Percutaneous hepatic perfusion (PHP) is a palliative intraarterial therapy for unresectable hepatic malignancies. During PHP, high-dose melphalan is infused via the hepatic artery to saturate tumor in the liver with the chemotherapeutic substance. The venous hepatic blood is filtered by an extracorporeal melphalan specific filtration system. Blood clotting in the extracorporeal filter system is prevented by administering unfractionated heparin (UFH) in high doses, which might be reversed with protamine sulfate after the procedure. Aim of this retrospective two-center-study was to analyze the potential effect of UFH reversal with protamine sulfate on complication rates following PHP.PROTAMINE); 13 patients/21 PHP in groupREDUCED_PROTAMINE received a reduced amount of protamine, and 28 patients/43 PHP did not receive UFH reversal with protamine (groupNO_PROTAMINE). Periinterventional clinical reports, findings and laboratory values were retrospectively evaluated. Complications and adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAEv5.0).All patients receiving PHP treatment between 10/2014 and 04/2021 were classified according to their intraprocedural coagulation management: 92 patients/192 PHP received full UFH reversal with protamine  were major events (CTCAE grade 3-5). No (0%) thromboembolic events were recorded in groupREDUCED_PROTAMINE and groupNO_PROTAMINE. Hemorrhagic events were registered after 24 PHP (13%) in groupPROTAMINE, two of which (1%) were major (CTCAE grade 3-4). In groupREDUCED_PROTAMINE, only minor bleeding events were recorded, and one major hemorrhagic event was documented in groupNO_PROTAMINE (2%). There was a significant difference between the percentage of post-interventional thrombopenia in groupPROTAMINE (39%) and groupREDUCED_PROTAMINE (14%) versus groupNO_PROTAMINE (23%) (p=.00024). In groupPROTAMINE one patient suffered from a severe anaphylactic shock after the administration of protamine.Thromboembolic events were recorded after 10 PHP procedures (5%) in groupOur retrospective study implies that there might be a link between the practice of protamine sulfate administration to reverse the full hemodilutive effect of UFH after PHP and the post-interventional risk of thromboembolic events as well as clinically significant thrombopenia. Our data suggest that the standard use of protamine sulfate after PHP in low-risk patients without clinical signs of active bleeding should be critically re-evaluated. Chemosaturation with percutaneous hepatic perfusion (PHP) is a minimally invasive therapeutic approach to treat primary or secondary hepatic malignancies. The therapeutic aim of PHP is to control intrahepatic tumor growth, palliate symptoms and extent survival. Effectiveness of this liver directed treatment has been demonstrated in several studies –7.PHP takes advantage of the unique vascular network of the liver: while the liver parenchyma is supplied dually via portal vein and hepatic arteries, liver tumors predominantly obtain their blood supply via the hepatic arteries . During It is substantial for a safe intervention to prevent clotting of the blood during the extracorporeal hemofiltration. Thus, unfractionated heparin (UFH) is administered before initiation of the extracorporeal circuit, commencing with an IV bolus of 400 U/kg body weight. UFH inactivates thrombin and activated factor X (factor Xa) through an antithrombin-dependent mechanism , 13. Becth century, it became apparent that the appropriate dosing management of protamine is crucial as inadequate protamine dosing can unexpectedly influence patient hemostasis [A major risk of extensive hemodilution is hemorrhage of all kinds. Therefore, all patients are screened for risk factors contraindicating extensive anticoagulation . In order to avoid unnecessary risks of hemorrhage following PHP, the manufacturer`s instructions recommend to administer protamine sulfate to antagonize UFH before removal of the large catheters and sheaths . Protamimostasis –19. In amostasis . The commostasis . Reportsmostasis , 21, allThe two centers contributing to this study initially used full dose protamine sulfate to reverse the heparin effect at the end of the PHP procedure according to standard procedure. Due to isolated but severe cardiovascular events, both centers modified the periprocedural protamine management.The aim of this retrospective study was to analyze the potential effect of protamine sulfate on complication rates following PHP with a particular focus on thromboembolic events and bleeding complications.This retrospective bi-center study was waived by the ethics committee of Hannover Medical School. In all patients, PHP was regarded as the most appropriate therapy based on a local multidisciplinary tumor board decision. Contraindications for PHP included a recent history of transient ischemic attacks, heart failure with a left ventricular ejection fraction < 40%, hemorrhage-prone intracranial lesions, significant chronic obstructive or restrictive pulmonary disorder. ECOG performance status before PHP had to score 0 or 1.PROTAMINE (groupPRO), groupREDUCED_PROTAMINE (groupREDPRO) or groupNO_PROTAMINE (groupNOPRO) according the intraprocedural coagulation management:PRO included 92 patients treated with 192 PHP  that received full UFH reversal with protamine sulfate after PHP.GroupREDPRO contained 13 patients treated with 21 interventions at Asklepios Clinic Hamburg-Barmbek receiving a significantly reduced amount of protamine sulfate as UFH reversal following PHP.GroupNOPRO counted 43 interventions in 28 patients from Hannover Medical School with no UFH reversal after PHP.GroupAll patients receiving PHP treatment either at Hannover Medical School between October 2014 and April 2021 (199 PHP in 93 patients) or at Asklepios Clinic Hamburg-Barmbek between April 2014 and April 2021 (57 PHP in 23 patients) were assessed for this study. The interventions were assigned to groupOf note, 17 patients were included in both groups as they received protamine sulfate in the first PHP and reduced or no protamine sulfate in the following PHP.PRO. In groupREDPRO, a reduced dose of protamine sulfate was administered, aiming for antagonization of approximately two thirds of the active UFH. No UFH neutralization was performed in groupNOPRO. Please refer to Fig. All PHP procedures are performed in an angio suite under general anesthesia. As previously described , 11, 22,PRO and groupREDPRO, the sheath was removed after administration of protamine sulfate , whereas in groupNOPRO, the sheath remained in place. All patients were transferred to ICU, where the remaining sheaths were removed after normalization of the coagulation status, femoral compression devices were utilized to compress the puncture sites to support hemostasis.After the chemosaturation, the introducer sheath in the left femoral artery was handled according to the immediate bleeding risk: in groupProcedural data were retrospectively obtained from radiology and anesthesiology reports. ACT measurements were assigned to following stages (i) first ACT before heparin administration (ii) ACT before initiation of the extracorporeal circuit (iii) ACT after PHP (iv) last ACT value measured before transfer to ICU.In both study centers, the periinterventional clinical reports, laboratory values and other PHP related findings were retrospectively assessed. The data were anonymized and shared for collaborative evaluation. For the analysis, the laboratory values of the first three postinterventional days were measured with the preprocedural baseline values. The Common Terminology Criteria for Adverse Events (CTCAEv5.0), which classifies the severity of adverse events into 5 levels (mild - death), was used to evaluate complications and adverse events. Major adverse cardiovascular events and peri-interventional mortality were analyzed .p-value of <0.05 was determined to be significant.Data were obtained retrospectively from medical records. Data are presented