% OSA and 65% controls), whereas lower levels of anxiety, similar in the two groups, were observed. In patients with OSA the PSQI score significantly positively correlated with the PHQ-9 score (rThe rate of reported sleep disturbance in patients with OSA during the first wave of the COVID-19 pandemic is one of the highest evidenced in literature so far. As for the general population, in these patients there is a strict link between the perceived sleep quality and the psychological distress caused by the pandemic. A further deterioration of sleep quality is a fearsome event in the life of these patients who face life-long sleep problems. Since its onset in December 2019, the ongoing COVID-19 pandemic has deeply affected worldwide people’s physical and mental health –6. SleepObstructive Sleep Apnea (OSA) is a chronic condition, acknowledged as major cause of sleep disturbance in the middle-aged population, in whom chronic sleep disruption is cause of psychological symptoms including anxiety and mild to severe depression. , 11. AltIn Italy, the first wave of the COVID-19 pandemic refers to a period between March and June 2020. This observational case–control study has been conducted in the Centre for Sleep Disorders, Respiratory Unit, University of Catania, between June and July 2020. During these 2 months we had a particularly high number of patients attending the Centre due to re-opening after the lock-down period. The study was carried out on the day on which patients with OSA using CPAP, all of them already followed in our centre, attended their scheduled follow-up visit. In fact, according to our local protocol, after the first year of CPAP treatment, patients attend a follow-up visit every year to undergo polygraphy, check compliance and for clinical evaluation. From a total of 231 patients attending the follow-up visit between June and July 2020 and considered eligible according to inclusion criteria, 5 patients refused to participate and 4 were unable to fill the questionnaires, so that 222 patients were finally included. We considered this sample to have sufficient power to detect differences between the groups, considering previous published data on the patient-reported outcomes that we were assessing , 19. It In this study we included patients with a diagnosis of severe OSA treated with nocturnal CPAP from at least 1 year. Inclusion criteria were: (1) apnea–hypopnea index (AHI) > 30 at diagnosis; (2) efficacy of CPAP assessed with a nocturnal polygraphy; (3) good compliance to the treatment assessed by records generated by the machine’s counter/software or by a remote monitoring software; (4) ability to fill the questionnaires and to sign informed consent. Exclusion criteria were: (1) patients with known psychiatric disorders or precedent symptoms of depression or previous use of any hypnotic or psychiatric drug; (2) patients in whom OSA was associated with any chronic neurological disorder; (3) patients with OSA uncontrolled by CPAP therapy. Healthy subjects, reporting no chronic illness, matched for age were used as controls. Controls were volunteers also recruited using advertisements and social networking sites. Data from controls were also collected, during June and July 2020.Patient’s demographic and clinical records were available in our database since the diagnosis was made. In the study day clinical data were updated and the Epworth Sleepiness Scale (ESS) was performed to evaluate somnolence. The regular use of CPAP was assessed using records generated by the machine’s counter/software or by remote monitoring software. All data for the study were collected during one single visit. The patients were first invited to recall their sleep habits and quality before the pandemic onset and to fill a PSQI questionnaire (pre) as accurately as possible. Successively the patients were invited to fill a second PSQI questionnaire (post), focusing on their sleep quality in the months after the onset of the pandemic. Successively, two more questionnaires on symptoms of depression and anxiety experienced during the pandemic period were administered. A staff member was present to provide assistance if required. A single study day was also scheduled for controls. During this day demographic data and clinical history to exclude chronic illness were collected. The controls were asked to fill the same questionnaires filled by the patients, including the ESS, and an identical procedure was followed.During the visit patients were informed that the questionnaires they were asked to fill were for research purpose and all signed an informed consent for collection of data and publishing. Also controls signed the same informed consent in the day they filled the questionnaires.Sleep quality in patients and controls was evaluated using the PSQI . This is“Coronavirus Anxiety Scale” (CAS) a recently developed specific tool to assesses physiologically-based, dysfunctional anxiety symptoms associated with the fear of COVID-19 [The level on anxiety was assessed by the COVID-19 . This fiCOVID-19 . HoweverCOVID-19 . The valCOVID-19 .To assess symptoms of depression we used the depression module of the Patient Health Questionnaire (PHQ), a well-known self-administered diagnostic instrument for common mental disorders. Specifically, the PHQ-9 is a module containing 9 items on a four-points scale (0–3). The test is commonly used as a screening tool for depression in primary care and it has been widely validated in the community. Cut-off point are: 5–9 mild depression, 10–14 moderate depression, ≥ 15 severe depression .The study has been approved by the local ethical committee and signed consents to participate and to publish data were obtained for all participants.2 test. Pearson correlation test was used when appropriate. Multiple logistic regression analysis was used to determine independent predictors of poor sleep quality. P value was significant when < 0.05. Statistic was performed using SPSS software 14.0 .Descriptive statistic was used for demographic data presented as mean ± standard deviation (SD) or percentage for each sub-group. Differences among groups were analyzed using the appropriate t-test for unpaired or paired data. Categorical variables were analyzed using χWe enrolled a total of 222 patients with OSA and 164 healthy controls. Demographic data of the study population are shown in Table During the first wave of the COVID-19 pandemic neither patients with OSA nor healthy subjects significantly changed their sleep habits. In the group with OSA 16% delayed bedtime and 21% anticipated by about 30 min, but most of them reported no change. In the control group only 9% anticipated while 15% delayed bedtime. The number of hours of sleep per night (6–7 h) was similar in the two groups and did not change during the pandemic, although sleep latency increased to a similar extent in both groups compared to the pre-pandemic period (Table P < 0.001). In both groups the mean PSQI score significantly increased during the pandemic  (Table P < 0.05), whereas in the control group the rate of poor sleepers increased from 29 to 40% (P < 0.05)  reported an abnormal level of anxiety  . In most of the cases symptoms of mild depression were complained, however a higher number of healthy subjects reported symptoms of moderate to severe depression compared to patients  Table .P < 0.05). Linear regression analysis showed that the PSQI score significantly positively correlated with the CAS score  and the PHQ-9 score   is exceptionally high. In these patients we showed a strict correlation between sleep disturbance and the level of anxiety and depression caused by the pandemic. The prevalence of these symptoms did not differ between OSA and healthy subjects.To our knowledge this is the first study investigating the effect of the COVID-19 pandemic on perceived sleep quality and psychological stress in patients with obstructive sleep apnea. Anxiety, depressive mood and sleep disturbance have been broadly reported during lockdown periods following the first wave of the COVID-19 pandemic, from March to June 2020 , 5, 6. TItaly, where this study was carried out, has been the gateway of the pandemic to Europe in February 2021. For this reason, in this country, one of the highest level of emotional distress in the world has been recorded. Casagrande et al. in an early study showed that, after the COVID-19 outbreak, among 2291 subjects from the general population, 57.1% complained poor sleep quality. A significant relationship was evidenced between sleep quality and generalized anxiety or symptoms of post-traumatic distress . These dOne first observation is that during lockdown periods home confinement has produced a change in people’s sleep habits as generally the population confined at home delayed bed-time and slept longer than usual . HoweverAn altered sleep pattern is an hallmark of untreated OSA and up to 100% of the patients report a subjective sensation of poor sleep quality with a PSQI score well above the cut-off limit . TreatmeThis is the first study addressing sleep issues during the pandemic in OSA, however few previous studies have been carried out in patients affected by other chronic conditions –28. One Another recent study evaluated the impact of the COVID-19 pandemic on patients with at least one chronic non-communicable disease including hypertension, diabetes, cardiovascular or respiratory disease. Compared to healthy controls, people with such chronic conditions had a 36% greater chance of impaired sleep, strictly associated with a state of emotional stress . The higIn conclusion, our data indicate that in patients with severe OSA treated with CPAP the quality of sleep, already poor before the pandemic, dramatically worsened after the onset of the COVID-19 pandemic. The prevalence rate of perceived sleep disturbance that we found in OSA is the highest reported in the literature, among healthy individuals or patients affected by other chronic diseases. During the first wave of the pandemic the level of emotional stress in patients with OSA did not differ from healthy subjects and was strictly associated with the occurrence of sleep disturbance. A further deterioration of sleep quality is a fearsome event in the life of patients who face life-long sleep problems, therefore great attention must be paid to their mental health.


Torsemide is a widely used diuretic in clinical practice. In this study, pharmacokinetic (PK) and pharmacodynamic (PD) simulations of torsemide for various population groups and exposure scenarios were performed through human-scale physiologically-based PK-PD (PBPK-PD) modeling of torsemide. For PBPK-PD modeling of torsemide, invitro and clinical data of torsemide reported previously were used. After exposure to clinical doses of torsemide, observed plasma (or serum) concentration and urine torsemide excretion profiles were used as PK-data, and observed urinary sodium excretion rate was used as PD-data. The model was then extended to take into account physiological and biochemical factors according to different CYP2C9 phenotypes or patient populations. The established model captured various torsemide clinical results well. Differences in torsemide PKs and PDs between patient groups or CYP2C9 genetic polymorphisms were modelologically identified. It was confirmed that degrees of differences in torsemide PKs and PDs by disease groups were greater than those according to different CYP2C9 phenotypes. According to torsemide administration frequency or dose change, it was confirmed that although the difference in plasma PKs between groups  could increase to 14.80 times, the difference in PDs was reduced to 1.01 times. Results of this study suggested that it is very important to consider disease groups in the setting of torsemide clinical therapy and that it is difficult to predict PD proportionally with only differences in PKs of torsemide between population groups. The PBPK-PD model established in this study is expected to be utilized for various clinical cases involving torsemide application in the future, enabling optimal drug therapy. Although clear evidence is lacking, this might be related to a decrease in the interaction between the transporter and torsemide due to increases in endogenous transporter inhibitors in CHF patient groups. For example, it has been reported that endogenous nitric oxide synthase inhibitors are increased in CHF patients  were 0.35–3.47%. These variations were not statistically significant . Proportions of CYP2C9 and OATP1B1 in overall torsemide PK-variabilities  were approximately 90–99% and 1–10%, respectively. Considering that potential covariates might not have been explored yet and PK-variability between individuals even within PK-differences due to different OATP1B1 phenotypes, the effect of OATP1B1 on torsemide PK-diversity was expected to be significantly lower than that of CYP2C9. 0-∞ according to a phenotypic combination of CYP2C9 and OATP1B1. As a result, in this PBPK modeling study, model simulations were mainly performed according to genetic polymorphisms of CYP2C9. Results according to CYP2C9 phenotypes were relatively more clearly accessible than quantitative reports on differences in transporter expression and activity according to OATP1B1 phenotypes. Since the in vivo metabolism of torsemide is mainly due to CYP2C9 . This might be related to the delay in the distribution from the initial absorption phase to the drug effect compartment after oral administration of torsemide. On the other hand, when torsemide was administered intravenously, there was no significant time difference between torsemide concentration and efficacy in healthy adults, cirrhosis patients, or CHF patients. These results are related to the direct transfer of torsemide to the site of action without a separate absorption process for intravenous administration (as bolus), unlike oral administration. Two-dimensional plots between the torsemide urinary excretion rate and urinary sodium excretion rate did not reveal any major time difference in healthy adult populations, cirrhosis patients, or CHF patients, regardless of the route of administration. As a result, considering the relationship between PKs and PDs of torsemide comprehensively, it was determined that the PK-PD relationship was closer to an instantaneous response (as a simple direct effect model) that showed an immediate effect than a delayed response. Therefore, it could be inferred that torsemide transferred into the blood was transported to the target very quickly to exert its drug effect. 