in relative and absolute values, mean or median (and interquartile range (IQR)). Continuous data were analyzed using Mann-Whitney-U test. A PRO included 192 PHP treatments in 92 patients, groupREDPRO consisted of 21 PHP in 13 patients and groupNOPRO of 43 PHP in 28 patients. For detailed patient characteristics please refer to Table Overall, 116 patients treated with 256 interventions  were included. GroupPRO, groupREDPRO and groupNOPRO respectively. Mean protamine sulfate used in groupPRO was 34 141 I.E., whereas in groupREDPRO, 27 368 I.E (p=0.036). were used. For a detailed record of the procedural characteristics please refer to Table Mean total UFH dose used for hemodilution was 41 059 I.E., 43 775 I.E. and 49 583 I.E. in groupPRO (median 128s) and groupREDPRO (median 119s) compared to groupNOPRO . No major complications occurred during the PHP procedures. The median intervention time  was 2h 38m (2h 16m – 3h). The median time of hospitalization was 7 (6-10) days in groupPRO, 6 (5-7) days in groupREDPRO and 7 (5-10) in groupNOPRO.Figure PRO: after 10/192 (5%) PHP procedures patients suffered from thromboembolic complications, six of which (3%) were major events (CTCAE grade 3-5):◦ One patient developed an embolic occlusion of the anterior and middle cerebral artery approximately five hours after the fourth PHP procedure. Immediate percutaneous thrombectomy was performed. Tragically, the patient deceased after hemorrhagic conversion of the ischemic infarction with subsequent brain herniation.◦ One patient presented with an occlusion of the left middle cerebral artery (MCA) and the distal right anterior cerebral artery approximately six hours following the first PHP procedure. Percutaneous recanalization and anticoagulation was immediately performed. Since the symptoms persisted, the patient was transferred to a neurologic rehabilitation clinic.◦ One case of basilar artery thrombosis on the day after PHP, possibly due to de novo auricular fibrillations. The same patient developed deep vein thrombosis followed by pulmonary embolism.◦ Central pulmonary embolism in one patient on the day after PHP.◦ Another case of deep vein thrombosis, symptom onset (increasing leg swelling) starting a few days after PHP.◦ One patient with a non-ST-segment elevation myocardial infarction (NSTEMI). Cardiac symptoms started on the evening after PHP.Group◦ On the morning after the fifth PHP, one patient with CCA presented with a transient hemiparesis. On cerebral MRI, a vascular, ischemic insult within the left-sided precentral cortex (most likely due to a thromboembolic event) was seen. The mild symptoms improved spontaneously, no lysis was performed.◦ In total three cases of ischemic posterior cerebri artery (PCA) infarction were diagnosed on cross-sectional imaging. In all cases, lysis was not performed in view of the mild symptoms.Minor (CTCAE grade 1-2):REDPRO: No (0%) thromboembolic events were recorded in groupPRO.GroupNOPRO: No (0%) thromboembolic events were recorded in groupPRO.GroupA detailed overview of the thromboembolic adverse events including treatment and sequelae (if present) is displayed in Table PRO: hemorrhagic events were recorded after 24/192 (13%) PHP, two of which (1%) were major (CTCAE grade 3-4):◦ On the day of the PHP one patient developed a bleeding aneurysma spurium at the puncture site in the left groin with consecutive bleeding anemia (hemoglobin drop of two points). Surgical treatment was successful.◦ One patient developed chronic ulcerous bleeding in the upper gastrointestinal tract 2 weeks after the second PHP. The ulcer was refractory to endoscopic and medical treatments and was treated surgically.GroupMinor (CTCAE grade 1-2) bleedings occurred after 22/192 interventions (12%) and included bleeding/hematoma at the puncture sites, vocal cord hematoma, intraocular bleeding, petechial bleeding, gastric ulceration and gastric and nasal mucosal bleedings (epistaxis) and bladder obstruction due to blood clots. Most hemorrhages occurred shortly after PHP.REDPRO: no major (CTCAE grade 3-4) bleeding events occurred (0%). Minor (CTCAE grade 1-2) bleedings occurred after 2/21 interventions (10%).GroupNOPRO: following 12/43 (28%) PHP procedures, patients suffered from hemorrhagic events, one of which (2%) was CTCAE grade 4:◦ The day after PHP, one patient developed an intracerebral bleeding in the right frontal lobe resulting in recurring convulsive syncope, dysarthria and dysphagia. The activated partial thromboplastin time at time of the event was 49 sec.. Unfortunately, despite intensive care treatment, the symptoms remained, the patient was discharged with a percutaneous endoscopic gastrostomy.GroupMinor events (CTCAE grade 1-2) were recorded after 11/43 PHP procedures (26%) including bleeding/hematoma at the puncture sites, and gastric and nasal mucosal bleedings, which were all self-limiting.PRO and groupREDPRO) versus patients not receiving protamine (groupNOPRO), a significant difference was found (p=0.00024).Table In respect to liver toxicity, there was a significant increase of aminotransferases as markers of hepatic injury Table .PRO one patient (1%) suffered from an anaphylactic shock after the administration of protamine. The allergic reaction was severe with hypotension, bronchospasm and skin and mucus membrane reactions. After immediate treatment, the symptoms resolved. Further complications are summarized in Table In groupFor chemosaturation with percutaneous hepatic perfusion (PHP), hemodilution with heparin is mandatory to ensure safe extracorporeal filtration. The results of this study indicate that UFH reversal with protamine sulfate after PHP might have an impact on both, post-interventional thromboembolic events and platelet count.th day after PHP were described [Hemorrhagic and thromboembolic events after PHP procedures performed with heparin reversal/protamine administration have been described in literature. In the landmark phase-III trial, Hughes et al. reported on one case of cerebral ischemia and myocardial infarction, each grade 3/4, within the first 72 hours after PHP . Additioescribed .Whereas the late post-interventional events (both in the mentioned literature as well as in our study cohort) are less likely a direct reaction to the administered protamine sulfate, a link between UFH reversal with protamine sulfate and the early periinterventional thromboembolic events is possible. However, other factors influencing thromboembolic events need to be considered. During cardiac surgery when cardiopulmonary bypass (CPB) is required, an acute systemic inflammatory response is provoked, which is mainly triggered by contact activation of blood by the artificial surfaces of the extracorporeal circuit . This miNOPRO (28%) compared to groupPRO (13%). These rates are comparable to the current literature, where hemorrhagic events after PHP include minor (grade 1/2) bleedings (esp. at the puncture sites) in up to 30% [Concerning bleeding rates our analysis found more hemorrhagic events in groupp to 30% , 21 as wp to 30% , haematep to 30% , epistaxp to 30% , vaginalp to 30%  or abdomp to 30%  hemorrhap to 30% , minor ip to 30%  and retrp to 30% . Since tTo date, the level of evidence for protamine dosing strategies is low and recommendations vary in the available guidelines , 19, 28.22. In our study cohort, one case (1%) of severe anaphylaxis was observed right after the administration of protamine sulfate. Fortunately, in our patient, the allergic reaction was responsive to treatment, whereas other studies describe that the risk of in-hospital death is significantly increased in patients with adverse events after protamine administration [While heparin - due to its reliability, availability and affordability - has found its way onto the World Health Organization’s list of essential drugs , its antstration .Furthermore, we noticed a significantly lower rate of relevant post-interventional thrombopenia in the groups not receiving protamine