0–∞ and Cmax and urine torsemide cumulative excretion values showed a difference within two-fold from the observed values. With regard to PDs, simulated values of sodium excretion rate in urine over time after torsemide administration showed a difference within two-fold from observed values. Two-fold error values were estimated as ratios between parameters or outcomes predicted by the model and parameters or outcomes calculated by observed values. Final two-fold error values were considered suitable only if they were between 0.5 and 2. As a result of checking the RMSE for judging the model fit using the residual degree between each individual observation value and the model prediction values, all values of torsemide PKs and PDs were below 100. As a result of the AIC check known to judge model fit by comprehensively considering the complexity and performance  of the model, all values of torsemide PKs and PDs were below 200. These model validation results suggested that the PBPK-PD model of torsemide established in this study well-fitted the observations overall. As a result of the normalized model sensitivity test for checking the range of change in the simulation result according to the change of model parameters, sensitivity values for AUC0–∞ and Cmax were all between +1 and −1, confirming that the normalized model sensitivity did not change according to the dose of torsemide. This suggested that parameters applied to the torsemide PBPK model established in this study were reflected at an appropriate level without being heavily biased on specific factors. As a result of the visual consistency check, it was confirmed that all observed torsemide plasma concentrations, urinary torsemide cumulative excretion amounts, and urinary sodium excretion rate values were in good agreement with values predicted by the PBPK-PD model. The developed torsemide PBPK-PD model was validated by a two-fold error, a quantitative comparison tool between simulated and observed values. As a result, all simulated values for torsemide plasma (or serum) AUCAs a result, it was found that the presented torsemide PBPK-PD model had characteristics as a universal model that could well explain changes in torsemide PKs/PDs  in various population groups . In this study, based on the PBPK-PD model of torsemide, we tried to suggest a precise drug therapy for CYP2C9 genetic polymorphisms and each disease such as cirrhosis, CKD, and CHF.The torsemide PBPK-PD model established based on clinical data was used to simulate PKs and PDs (of torsemide) in healthy adult populations with CYP2C9 genetic polymorphisms, CKD patients, cirrhosis patients, and CHF patients according to torsemide dosing intervals or doses. Model simulation results confirmed that the average plasma (or serum) concentration at steady-state and PDs (as the rate of sodium excretion through urine) increased by approximately three times when the dosing interval became shorter (from 12 h to 4 h) after torsemide was administered at multiple doses. In addition, it was confirmed that the difference between the minimum and maximum urinary sodium excretion rates (12.08–75.68 at 12 h and 66.97–95.83 at 4 h) at steady-state decreased by approximately two times as the torsemide dosing interval became shorter. This suggested that urinary sodium excretion could be increased by increasing torsemide dosing frequency in healthy adult populations.As a result of additional model simulations, it was confirmed that torsemide had to be administered more frequently or at higher doses in cirrhosis and CHF patient groups in order to obtain an effect similar to that of healthy adult groups in terms of PDs. That is, in the case of cirrhosis patient groups, when torsemide was administered at intervals of 8 h, it was confirmed that the average sodium urine excretion was similar to that of healthy adult groups administered at intervals of 12 h. In the case of CHF patient groups, it was confirmed that the average sodium urine excretion was similar to that of the healthy adult groups when the dose was five times higher (at 50 mg) than that of healthy adult groups with a frequency of 4 h. According to torsemide administration frequency or dose change, the difference in plasma (or serum) PKs between groups was 14.80 times (0.46 to 6.81). However, it was confirmed that the difference in PDs was reduced to 1.01 times (31.90 to 32.34). This was an important result, suggesting that differences in torsemide PKs in healthy adults and various patient groups did not reflect a proportional PD-effect. In other words, it implied that within the same categorical group, the PD-difference could be predicted in a proportional relationship only with PKs of torsemide. For different categorical groups , the PD-difference could not be easily predicted with PK-difference alone.A limitation of this study was that the parameter changes applied to predict torsemide PKs and PDs in the patient groups did not fully reflect all actual factors. In reality, many physiological and biochemical factors could change with large individual differences depending on patient groups. However, it was not suitable for the scale of this model to consider all physiological factors. In this study, modeling and simulation of torsemide PKs and PDs were performed by partially reflecting well-known systemic factors for each patient group. In order to explain all physiological phenomena as models, further experimental studies of parameter-related information as well as bulk-up of the model size to explain detailed body actions will be needed. Although the bulk-up of the model and the addition of detailed parameters will increase the complexity of the model, it will more precisely predict PKs and PDs of torsemide. Nevertheless, the established PBPK-PD model for torsemide in this study was applicable not only to healthy adult populations but also to various patient populations. This is very important in that it is a very simple and efficient modeling approach that could be widely applied to many exposure scenarios or clinical cases. Another limitation of this study was the limitation of the data that could be accessed. In particular, for PD-data of torsemide, it will be necessary to conduct clinical studies of cirrhosis and CHF patients with different severities (such as a very severe group). The torsemide PD-model could be further improved through clinical investigation of other effective factors besides urinary sodium excretion as a PD-indicator of torsemide. In addition, this study has limitations in modeling and simulating torsemide PKs and PDs according to the application of torsemide alone. In actual clinical practice, combining with other drugs is frequently performed. Thus, a quantitative prediction study considering its interactions with various drugs will be needed in the future. Such studies will expand its clinical applicability.In this study, a PBPK-PD model for torsemide was established based on several invitro and clinical data from healthy adults. By reflecting physiological and biochemical changes according to cirrhosis, CKD, and CHF patient groups in the model, PKs and PDs of torsemide for each patient group were further simulated. The PBPK-PD model established in this study captured well theresults of various torsemide clinical data overall. Simulation of torsemide PKs and PDs according to different CYP2C9 phenotypes in healthy adult populations confirmed that the effect of CYP2C9 genetic polymorphisms on torsemide PK and PD diversities was not as great as the difference between disease groups. The difference in torsemide PDs according to disease groups was larger than that of PK. The absence of PD proportional to the degree of PK-difference suggests that it is very important to consider disease groups during the clinical application of torsemide. According to the simulation results of the torsemide PBPK-PD model, it was necessary to increase the dose and frequency of torsemide administration for cirrhosis and CHF patients in order to show the same level of PDs as in healthy adults. The significance of this study was that it provided us an opportunity to predict PKs and PDs of torsemide for various groups and to establish quantitative clinical therapies based on modeling. The PBPK-PD model for torsemide established in this study can be expanded and applied to drug-drug interaction studies with other concomitant drugs.


While there has been significant research on the pressures facing acute hospitals during the COVID-19 pandemic, there has been less interest in downstream community services which have also been challenged in meeting demand. This study aimed to estimate the theoretical cost-optimal capacity requirement for ‘step down’ intermediate care services within a major healthcare system in England, at a time when considerable uncertainty remained regarding vaccination uptake and the easing of societal restrictions.Demand for intermediate care was projected using an epidemiological model (for COVID-19 demand) and regressing upon public mobility (for non-COVID-19 demand). These were inputted to a computer simulation model of patient flow from acute discharge readiness to bedded and home-based Discharge to Assess (D2A) intermediate care services. Cost-optimal capacity was defined as that which yielded the lowest total cost of intermediate care provision and corresponding acute discharge delays.Increased intermediate care capacity is likely to bring about lower system-level costs, with the additional D2A investment more than offset by substantial reductions in costly acute discharge delays . Results suggest that completely eliminating acute ‘bed blocking’ is unlikely economical (requiring large amounts of downstream capacity), and that health systems should instead target an appropriate tolerance based upon the specific characteristics of the pathway.Computer modelling can be a valuable asset for determining optimal capacity allocation along the complex care pathway. With results supporting a Business Case for increased downstream capacity, this study demonstrates how modelling can be applied in practice and provides a blueprint for use alongside the freely-available model code. Many health and care systems have experienced unprecedented pressures as a result of the global COVID-19 pandemic . With raEffectively managing intermediate care capacity is especially important in times of high COVID-19 incidence. First, insufficient capacity puts severe pressure on upstream services, propagating ‘blockages’ in patient flow that, in turn, lead to increased stress on the (more expensive) acute care bed base, emergency department overcrowding, cancellation of elective procedures, and ambulance offload delays , 11. SecThe objective of this study was to estimate appropriate capacity requirement for intermediate care services within a major English healthcare system at a time of considerable uncertainty in the determinants of patient demand during the COVID-19 recovery period, namely vaccination uptake and the easing of societal restrictions. In assessing the most appropriate capacity requirement, consideration was given to the cost of both intermediate care service provision and the acute capacity required to support any delays in discharging patients . The amount of intermediate care capacity yielding the lowest total cost was defined as the theoretical cost-optimal capacity requirement, whose estimate was sought by means of an empirically informed computer simulation study.In common with many health and care services around the world–particularly those following a European or North American model–intermediate care is used in the UK to ‘bridge’ the gap between acute hospital and the usual place of residence for individuals typically of older age and greater complexity , 19. TheIn the English National Health Service (NHS), the Discharge to Assess (D2A) model , one of Computer modelling has proved a useful resource in supporting effective healthcare management, with recent decades demonstrating a variety of influential case studies , 22. MucIn the few modelling studies that do consider the interaction between acute and community care, the scope is often restricted to a specific type of disease, such as stroke care, childhood asthma, or other chronic diseases , 29. YetDespite the recognised importance of intermediate care during COVID-19 , no modeThe Bristol, North Somerset and South Gloucestershire (BNSSG) healthcare system covers a population of approximately one million individuals in South West England. Acute services are provided by two hospital trusts and intermediate care is provided through D2A pathways by a single community services provider. At the time of the study (May 2021), the D2A pathways had high occupancy rates with all 546 of the available daily home visits being used in the P1 pathway, 85% of the 177 P2 beds in use, and all 172 of the available P3 beds in use. This contributed to significant delays to accessing the three pathways, with 64, 62 and 83 patients in acute care ready and awaiting discharge . Mean D2A lengths of stay were 13, 29 and 43 days for the P1-3 pathways, with respective standard deviations of 16, 22 and 31 days illustrating significant variation.Around the time of the study, new COVID-19 hospitalisations were reducing from their peak on 21 January 2021 which had followed the imposition of a national lockdown on 5 January 2021. While acute COVID-19 bed occupancy in BNSSG was just 1.4% of its 439 peak, much uncertainty remained regarding the easing of societal restrictions (which began 8 March 2021 and were due to end by 21 June 2021), and the uptake of the vaccine . Uncertainty also existed around the ability to reduce D2A lengths of stay to their target levels from actual durations that were considered to be too high and unaffordable in the longer term. For the BNSSG healthcare system, the concern was how these three aspects of uncertainty would affect future intermediate care demand, and thus determine appropriate capacity requirement.Scenario analysis was performed in order to examine the sensitivity of modelled capacity requirement to the above-mentioned aspects of uncertainty .On 22 February 2021, the UK government published its ‘roadmap’ for the easing of societal restrictions, with four incremental relaxations to take effect no sooner than 8 March, 12 April, 17 May and 21 June . At the In order to project intermediate care demand directly caused by COVID-19 infection, an epidemiological model of the ‘Susceptible-Exposed-Infectious-Recovered’ type was used . DevelopFor projections of intermediate care demand not directly caused by COVID-19 infection, a regression model linking non-COVID-19 emergency admissions to levels of public mobility was used . PreviouBoth the above demand models produced acute admission projections which were converted to D2A pathway demand through the following assumptions: a 6-day mean acute care length of stay; a 19% proportion of acute discharges requiring intermediate care; and a 54%, 20% and 17% split of intermediate care patients to D2A pathways P1-3 respectively . These values were estimated using data from the BNSSG system at the time of the study.Combining both the COVID-19 and non-COVID-19 components of projected demand yielded the total demand expected under the various scenarios . From thComputer simulation is considered a well-established and conceptually appropriate approach to modelling demand and capacity in healthcare systems , 22. In A separate model was constructed for each of the P1-3 D2A pathways and the eight scenarios considered . At the Simulations were run over a range of intermediate care capacity configurations, in order to reflect various choices or targets considered by healthcare managers and planners in the BNSSG health system. For each of these, the key output measure of interest was the total cost of both intermediate care service provision  and the acute capacity required to support any delays to discharge . In calculating this, the unit costs (per patient per day) used are £346 for acute