sulfate compared to patients receiving protamine sulfate. Early and transient thrombopenia has been described in most PHP studies as a predominant side effect after PHP , 33–35. It should be kept in mind that PHP is a therapy approach for the palliative setting and even if a performance status ECOG 0 or 1 is a requirement for PHP treatment, the health status of our patients is fragile. Taking into account the potentially severe consequences of an anaphylaxis as well as the increased risk of both thromboembolism and thrombopenia, the necessity and value of UFH reversal with protamine sulfate should be assessed and adapted to the individual patient’s risk profile. One one hand, we regularely see patients who can be discharged from the ICU or intermediate care almost immediately after the procedure. In these patients, the administration of protamine can help as it reduces the time to ambulation and the time to hemostasis  without descriptive and hypothesis-generating than conclusive, especially as in some cases the direct link between the coagulation management and the adverse event might be implied but cannot be proven.A major limitation of this study is the retrospective study design, with all its potential confounders. Due to the retrospective nature, the study groups differ in size. Also, differences in ACT measurements due to the ACT measurement devices used should be considered. Furthermore, post-interventional blood samples may have been taken at different time points of the day. Due to the bicentric study design, inter-center differences might be underestimated. Most studies we used for comparisons were analyzing cardiac surgery with CPB, which clearly reduces the comparability. Previous reports on this specific matter are not available; thus, our data are rather Our study implies that the use of protamine sulfate to reverse the hemodilutive effect of UFH after PHP might increase the risk of thromboembolic events as well as clinically significant post-interventional thrombocytopenia. Beyond that, protamine sulfate can provoke severe allergic reactions that potentially have an impact on the post-interventional mortality. In summary, we conclude that a paradigm shift regarding the standard use of protamine sulfate after PHP in low-risk patients without clinical bleeding signs should urgently be discussed. Certainly, appropriate after-care  for patients receiving reduced or no protamine sulfate is necessary to ensure fast response in the unlikely event of significant bleeding complications.


Due to the widespread use of magnetohydrodynamic (MHD) in electromagnetic targeted therapy, malignant tumor therapy, magnetic microscopy, regulating blood circulation following operations, and fluid pumping in industrial and technical processes. The main goal of the article investigates the analysis of a dusty Brinkman fluid flowing through fluctuating parallel plates with an inclined relative magnetic field. The study aims to analyze the relative magnetic phenomena which is fixed relative to the fluid (MFFRF) or plate (MFFRP), and its impact on fluid and particle motion. The mathematical modelling of the fluid is established through a conventional partial differential equations, and Buckingham's pi theorem is utilized to obtain dimensionless variables. Poincare-Lighthill perturbation technique (PLPT) is employed to derive the solution, with the aid of the program Mathcad-15, the findings are displayed graphically for both velocities. The study indicates that the relative magnetic field significantly influences fluid and particle motion which can be utilized to control fluid pumping in industrial operations and blood flow during surgery. New studies on non-Newtonian fluids have identified Brinkman-type fluids. Brinkman-type flow is utilized extensively in numerous fields of engineering and science, including aquifer hydrology, geotechnical engineering, rock mechanics, and chemical engineering. Brinkman originally utilized the Brinkman type model in 1949  investigThe latest evidence has focused on the two-phase character of dusty liquid simulation dynamics, which has sparked a great deal of curiosity. This phenomenon is observed in fluid (liquid or gas) fluxes including solid particles. The usage of the dusty fluid also be envisioned in rain degradation, precipitation, and missile launchers, among others. These features have accelerated the modelling, solution, and analysis of the migration of dusty fluids. Venkatesh and Kumara  studied Magnetohydrodynamic (MHD) boundary layer has applications in technology, geological sciences, and engineering linked to numerous mass and heat transport flow concerns that have been investigated. Dar and Elangovan  examinedNo attempt has been made, to the best of our knowledge, to pinpoint the precise solutions and contrasting effect of fluid and dust particle velocity and temperature distribution for the Brinkman fluid flow with heat transfer along the upright parallel plates, despite a comprehensive review of the aforementioned literature. In light of this, the present work considers the purpose of an inclined relative magnetic field analysis of a Brinkman-type dusty fluid passing through a fluctuating parallel upright plate with wall share stress. MFFRP and MFFRF magnetic phenomena are engaged. Using the PLPT to produce various graphical outputs for velocity and temperature using the MATHCAD-15 package.2Tp is denotes the particle's temperature as shown in Let's consider entirely developed unidirectional, the unsteady flow of electrically conducting viscoelastic, free stream fluctuating Brinkman-type dusty fluid in a vertical channel is explored in this article. The viscoelastic Brinkman-type dusty fluid is flowing with a transverse magnetic field applied. Since of the low magnetic Reynolds number, the electric field resulting from charge polarization and the induced magnetic field are not included i.e. The following are the velocity and temperature fields:The Brinkman fluid constitutional equations are ,12,34. satisfies the given physical conditions represents the validity of our computations.4Keeping in mind the influence of flow parameters on the temperature and velocity profiles, this section is devoted to conveying the physical interpretation of the exact results from inclined relative magnetic field evaluation of Brinkman type dusty fluid using Poincare–Lighthill perturbation technique via a fluctuating vertically parallel plates together with wall share stress, as shown in The two upper sub-graphs of The two upper sub-graphs of 5•The amplification of the dust particle and fluid velocities is traceable to an upshot of particle concentration parameter •Improved values of Brinkman parameter •Enhanced values of thermal Grashof number •The upswing values of particle concentration parameter •The upsurge of the fluid and dust particle temperature against time can be seen when the heat absorption parameter The examination of inclined relative magnetic field analysis of Brinkman-type dusty fluid is carried out in a fluctuating upright parallel plate along with wall share stress. Buckingham's pi theorem is utilized in dimensionless equations. The model of the flow is rearranged and then executed via Poincare–Lighthill perturbation technique considering the relative magnetic phenomena of MFFRP or MFFRF to obtain solutions for temperature and velocity profiles in both dust particles and fluid velocity with the support of Mathcad- 15 software. Arising from the study, the key findings listed below are:Dolat khan, Kanayo Kenneth Asogwa and Wiboonsak Watthayu; conceived and designed the experiments; Dolat khan, Poom Kumam and Wiyada Kumam; performed the experiments; Wiboonsak Watthayu, Wiyada Kumam and Musawa Yahay Almusawa; analyzed and interpreted the data; Dolat khan, Musawa Yahay Almusawa and Poom Kumam; contributed reagents, materials, analysis tools or data; Dolat khan and Kanayo Kenneth Asogwa; wrote the paper.No Data associated in the manuscript.