and £125 for P1 , £150 foBaseline scenario, the estimated cost-optimal capacity requirements for D2A Pathways P1-3 are 700, 275 and 335 respectively . An example of this is the higher number of acute beds blocked accepted for P3 (mean 6.89) when compared to P1 (0.88) and P2 (2.68), given the 14:5:6:7 ratio between acute and P1-3 unit costs. Variability in acute discharge delays, alongside D2A service occupancy, is illustrated in Greater hospital demand, resulting from a reduction in vaccination uptake in the baseline assumption of 90% to 75%, is shown to increase cost-optimal D2A capacity requirement by between 7% and 11% ceteris paribus (Scenario 5 c.f. Scenario 1). Even with this additional capacity, and a 2–6% lower occupancy, the additional demand for D2A services leads to a 16% increase in mean acute discharge delays across the D2A pathways, with total costs rising by up to 11.4%. Additionally, if the end to societal restrictions is delayed by two months, then this decreases the number of hospital admissions (both directly and indirectly related to COVID-19) occurring within the remainder of 2021, leading to a reduction in the cost-optimal capacity requirement for the year (Scenario 7 c.f. Scenario 5). If, at the same time, length of stay can be reduced from those actually occurring at the time of the study to target levels, then the cost-optimal capacity requirement can be significantly reduced to levels similar to those at the time of the study . Thus, the effect of the greater demand for D2A services can be mitigated while at the same time attaining a more cost-efficient service with reduced acute discharge delays (meaning less wastage and improved patient experience).While there has been speculation that system-level costs can be reduced by greater downstream investment in complex care pathways, there has been a deficit of clear evidence to support these anecdotal claims. Through development and application of a conceptually appropriate computer model to a large health economy operating the D2A model of care used in the UK, our study demonstrates the potential value of increasing intermediate care capacity, specifically during recovery from the COVID-19 pandemic. Results show that the additional service provision cost is offset by savings associated with reduced delays to acute discharge, thus suggesting that balancing capacity across the complex care pathway is not a zero-sum game, and that net costs can be reduced through appropriate capacity allocation. Alongside financial advantages, further benefits of lower acute discharge delays–while not quantitatively assessed–are likely to extend to improved patient outcomes and experience through reduced medical complications and impacts on patient activation and independence.Results). This is explained by the cost of intermediate care provision increasing linearly with capacity, whereas acute discharge delay costs increase rapidly and nonlinearly below a certain level of capacity  acute care cost saving. Yet, as ‘date ready for discharge’ is not always recorded in acute hospital datasets, it is difficult to quantify the magnitude of this cost and thus set out the scope for potential savings in making any case for change. Some scale is, however, attainable from one relevant identified study which estimated that the national cost “ly £820m .The next main finding is that there are higher costs where intermediate care capacities are under the cost-optimal level than above it. Thus, from a practical standpoint, if there is doubt about the value of this level, it is better to pitch higher than lower in setting the intermediate care capacity requirement. Finally, given the economic need for at least some acute discharge delays, this study cautions any use of performance targets to completely eliminate acute bed blockages; instead, hospital managers should aim for an amount which reflects wider pathway performance. This may pose a challenge for health systems with insufficient integration of constituent organisations .For the healthcare system considered in this study, results were shared with senior managers on 2 June 2021. This was less than three weeks following the most recent input data (14 May 2021), with modelling and analysis performed rapidly in order to ensure relevancy. It should be acknowledged, and expected, that, given the paucity of past modelling in this domain (both within our system and more widely), a certain level of familiarity needs to be gained in crystallising practical understanding and actions. Combined with the pressures of COVID-19, this reduced the ability to associate particular decisions with model outputs in the short term. However, in the longer term, the modelled results  have played a central role in a Business Case (written in summer 2021) setting out increased D2A capacity requirements for the remainder of the year.The model and key results of this study will be especially portable to healthcare systems within the UK, given the common problem of acute discharge delays and widespread adoption of the D2A model of care , 20, 41.While it would be prudent to review all model parameters for applied use outside the UK, the model itself–open source and publicly available–would be expected to remain conceptually appropriate, given the similar ways in which intermediate care pathways are structured in UK and non-UK healthcare systems . These sAs a simplifying assumption, the computer model works on the basis of a ‘7 day’ operational service, with no effect of day of week on patient admission and discharge . The effect of this is to underestimate acute discharge delays, with the actual number of acute beds required being greater than that modelled  and, as well as being conceptually appropriate, it was straightforward to implement . Additional confidence was gained through having worked closely alongside NHS analysts, managers and clinicians throughout the project, thus increasing scrutiny at each step of the modelling journey. While not a comprehensive assessment of output validity, some attempts can be made. First, the mean D2A service occupancy  is broadFinally, a possible limitation of any study concerning a relatively novel viral disease arises from the evolving nature of both variants and available treatments. For complex discharge pathways, perhaps the greatest effect is on the volume of COVID-19 patients requiring intermediate care. As the 2021/22 Omicron wave has shown, a milder strain can significantly reduce numbers requiring hospitalisation . And newThere is a plethora of directions for future work. First, investigators may seek to quantify the impact of acute discharge delay on patient outcomes and experience, and thus develop a multi-objective analysis not fixated solely on cost. This would be expected to further penalise acute discharge delays, leading to a higher intermediate care capacity requirement.Second, in addition to considering ‘step-down’ care from acute to community care, the model could be extended to include ‘step up’ care . Given that community service providers have a fixed resource for addressing both such aspects of care, modelling could be useful in calculating the optimal demarcation.Third, the model could be extended further downstream into social care, as insufficient capacity here causes similar issues for intermediate care that intermediate care, in turn, causes for acute hospitals. With the recently published White Paper on the future of the NHS paving the way for enhanced health and care integration , healthcS1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(DOCX)Click here for additional data file.S4 File(DOCX)Click here for additional data file.


Prdm1 mutant mice are one of the rare mutant strains that do not develop whisker hair follicles while still displaying a pelage. Here, we show that Prdm1 is expressed at the earliest stage of whisker development in clusters of mesenchymal cells before placode formation. Its conditional knockout in the murine soma leads to the loss of expression of Bmp2, Shh, Bmp4, Krt17, Edar, and Gli1, though leaving the β-catenin-driven first dermal signal intact. Furthermore, we show that Prdm1 expressing cells not only act as a signaling center but also as a multipotent progenitor population contributing to the several lineages of the adult whisker. We confirm by genetic ablation experiments that the absence of macro vibrissae reverberates on the organization of nerve wiring in the mystacial pads and leads to the reorganization of the barrel cortex. We demonstrate that Lef1 acts upstream of Prdm1 and identify a primate-specific deletion of a Lef1 enhancer named Leaf. This loss may have been significant in the evolutionary process, leading to the progressive defunctionalization and disappearance of vibrissae in primates. The whisker follicles (or vibrissae—from the Latin vibrio) are complex, self-renewing sensory micro-organs loaded with multipotent epithelial stem cells localized on the snout ,2. TheseConserved throughout evolution, whiskers underwent a reduction throughout the primate adaptive radiation  and disaThe processing of whisker-acquired information occurs in the barrel cortex, where each whisker is represented by a discrete and well-defined cytoarchitectonic structure referred to as the barrel . The barPrdm1  is a zinc-finger transcriptional repressor ..Wnt1Cre Prdm1 in the developing barrel cortex—and thus that the barrel cortex phenotype can be ascribed to the loss of Prdm1 in the nervous system—we crossed Prdm1Cre with ROSAYFP mice and looked at YFP expression in the cerebral cortex  the primitive nasal cavity, (b) the vomeronasal organ, and (c) the tongue of five Lef1 KO embryos. Out of five Lef1 KOs, three domes did not express Prdm1. As for the remaining two embryos, we could observe Prdm1 expression in 2/28 and 4/27 domes  suggests that its regulatory region is located on the centromeric side of the gene in the adjacent gene desert  ,23human,Lef1. The analysis was conducted on whole micro-dissected whisker pads at E12.5 using primers positioned in the promoter of Lef1. The adult kidney was used as the negative control as Lef1 is not expressed in this tissue . We quantified the number of contacts from the Lef1 promoter to Leaf in the E12.5 whisker pad and compared them to the adult kidney, tissue in which Lef1 is expressed at low levels .In the E12.5 whisker pad, the promoter of w levels B. We fouLef1. Similarly, we showed a high statistical significance between the scores mapping Lef1 in the E12.5 whisker pad compared to the adult kidney , suggesting productive long-range interactions between Leaf and Lef1 in the whisker pad, confirming our observations from the specular viewpoint.In the reciprocal experiment, we scored the contacts from the murine Leaf enhancer with the promoter and coding sequence of Lef1 promoter (and vice versa).To validate Leaf as an enhancer, we then performed CUT&Tag  on E12 wAr) is active in the murine whisker mesenchyme during development [Ar in mice results in reduced growth of whisker follicles in mice without their full disappearance.It was recently demonstrated that a specific enhancer of the androgen receptor gene  is indispensable to induce Prdm1 expression, though the mechanism by which this occurs needs further investigation. We envision the cascade leading to whisker formation as a circuit where genes are activated in a specific sequence to start its formation and sustain its growth. As for the first dermal signal, Lef1 and subsequently Prdm1 represent the first genes of the circuit that trigger the successive phases .Our experiments clearly indicate that elopment . Intriguelopment , indicatPrdm1/Sox2 in the embryonic whisker mesenchyme gives rise to several lineages of the adult whisker, including the DP and DS, thus, representing a population of multipotent progenitors. This result explains the common inductive properties of the DP and DS, as reported by others [We show that the population of cells expressing y others . AdditioPrdm1 expression, the afferent branches of the infraorbital nerve do not organize into plexi surrounding the mesenchymal condensates but terminate as free nerve endings. Axonal guidance is most probably absent because of the lack of nerve guidance molecules secreted by Prdm1 positive cells. The Wnt1Cre driven Prdm1 KO (cKO2) mice lack almost all macro vibrissae, although they retain micro vibrissae; we can, thus, describe Prdm1 as strictly necessary for macro vibrissae development. Those conditional knockout mice have major rearrangements in the barrel cortex also affecting the representation of micro vibrissae with relevant evolutionary consequences.We demonstrate that in the absence of Lef1 that is specific to several primates  is flanking a well-conserved region among many mammals, altogether forming a regulatory element named Leaf. Using 4C-Seq analyses and H3K4me1 CUT&Tag, we have shown that Leaf is an enhancer in E12 embryonic whisker pads.King and Wilson  postulatPrdm1 cKO2 mice), as well as cheeks and eyebrows, humans are the only known mammals to have lost both. In the model we envisage, whisker loss was a multi-step process that started during the divergence of the species and that relied on the loss of tissue-specific regulatory elements of several genes involved in whisker formation. More specifically, the loss of Leaf and other putative enhancers might have contributed to the downregulation of the expression of genes fundamental for whisker development in the snout of primates, thus, contributing to whisker loss together with other mechanisms that have yet to be identified.While great apes have lost macro vibrissae, although retaining the micro vibrissae on lips (a phenotype reminiscent of our


Treatment options for patients with Human Epidermal growth factor Receptor 2 positive (HER2+) metastatic breast cancer are rapidly changing, especially for patients with brain metastasis. Historically, treatment options for brain metastasis were focused on local therapies, radiation and surgery. There are now multiple targeted therapies that are able to treat brain metastasis and prolong the lives of patients with HER2+ breast cancer. With the growing number of treatment options, making medical decisions for patients and clinicians is more complicated. This paper reviews the treatment options for patients with HER2+ breast cancer brain metastasis and provides a simplified algorithm for when to consider delaying local treatments.In the past 5 years, the treatment options available to patients with HER2+ breast cancer brain metastasis (BCBM) have expanded. The longer survival of patients with HER2+ BCBM renders understanding the toxicities of local therapies even more important to consider. After reviewing the available literature for HER2 targeted systemic therapies as well as local therapies, we present a simplified algorithm for when to prioritize systemic therapies over local therapies in patients with HER2+ BCBM.  