Funding statement. The grant number statement for the Shenzhen Basic Research Fund was displayed as “RCYX2020071411473419”. The correct grant number is “RCYX20200714114734194”. The correct Funding statement appears below.In the published article, there was an error in the “This work was partly supported by the National Key Research and Development Program of China under grant No. 2018YFB0204403, the Strategic Priority CAS Project XDB38050100, the National Science Foundation of China under grant no. U1813203, the National Natural Youth Science Foundation of China under grant no. 31601028, the Shenzhen Basic Research Fund under grant nos. JCYJ20190808163801777, KQTD20200820113106007, and RCYX20200714114734194, and the CAS Key Lab under grant no. 2011DP173015.”The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


RSVPreF3 OA was recently approved by the United States FDA for the prevention of RSV-related lower respiratory tract disease (RSV-LRTD) in adults ≥ 60 years of age (YOA). We present persistence of vaccine efficacy (VE) of a single RSVPreF3 OA dose, along with VE and safety of annual revaccination dose, over 2 RSV seasons.In this phase 3, placebo-controlled, multi-country study (NCT04886596), adults ≥ 60 YOA were randomized 1:1 to receive RSVPreF3 OA or placebo before RSV season 1. RSVPreF3 OA recipients were then re-randomized 1:1 before RSV season 2 to receive a second RSVPreF3 OA dose  or placebo (RSV_1dose group); participants who received placebo pre-season 1 received an additional placebo dose (placebo group). VE against first occurrence of RSV-LRTD (confirmatory secondary objectives), severe RSV-LRTD, RSV-LRTD by age, baseline comorbidity and frailty status, and RSV-related acute respiratory illness (ARI) was assessed over 2 seasons. Reactogenicity and safety were also evaluated.Of 24,973 participants vaccinated before season 1, 24,967 were included in the current VE analyses . The median follow-up over 2 seasons was 17.8 months. VE of a single dose of RSVPreF3 OA against RSV-LRTD over 2 seasons was 67.2% ; VE of annual revaccination over 2 seasons was 67.1% (97.5% CI: 48.1–80.0). Sustained VE was observed over 2 seasons against severe RSV-LRTD, against RSV-LRTD among participants 60–69 YOA, 70–79 YOA, those with ≥ 1 baseline comorbidity of interest, pre-frail participants and against RSV-ARI . The reactogenicity  and safety profile of the second RSVPreF3 OA dose was in line with the first dose.One dose of RSVPreF3 OA is efficacious against RSV-LRTD in adults ≥ 60 YOA over 2 full RSV seasons, as well as against severe RSV-LRTD, and in adults with advanced ages and underlying comorbidities. Revaccination after 1 year does not appear to confer additional efficacy benefit for the overall population. The second RSVPreF3 OA dose had a clinically acceptable safety profile. The clinical development program will further evaluate persistence and the best timing for revaccination.Funding: GlaxoSmithKline Biologicals SAMichael G. 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Prof, Abbot: Principal Investigator in randomized controlled trials|Ablynx: Principal Investigator in randomized controlled trials|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|AstraZeneca: Honoraria|Biofabri: Advisor/Consultant|Biofabri: Board Member|Biofabri: Grant/Research Support|Biofabri: Honoraria|GSK: Advisor/Consultant|GSK: Grant/Research Support|GSK: Honoraria|GSK: Clínical trials fees paid to my institution|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Janssen: Clínical trials fees paid to my institution|Medimmune: Principal Investigator in randomized controlled trials|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Moderna: Honoraria|MSD: Advisor/Consultant|MSD: attending meetings and/or travel, Principal Investigator in randomized controlled trials|Novartis: Principal Investigator in randomized controlled trials|Novavax: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Honoraria|Pfizer: Clínical trials fees paid to my institution|Regeneron: Principal Investigator in randomized controlled trials|Roche: Principal Investigator in randomized controlled trials|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Sanofi: Clínical trials fees paid to my institution|Seqirus: Principal Investigator in randomized controlled trials Tino F. 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Purpose: the purpose of this theoretical study was to analyze the heat transfer in the fluid–particle suspension model under the effects of a porous medium, magnetic field, Hall effects, and slip boundary conditions in a convergent channel with the addition of electrokinetic phenomena. The Darcy–Brinkman (non-Darcy porous medium) model was used to assess the effects of the porous medium. Methodology: the rheological equations of both models were transformed into a dimensionless form to obtain the exact solutions of the fluid and particle phase velocities, pressure gradient, volumetric flow rate, stream function, temperature distribution, and heat-transfer rate. To obtain an exact solution to the models, the physical aspects of the parameters are discussed, analyzed, and reported through graphs, contour plots, and in tabular form. Findings: mixing in hafnium particles in a viscous fluid provide 1.2% more cooling compared to with a regular fluid. A reduction of the streamlines was observed with the contribution of the slip condition. The utilization of the Darcy parameters upgraded both the fluid flow and temperature profiles, while the heat-transfer rate decreased by up to 3.3% and 1.7% with the addition of a magnetic field and porous medium, respectively. Originality: the current study is an original work of the authors and has not been submitted nor published elsewhere. The purpose of this theoretical study was to analyze the heat transfer in the fluid–particle suspension model under the effects of a porous medium, magnetic field, Hall effects, and slip boundary conditions in a convergent channel with the addition of electrokinetic phenomena. Much research is devoted to the search for different types of nanoparticles that have good mechanical properties  to promote the heat-transfer analysis of the systems. Due to the distinguished properties of nanoparticles to increase heat transfer, nanofluids are used in various scientific processes . The nanoparticles are also effectively used in many chemical processes and modern biotechnology  with a maximum volume fraction of 4% to promote their applications in the cooling process. Bhatti et al.2 used a suspension of cobalt oxide and graphene nanoparticles in a carrier fluid to examine the applications of nanofluids in solar energy. They employed a successive linearization method to obtain numerical solutions to the problem. Their findings revealed that both nanoparticles could upgrade the heat-transfer rate, while skin friction displayed the opposite behavior. Hussain et al.3 suspended gold nanoparticles in a couple of stress fluids to discover their applications in gland and tumor remedies. They used a semi-analytical technique to obtain computational results for their model. Their results revealed that gold nanoparticles are the best option to kill the affected cells of