Brain metastases (BMs) from solid tumors have classically been approached in a tissue agnostic manner with a focus on local therapy options. The presence of a BM has historically been considered an exclusion criterion for most systemic clinical trials due to the perception that BMs confer poor prognosis. Data from more modern cohorts challenge this notion, driven both by the availability of targeted and brain-penetrant therapies, and also by the improvement in magnetic resonance imaging (MRI) technology, which has increased early detection of small and clinically asymptomatic brain metastases. This led to the inclusion of patients with untreated and asymptomatic brain metastases in registration trials for novel therapies including tucatinib and trastuzumab deruxtecan (T-DXd). As a result, over the past three years, there is growing evidence of the radiographic and symptomatic response of breast cancer brain metastasis (BCBM) to systemic agents. The options of systemic therapy for treatment of BCBM have raised the question of when to use local therapy in HER2+ BCBM. This paper reviews the available literature for systemic agents for HER2+ BCBM, evidence and toxicities of local therapy and discussion of clinical situations where delaying local therapy may be favored. Determining the true incidence of BCBM is associated with our ability to detect BCBM. Early autopsy studies predating the clinical use of the MRI found the incidence of BCBM to be 30%. However, only 31% of pathologically confirmed BCBM cases had known clinical involvement during life and only 14% were felt to be the immediate cause of death [The incidence of BCBM varies by subtype as reported in a recent meta-analysis of articles published between 2000–2020, with the pooled cumulative incidence of BM being 31% for HER2+ and 32% for triple negative subgroup, while the hormone receptor (HR) was notably lower at 15% .Risk factors for BCBM established by The International Breast Cancer Study Group (IBCSG) include the presence of lung metastasis, HER2+ disease, hormone receptor (HR) negative disease and age < 35 . While sIn parallel with the increasing incidence of BCBM, the overall prognosis is improving in patients with HER2+ BCBM. Improved prognosis is likely driven by the targeted systemic agents as highlighted by a retrospective series of 123 patients with HER2+ BCBM divided patients into three cohorts by treatment years corresponding to the development of trastuzumab 1998–2007), lapatinib (2008–2012), and pertuzumab (2013–2015). Median survival improved from 3.6 to 6.6 to 7.6 years in successive cohorts [, lapatinCurrently, RANO-BM is the preferred criteria for evaluating the response of a BM and defines a measurable disease as greater than or equal to 10 mm . Using tTo date, there is wide variation in prospective studies of BCBM. Historically, only patients with BCBM treated with definitive radiation therapy (XRT) that were asymptomatic and stable on follow-up imaging were allowed in clinical trials. More recently, patients with asymptomatic, untreated, small BCBM or BCBM that have asymptomatic progression despite XRT have been included. Given the narrow scope of patients enrolled in clinical trials, the recently updated ASCO guidelines for management of HER2+ BCBM do not recommend trials of systemic therapy for newly diagnosed symptomatic BCBM . In clinTrastuzumab is a monoclonal antibody against the extracellular domain of HER2, which received initial approval in 1998 as the first HER2-targeted therapy. Unfortunately, standard dosing of trastuzumab has limited ability to cross the blood–brain barrier (BBB) as demonstrated by a study of patients with paired serum and cerebrospinal fluid (CSF) samples. The study collected CSF and serum samples before or after radiation and found that the baseline CSF:serum ratio of trastuzumab is only 1:420, which only improved to 1:49 after radiation . DespiteRecently, the phase 2 PATRICIA study tested high-dose trastuzumab (6 mg/kg intravenous weekly) with pertuzumab, a monoclonal antibody that blocks HER2 dimerization , in patients with progressive BCBM. In 39 patients, there were 4 PR and CNS ORR was 11% . NotablyLapatinib is a first-generation tyrosine kinase inhibitor (TKI) that acts as a dual-inhibitor of HER1/HER2 with the ability to cross the BBB. In patients with progressive BCBM following prior radiation, lapatinib monotherapy resulted in a 20% or greater decrease in diameter of BCBM in 21% of patients (only 6% when the response was defined as a 50% or greater reduction in longest diameter) . When thNeratinib is a second-generation TKI which acts as an irreversible pan-HER TKI with activity in BCBM, even in patient who were previously treated with lapatinib. The TBCRC022 trial evaluated both patients previously treated with lapatinib and patients who were lapatinib naïve with BCBM that were progressive despite radiation. In 37 lapatinib-naïve patients with HER2+ BCBM, neratinib-capecitabine resulted in an ORR of 49% and a mPFS of 5.5 months, signifying intracranial activity . It is nSubsequently, the phase 3 NALA study compared neratinib-capecitabine to lapatinib-capecitabine in metastatic HER2+ breast cancer in patients who had progressed on two or more HER2+ directed therapies . The stuTucatinib, a third-generation oral TKI that is selective for the kinase domain of HER2, was FDA approved in 2020. The registration phase 3 HER2CLIMB trial studied the addition of tucatinib or placebo to trastuzumab–capecitabine in patients with metastatic HER2+ breast cancer and had a prespecified endpoint of activity in HER2+ BCBM . The stuTrastuzumab emtansine (T-DM1) was the first antibody-drug conjugate (ADC) approved in second line for treatment of metastatic HER2+ breast cancer after progression on trastuzumab and pertuzumab, based on the EMILIA trial . This trTrastuzumab deruxtecan (T-DXd) is the second ADC to be approved for metastatic HER2+ breast cancer but differs from T-DM1 due to a cleavable topoisomerase I inhibitor intended to act on both HER2+ and nearby cells. T-DXd was first approved in 2019 as a third-line therapy for HER2+ mBC based on results from the phase 2 DESTINY-breast01 trial . HoweverThe future use of T-DXd is expanding with the results of the DESTINY-Breast04 trial, which evaluated survival of patients with mBC with low levels of HER2 (IHC1+ or IHC2+ with negative FISH) treated with T-DXd compared to treating physician’s choice chemotherapy (TPC). In patients with HR+ HER2 low mBC, the OS was 23.9 months for T-DXd vs. 17.5 months for TPC, and in the overall cohort it was 23.4 months vs. 16.8 months. Similarly, the mPFS was improved with T-DXd at 10.1 vs. 5.4 months in HR+ patients, and similarly improved in the overall cohort at 9.9 vs. 5.1 months . Of the Two trials have now specifically studied the utility of T-DXd in BCBM. The ongoing five-cohort DEBBRAH trial recently reported interim results for HER2+ BCBM, and the intracranial ORR for asymptomatic, untreated BCBMs was 50%, whereas for progressing BCBMs it was 44% . PerhapsSimilarly, the prospective single arm phase 2 TUXEDO-1 trial evaluated T-DXd activity in HER2+ patients with active brain metastases. The first 15 patients have been reported with an intracranial response rate of 73.3% and a mPFS of 14 months .There are two ongoing studies evaluating T-DXd in HER2+ stable or progressing BCBMs that will further contribute to understanding of the role in management of BCBM. The DESTINY-Breast07 is a phase 1b/2 trial evaluating T-DXd in combinations with durvalumab, pertuzumab, paclitaxel, or tucatinib for patients with stable, treated brain metastasis. For patients with active brain metastasis, there are two arms evaluating T-DXd in combination with tucatinib as well as monotherapy. Additionally, the phase 3b/4 DESTINY-Breast12 is evaluating survival as well as QOL and cognitive function of T-DXd in patients with or without BCBM.The role of surgery in the treatment of BMs is limited to patients with (1) a single large BM, (2) a need for symptom control and/or (3) a need for diagnosis. The data guiding the role in surgery in BMs come from studies of mixed populations of BMs as there have been no prospective studies examining the role of surgery in BCBMs.In 1990, Patchell published the fundamental study supporting survival benefits to surgical resection in patients with a single large BM . This stIt is notable that both of these prospective studies were before the use of SRS, modern MRI and chemotherapies with activity in BMs. There is, however, a multicenter retrospective study of 223 patients with a larger  BM treated with either single fraction stereotactic radiosurgery (SRS) alone or with surgery and SRS . This stWhile there is only level 1 evidence for surgical resection in single large