tumors or glands due to their larger atomic number. Xu et al.4 showed the brilliant advantages of ultrasmall-sized nanoparticles in biomedical engineering (tumor therapy) and showed that nanoparticles sized less than 7 nm were more effective in kidney and tumor treatment compared to larger-sized nanoparticles (100–200 nm). Aljohani et al.5 chose a fractional derivative approach to show the applications of different types of nanoparticles in solar collectors to store solar energy. Some important results of nanofluids in different configurations were also reported by Dharmaiah et al.6–8 and Vedavathi et al.9Colloidal suspensions of nanoparticles generated by carbides, metal oxides, 10–13etc. Various models have been proposed by different authors to simulate the porous medium effects, such as Darcian and non-Darcian models, and non-equilibrium models. In 1856, Darcy proposed the porous medium model for assessing fluid flow through a porous medium experimentally by considering the linear relationship between the drop in pressure and the flow rate. The extensive body of literature suggests the importance of the porous medium in heat and flow analysis. For instance, Al Hajri et al.14 analyzed the importance of the porous medium in the heat-transfer analysis of a Maxwell fluid through a square conduit. The applications of a porous medium with heat transfer along a stretched cylinder were provided by Reddy et al.15 Asghar et al.16 used the Sisko fluid model to discuss the heat transfer with the porous medium in a curved channel by using the implicit finite difference method. Ramesh17,18 chose a non-uniform tilled channel model to discuss peristaltic flow under the influence of a porous medium and presented an exact solution to the problem.Fluid and heat transfer in a porous medium are attracting increasing interest from researchers due to their wider applications in geothermal systems, food industries, the insulation of buildings, the design of nuclear reactors, the manufacturing of thermal isolators, oil production, solar power reactors, hot rolling, drying technologies, the control of pollutant spread in groundwater, and in compact heat exchangers,i.e., the heat transfer) by utilizing a porous medium with nanofluids. Zhao et al.22 conducted a study on the utilization of Mg gas infiltration to produce MgB2 pellets, incorporating micro-sized B and nanosized powders. Zhang et al.23 investigated the energy absorption of water jet penetration on the 2A12 aluminum alloy. Chen et al.24 focused on the significance of the first hidden-charm pentaquark in relation to its strangeness. Also, the applications of nanofluids with a porous medium in heat-transfer analysis were reported by Nabway et al.,19 Kasaeian et al.,20 Mahdi et al.,21 Hussain et al.,25,26 Ge-JiLe et al.27 Cai et al.,28 Chen,29 and Du et al.30 in recent works on the applications of nanofluids in different applied fields.Various engineering applications of heat transfer with porous media have been observed where cooling or heating is a very important factor, such as combustion systems, the cooling of turbine blades, the cooling of electronic devices, chemical reactors, storage in thermal-transport systems, and composite fabrication. The mixtures of low or high thermal fluids that appear in such applications can affect the output of these devices. In this situation, this issue can be resolved, and the performance of these devices can be increased  electro-osmotic flow of a rheological fluid through a convergent shape geometry with a porous medium and the Hall effect have not been considered yet. Yet, we were motivated investigate these because of the potential applications of the slip boundary conditions in electro-osmotic flow to aid the design of reliable microfluidic devices and to ensure the effective operation of such devices. Here, the problem of slip boundary conditions can have a significant role in the study of heat and flow analysis to characterize the behavior of micro- and nanofluids through a microchannel. Currently, “no-slip” conditions are commonly used in the problem of microfluidic flows, but a key limitation of the no-slip condition is that it may fail to solve micro-, nanoscale fluid problems (depending on the roughness interface and the fluid–solid interface interaction).2.Vvf =  and Vvp =  are the velocity vectors of the fluid and particulates.Consider the time-independent flow of a rheological fluid suspended by the addition of 40% hafnium solid spherical particles in as convergent channel as shown in The following assumptions are taken to simplify the given flow problem.Ex is applied along the x-axis direction.1. An external electric field 2. The Debye–Hückel linearization approximation is applied.x and y are chosen in the axial and normal-to-flow directions, respectively.3. The flow is considered in the Cartesian coordinate systems in which 4. The fluid is electrically conducted while the channel is non-electrically conducted.B0 is applied normal to the flow direction.5. A constant magnetic field 6. The magnetic Reynolds number is very small, so the induced magnetic field is negligible.7. The Hall current is considered while the ion slip effects and buoyancy force are neglected.8. The flow and particle interact as a continuum.9. The fluid and particle velocities are irrotational.10. The Joule heating and thermal radiative heat flux effects are omitted.y = 0 while y = h(x) and y = −h(x) are the upper and lower boundaries of the divergent channel, respectively.11. The flow is symmetric along the center line of the channel 12. The hafnium particles are considered to be in a spherical shape with equal size and uniformly distributed in the fluid.13. The fluid and hafnium particles are coupled in terms of the drag force and heat transfer between them.T0 and T1, respectively.14. The top and lower walls of the channel maintain the temperatures 2.133,34The rheological equations for the fluid phase in the vector form are defined asR = , the electric current J = , and the Cauchy stress tensor Tij are expressed in the following form:Df(=6πμr) is called the Stoke drag coefficient, r is the radius of the hafnium particle, φ(0 < φ < 1) is known as the porosity of porous medium, k*(k* > 0) is the permeability of the porous medium, σe is the electrical conductivity, ωe is the cyclotron frequency of electrons, τe is the electron collision time, A is known as the kinematical tensor, E is the electric field, and the total magnetic field is B = B0 + b, in which B0 is the applied magnetic field and b represents the induced magnetic field, which is assumed to be negligible due to taking a low magnetic Reynolds number. Here, we chose E =  = 0, due to the absence of applied polarization voltage. So the total uniform magnetic field with magnetic flux density is B = B0 = . From the above assumption, 35–38The Darcy resistance m1 = ωeτe ≈ O(1) is called the Hall current parameter. Solving From the above Jx and Jx are the components of the current vector J in the x- and y- directions, respectively while m is the Hall current parameter.In 2.239,40The rheological equations for the particle phase in vector form are defined as41The vector form of the heat equation with viscous dissipation effects is defined asThe components form of the fluid and particle phases flow equations are defined asThe boundary conditions areIntroducing the dimensionless variable to convert the above-governing equations into dimensionless formIn view of the above equation, the dimensionless fluid–particle phase problem is expressed as (the bar has been removed)The boundary conditions are is called the magnetic field parameter,  is known as the porous medium parameter, Df is the drag force, and Br is called the Brinkman number.In i.e., the exact expressions for the fluid, particle, and temperature, is expressed asThe exact solution, The expression of the total volumetric flow is obtained from the following mathematical expression asp/dx givesSolving the above equation for d and given asThe expression of the stream function is calculated from the following mathematical relation The expression of temperature distribution can be obtained from (21) and allows obtaining the following analytical expression:As an important physical quantity, the heat-transfer rate is calculated by using the relation G1,G2,G3,G4,G5, and R1,R2,…,R22 are defined in the appendix.The constants 3.m → 0, the problem is reduced to the single phase of an MHD electro-osmotic Newtonian fluid flow with heat transfer analysis in a convergent channel under the effects of slip boundary conditions, a porous medium, and Hall current without hafnium particles.1. It is interesting to note that for am1 → 0, the problem is reduced to the multiphase electro-osmotic flow of a Newtonian fluid with heat-transfer analysis in a convergent channel under the effects of slip boundary conditions, a porous medium, and a magnetic field with a 40% suspension of Hafnium particles.2. When Dp → ∞ corresponds to heat-transfer analysis of a biphase liquid flow of an MHD Newtonian fluid under the action of the Hall current and slip boundary conditions in a convergent channel with a 40% suspension of hafnium particles.3. The finite value of m0 → 0, the problem is transformed into a simple multiphase pressure-driven flow of an MHD Newtonian fluid with heat-transfer analysis under the impact of the Hall current and slip boundary conditions in a convergent channel with a 40% suspension of hafnium particles.4. For Ha → 0, the problem is reduced to the thermal transport of an MHD Newtonian fluid with a porous medium in a fluid–particle suspension through a convergent channel under the influence of the slip boundary conditions and Hall current.5. When vs = tp = 0, the problem is reduced to thermal analysis of an MHD Newtonian fluid in a fluid–particle suspension in convergent channels without wall properties.6. For Dp → ∞ and m1 = 0, the results of Hussain et al.33 and Ellahi et al.34 can be recovered, i.e., the flow of a Newtonian nanofluid through a convergent channel without a heat-transfer mechanism.7. When 4., magnetic parameter , Hall parameter (m1 = ωeτe), velocity slip parameter , Darcy parameter , Brinkman number , particle suspension parameter (am), and thermal slip parameter . The solution to the considered problem is obtained with the help of mathematical software and presented as closed-form expressions of the fluid and particle velocity, stream function, total volumetric flow rate, pressure gradient, temperature distribution, and local heat-transfer rate. The range of the involved parameters for computation results is listed in In this section, we analyze the graphical behavior of the important physical quantities, namely the fluid and particle velocities, stream function, temperature distribution, and heat-transfer rate under the involved parameters of the study, namely the Debye length parameter Mp) on both the fluid and particle velocities are displayed in i.e., Lorentz force (J × B). Basically, the greater the values of the magnetic field parameter, the larger the magnetic field produced relative to the viscosity of the fluid, which enhances the Lorentz force acting on the fluid particles and reduces the motion of the fluid particles. The influence of the Hall parameter on the velocity distribution is highlighted in i.e., the magnetic field parameter disturbed the fluid flow, which caused a reduction in the fluid velocity, while the Hall parameter supported the motion of the fluid particle, and the velocities distribution increased against it. Since m1 = ωeτe, i.e., the cyclotron frequency of electrons and the electron collision time have a direct relationship with the Hall parameter, which means that when the Hall parameter is increased, then the cyclothron frequency of the electrons in the fluid particles increases, which causes an increase in both velocities' distribution. This can also be expressed by another mathematical relation , i.e., the greater values of the Hall parameter diminish the electrical conductivity, which causes a reduction in the damping force, and as a result the velocity of both phases increases against the Hall parameter. Dp). Physically, this means that the Darcy parameter reduces the drag force in the fluid particles, which causes an enhancement in the velocity profile via the Darcy parameter. We can also express that, for increasing values of the Darcy parameter, a more permeable porous medium will exist, which will provide less resistance to the fluid particles as a result of the velocities profiles enhancement. The effects of the Debye length parameter (m0) on the velocities are examined in , i.e., the Debye length parameter is defined as “the height of the channel (a) over the Debye thickness (λd)”, when the height of the channel increases, then the velocity distribution will increase, and as a result an electrical double layer arises. The effects of the coefficient of the volume fraction on velocity profiles are shown in i.e., the fluid with the suspension of hafnium particles). The physical reason for this is that when the solid tiny particles of hafnium are mixed in simply, then these particles generate internal friction in the resultant fluid (multiphase fluid), which retards the fluid flow. via the velocity slip parameter, i.e., the velocity profiles increased and decreased in the interval x ∈ U and x ∈ , respectively.The effects of the magnetic field parameter ( on the temperature distribution is illustrated in m1 = ωeτe) on the temperature profile, and we could observe that this parameter enhanced the temperature distribution, and the maximum temperature was noted to be in the center of the channel. The variations of temperature against the Darcy parameter  and Debye length parameter  are shown in m) and velocity slip parameter  on the temperature of the fluids and particles, respectively. Both figures show the decreasing behavior of the temperature distribution via the coefficient of the volume fraction and velocity slip parameter. The physical reason is that when hafnium particles are suspended in the fluid, they absorb the heat, and as a result, the temperature decreases. Thus, we can say that the viscous fluid with the suspension of hafnium particles plays a significant role in the cooling process compared to in a regular viscous fluid.  