BM, there are multiple surgical case series that report for patients where all BMs are surgically removed; survival is comparable to patients who underwent surgical resection for a solitary brain metastasis ,39,40. SClinically, surgical removal of a BM is often considered when a patient’s functional status may be improved with surgical intervention. Surgery may provide symptomatic benefit for patients with a large (>2.5 cm diameter) symptomatic lesion in a surgically amenable location. An example of a surgically amenable location could be an intraventricular metastasis that causes obstructive hydrocephalus, and resection of the mass would allow for treatment of intracranial pressure. Another example may be a large frontal lobe metastasis where resection of the mass could improve hemiplegia by relieving the mass effect. In these clinical scenarios, surgery may reduce the length of time that patients require steroid therapy and may improve a patient’s functional status so that the patient may be eligible for systemic therapies post-operatively. While it is unlikely that a prospective study would be able to capture these complex clinical scenarios, a retrospective study of 750 patients, of which 15% had BCBM, did find that functional status was significantly improved by surgical resection with an increase in median KPS from 80 preoperatively to 90 post-resection .Additionally, surgery may play an important diagnostic role in patients with BCBM. Some patients present with life threatening mass effect from BMs without a known primary cancer diagnosis. In this setting, surgical removal of the symptomatic BM provides diagnosis as well as symptomatic benefit even in the setting of multiple BMs. Additionally, in the setting of progressive symptomatic or radiographic changes following radiation, surgery can provide relief of symptoms as well as clarify if the changes represent recurrent disease or radiation necrosis.However, the above benefits to surgical resection of BCBM must be balanced with the risks of surgery. Venous thromboembolic events (VTE) are the most reported complication following surgery for a BM . While lIn addition to postoperative complications, surgery for BCBM has also been associated with an increased risk of leptomeningeal metastasis (LM) in multiple retrospective studies ,44. The SRS has become the cornerstone of local therapy for BCBM, particularly given that BCBMs are sensitive to radiation. While guidelines support the use of SRS alone for 1 to 4 BMs, given improved technology, SRS is often considered for patients with up to 10 small BMs. The safety of this is supported by Yamamoto et al. who enrolled 12% BCBM .In multiple randomized phase III trials, WBRT in addition to SRS was associated with improved local control but not overall survival or functional independence compared to SRS alone ,48,49,50SRS is often used in combination with the surgical removal of a BM to improve local control. While adjuvant SRS has historically been considered the standard ,53, multIn the recent years, hypofractionated SRT and staged SRS have gained popularity in the management of patients with larger brain metastases with a favorable therapeutic ratio ,58,59. FIn addition to the cognitive impacts, both SRS and SBRT have the risk of radiation necrosis. The incidence of radiation necrosis in patients with BCBM is unclear but has been reported to be between 5–25% . While mUse of WBRT for treatment of BCBM was established with studies with the median OS of 4–6 months ,63. WithIn the treatment of BCBM, there are multiple elements of the clinical situation that may impact treatment decisions for patients that prospective clinical trials are not able to comprehensively evaluate. For all treatment decisions, patients’ clinical performance, prognosis and status of systemic disease are essential considerations. However, for BCBM, the 2022 ASCO guidelines include total number of BCBM, size of the BCBM, as well as the presence or absence of symptomatic mass effect under the consideration for treatment options . The claWhile the clarification of symptomatic mass effect is important, it is notable that the ASCO guidelines only factor symptoms into decisions in the setting of newly diagnosed BCBM and not for BCBM that have progressed despite prior local therapy. For progression of BCBM previously treated with WBRT or SRS, trial of systemic therapy is considered for all types of progression, regardless of symptoms or mass effect. Given multiple HER2+ targeted systemic therapies with efficacy in BCBM, we propose a simplified algorithm favoring systemic therapies over local therapies for patients with HER2+ BCBM .In this proposed algorithm, consideration of systemic therapy must be placed in the context of the current state of systemic disease. With the development of a limited BM in the setting of stable extracranial disease, local therapy is recommended to continue clinical benefit of current systemic therapy. However, when there is development of an extensive BM and the only local therapy available is WBRT, the risks of WBRT must be balanced against the risks of change in systemic agents. In this setting, if one of the agents listed in For patients with both intracranial and extracranial progression, using symptoms to guide the use of systemic therapy perhaps is more appropriately categorized as symptoms that are likely to improve with local therapy compared to simply identify symptoms as the presence or absence of mass effect. Clinical experience has demonstrated that even symptoms from profound mass effect may improve with use of systemic therapy. This can allow for initiating treatment for both intracranial and extracranial disease without delays for recovery time from surgery or radiation therapy. Notably for both tucatinib and T-DXd, currently there is not safety data to guide timing of radiation with systemic therapy. Similarly, patients with both hormone receptor positive and HER2+, HER2+ targeted therapy are preferred for treatment of the BCBM given limited data for response to hormonal therapy. Ultimately, identification of what symptoms localize to which BCBM and the likelihood of improvement with treatment is best performed in partnership with a brain metastasis clinic or multidisciplinary team composed of medical oncologists, radiation oncologist, oncologic neurosurgeons and if available, neuro-oncologists.The above discussion focuses on HER2+ BCBM. However, with the evolving data for T-DXd in patients with low HER-2 expression, the definition of HER2+ BCBM will likely expand from a binary biomarker. Even within the binary definitions for HER2+ expression, type switching does occur between BM and systemic disease. Multicenter work demonstrated 22.8% of patients have biomarker status change from the primary site of the disease to BCBM . In thisAs noted above, for patients on tucatinib or T-DXd who need radiation therapy, at this time there is a lack of data regarding safety for the use of radiation with these agents. Data to guide if the therapy needs to be held and the duration of washout before, during and after radiation therapy are of high clinical need. Additionally, further evaluation into early or delayed radiation therapy and impact on survival as well as QOL is urgently needed.The hope for prolonged quality of life for patients with HER2+ BCBM has never been more promising. There are now multiple targeted therapies with activity for untreated or progressive BCBM, which is wonderful for patients and challenging for oncologists to make the best choice in what are always unique and complicated scenarios. Shared decision making with patients in treatment planning remains essential, especially now with so many options available. The necessity of multidisciplinary care in the treatment of BCBM remains with the medical oncologist having an increasing role in the treatment of BCBM. More research is needed to identify optimal treatment algorithms and comparison of efficacy of systemic as well as local therapies in patients with BCBM.