and thermal slip parameter . These figures show increasing trends via considering the Brinkman number and thermal slip parameter. The physical reason for the increasing temperature against the Brinkman number is that when the Brinkman number increases, the viscous dissipation produces the condition of the heat-transfer mode, which enhances the temperature profile. The impacts of the magnetic parameter, Darcy parameter, Hall parameter, and velocity slip parameter on the stream function are captured in i.e., the stream function obtains a greater magnitude with consideration of a porous medium as compared to a clear medium  and increased in the region Q > 0 & ΔP > 0  when increasing the coefficient of the volume fraction and the Darcy parameter (see via the magnetic field parameter in the retrograde pumping region (Q > 0 & ΔP > 0) and decreased via the magnetic field parameter in the co-pumping region (0 < Q & 0 < ΔP), see m0 = 0 and m0 ≠ 0 and it could be noted that the pressure rise showed a similar trend against the velocity slip parameter and Debye length parameter, as can be seen in versus the coefficient of the volume fraction for the two different cases, i.e., when the magnetic field and slip conditions are ignored, and when the magnetic field and slip conditions are included, we see that the pressure rise decreased in the region 0 < Q & 0 < ΔP  and increased in the region Q > 0 & ΔP > 0 (i.e. the co-pumping region) when increasing the coefficient of the volume fraction am3)The coefficient of particle fraction (kg mδThe wave numberDfThe drag forcem0The Debye length parameter (m)vsThe velocity slip parameterBrBrinkman numberyThe coordinate axis (m)QTotal volumetric flow rateQpThe volumetric flow rate of particle velocityμs−1 s−1The viscosity kg mvvpThe component of particle velocity (m s−1)MpThe magnetic field parameterΦThe electro-osmotic potential function (V)T0The temperature of the lower wall (K)lThe length of the channel (m)ρf−3)The density of the fluid (kg mσe−1)The electrical conductivity (s m∇The dell operatorDpThe Darcy parameterφThe porosity of the porous mediumk*2)The permeability of the porous medium (mVvp−1)The velocity vector of the particle phase Exx direction (V m−1)The component of the electric field in k1The thermal slip constantψ2 s−1)The stream function uhs−1)The electro-osmotic velocity (m saThe wave amplitude (m)ptThe thermal slip parameterxThe coordinate axis (m)hThe wall of the channelQfThe volumetric flow rate of fluid velocityβThe amplitude ratiouvp−1)The component of fluid velocity n0The bulk ionic concentrationK−1)The thermal conductivity ωeThe cyclotron frequency of electronsB0−2)The strength of the magnetic field th components of the stress tensorThe (Vvf−1)The velocity vector of the fluid phase (m sg−2)The gravitational force (m stThe time (s)τeThe electron collision timehbThe Boltzmann constantEyy direction (V m−1)The component of the electric field in p−2)The pressure (N mfThe fluid phasepThe particle phasevfThe fluid velocityvpThe particle velocityThe authors have no conflict of interest related to this study.


S. pneumoniae (SPN) from the USA, as well as the resistance (R) mechanisms in tetracycline (TET) non-susceptible (NS) SPN.Major guidelines recommend β-lactams, macrolides, doxycycline (DOX) or respiratory quinolone monotherapy for outpatients with non-severe community-acquired bacterial pneumonia (CABP). Combination therapy is recommended for outpatients with comorbidities. Omadacycline (OMC) was equivalent to moxifloxacin as monotherapy for adults with CABP and was approved for CABP by the US FDA (2018). The activity of OMC and comparators was evaluated against 1,038 SPN from 31 USA centers (2019-2021) were tested by CLSI broth microdilution. Isolates were from CABP (933), bloodstream infection (72), or nosocomial pneumonia (33). A selection of 119 SPN with DOX MIC of 0.25 - >8 mg/L were subjected to genome sequencing for screening of acquired TET-R genes and target site mutations, and serotyping (ST).tet(M), and TET-NS had low S to DOX (6.6% S) and azithromycin (3.3% S). TET target site mutations were not observed. SPN belonged to 21 ST; 22F and 35B were the most common among TET-S SPN, whereas 15A, 19A, 09N, and 23A were common among TET-NS SPN.Most SPN isolates were susceptible (S) to OMC , levofloxacin  and tigecycline . Other agents had limited activity overall  with decreased S against isolates from certain US regions (Table). Only OMC (100% S), LEV (96.8% S) and TIG (96.7% S) were active against TET-NS  SPN. Cefpodoxime (70.5% S) and amoxicillin-clavulanate (82.0% S) had suboptimal activity against this R subset and other agent had S ≤36.1%. Isolates from the Pacific region tended to be more S than those from other regions. All TET-NS and 1 TET-S  isolates carried tet(M).Options recommended for the empiric treatment of outpatients with CABP show low S against SPN from the US, except against isolates from the Pacific region. Tet(M) remains the dominant R mechanism, which did not affect OMC activity but significantly altered DOX activity. These data suggest that OMC represents a potential empiric option for treating pneumonia caused by SPN in the USA, including against isolates carrying Lalitagauri M. Deshpande, PhD, Melinta: Grant/Research Support|Paratek: Grant/Research Support Michael D. Huband, BS, BARDA: This study has been funded in part by BARDA under Contract No. 75A50120C00001.|Entasis: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support Sarah Charbon, MHS, MLS(ASCP)CM, Paratek: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|bioMerieux: Grant/Research Support|Cipla: Grant/Research Support|CorMedix: Grant/Research Support|Entasis: Grant/Research Support|Melinta: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Basilea: Grant/Research Support|Cipla: Grant/Research Support|Entasis: Grant/Research Support|GSK: Grant/Research Support|Paratek: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support


Plan sponsors encourage the use of mail order pharmacies because they believe mail order dispensing will lower their prescription drug costs. Health plans and pharmacy benefit management companies (PBMs) usually offer patients substantially lower copayments to incentivize them to use mail order pharmacies. A number of health plans and PBMs now require patients to use these pharmacies for maintenance prescriptions.To (a) compare costs for prescriptions dispensed through mail order and retail pharmacies in Medicare Part D plans and (b) examine whether mail order or retail pharmacies provided lower all third-party costs for each of the top 300 products; the relationship between whether a product was available generically and whether mail order or retail pharmacies provided lower prices; and the generic substitution rates at mail order and retail pharmacies.The sample for this study consisted of 2010 Medicare Part D prescription drug data for the 300 products with the highest sales at mail order pharmacies. The prescriptions included in the study were dispensed in the initial coverage limit phase of Part D by retail or mail order pharmacies to patients who were insured by Part D for 12 months in 2010, who received no Part D subsidies, and who were alive for the full year in 2010. Mean-per-unit costs were calculated for both mail order and retail prescriptions for each of the top 300 products. Products were defined by Medi-Span Generic Product Indentifier. Summary statistics for the overall costs of mail order and retail prescriptions were calculated as the weighted mean-per-unit costs of the top 300 products. The weighting factor for both mail order and retail prescriptions included both the mail order quantity dispensed per prescription and the number of prescriptions dispensed. Weighting both mail and retail prescriptions by mail order quantities dispensed and numbers of prescriptions ensured that the results reflected actual cost differences rather than differences in the mix or quantities of prescriptions dispensed. These calculations were made for total costs, costs covered by the Medicare Standard Benefit (MSB), costs paid by all third-party payers (including Medicare), and patient costs.The top 300 products accounted for 84.8% of mail order costs. Among all prescriptions in the sample—both mail order and retail—mail order prescriptions accounted for 7.8% of prescriptions dispensed and 14.1% of total spending. Comparison of 90-day or greater supplies indicated that costs per unit of medication for retail pharmacies were lower for total costs ($0.94 for retail pharmacies vs. $0.96 for mail order pharmacies), MSB costs ($0.59 for retail pharmacies vs. $0.63 for mail order pharmacies), and all third-party payer costs ($0.64 for retail pharmacies vs. $0.72 for mail order pharmacies), but higher for patient costs ($0.31 for retail pharmacies vs. $0.24 for mail order pharmacies). Retail pharmacies had lower all third-party payer costs for 244 products, while mail pharmacies had lower costs for 56 products. Retail pharmacies were more likely to have lower costs for products that included generic alternatives, while mail order pharmacies were more likely to have lower costs for products that included only branded drugs. Generic substitution rates were 91.4% for retail pharmacies versus 88.8% for mail order pharmacies. Results from secondary analyses that compared all prescriptions which met the inclusion criteria, regardless of days supply, and that compared exactly 90-day supplies, yielded similar results.Third-party payers, including Medicare, paid more for prescriptions dispensed at mail order pharmacies than for those dispensed at retail pharmacies in the Medicare Part D program. The higher payments appeared to result, for the most part, because of higher patient cost sharing at retail pharmacies. Further, total costs—including both third-party payer and patient payments—for 90-day and 90-day or greater supplies were lower at retail pharmacies than at mail pharmacies. These results suggest that, all other things being equal, Medicare Part D plan sponsors do not realize savings when patients use mail order pharmacies.


Adherence to antiretroviral therapy (ART) remains the main predictor of sustained HIV virologic suppression for people with HIV (PWH). Mail-order pharmacy services are often offered to patients as an alternative option to traditional pharmacy services. Some payers mandate ART to be dispensed from specific mail-order pharmacies regardless of patient choice complicating ART adherence for patients affected by social disparities. Yet, little is known about patient perspectives regarding mail-order mandates.Eligible patients of the HIV program at University of Nebraska Medical Center with experience receiving ART from both a local and mail-order pharmacy were invited to complete a 20-question survey with three core sections: experiences/perspectives on local and mail-order pharmacy settings; pharmacy attributes rankings; and pharmacy preference. Paired t-tests and Mann-Whitney tests were used to compare the agreement scores of pharmacy attributes.Sixty patients  responded to the survey. Mean age was 52 years. Most were male (93%) and White (83%). The majority of participants were on ART for HIV treatment (90%) and 60% were using mail-order pharmacies for their prescription services. Significant scoring differences (p<0.05) were observed for all pharmacy attributes favoring local pharmacies. Refilling ease was the most important attribute noted. More respondents (68%) preferred local pharmacies versus mail-order pharmacies. Payer associated mail-order pharmacy mandates were experienced by 78% with half believing the mandates impacted their medical care negatively.In this cohort study, respondents preferred local pharmacies compared to mail-order pharmacy for ART prescription services and noted ease of refilling as the most important pharmacy attribute. Two-thirds of respondents believed mail-order pharmacy mandates negatively affected their health. Insurance payers should consider the removal of mail-order pharmacy mandates to allow patient choice of pharmacy, which may help remove barriers to ART adherence and improve long-term health outcomes. Adherence to antiretroviral therapy (ART) among people with HIV (PWH) is essential to sustain viral suppression, reduce the development of HIV drug resistance, and improve long-term health outcomes . SimilarVarious strategies have shown to improve ART adherence, such as smartphone applications and blister packages ,12. An aDue to high cost and complexity, ART regimens are increasingly designated by payers as specialty medications on insurance formularies. Specialty pharmacies often facilitate dispensations of complex, high cost, high touch specialty medications and provide adherence support . While higher ART adherence rates among PWH have been observed at specialty pharmacies ,17, receLittle is known about patient perspectives regarding payer administered mail-order mandates and pharmacy services for ART among PWH or those on PrEP. Further insight into patients’ perspectives on pharmacy settings may help remove barriers to ART adherence and improve long-term health outcomes. In this study, we aimed to evaluate patient perspectives on various aspects of prescription services among participants with experience receiving pharmacy services from both a local pharmacy and a mail-order pharmacy.We conducted a prospective, cross-sectional survey study of patients receiving care at the University of Nebraska Medical Center HIV clinic, the Specialty Care Center (SCC). Inclusion criteria for study entry were: 1) age greater than 19 years old; 2) retained in care for ≥6 months; 3) prescribed ART for HIV treatment or PrEP; and 4) experience receiving pharmacy services from both a local pharmacy and mail-order pharmacy. Participants were excluded if they did not complete the survey entirely, were participating in an industry study, or non-English speaking.Local pharmacies were defined as an “in-town, local pharmacy, where patients had the option to pick up medications” whereas a mail-order pharmacy was defined as an “out-of-town pharmacy, where the medications had to be mailed to patients’ home”.We designed a survey to measure the patients’ perspectives and preferences of pharmacy services. The survey consisted of 20 questions divided into three sections: experiences/perspectives on both pharmacy settings, ranking of pharmacy attributes, and pharmacy preference. The first section used a 5-point Likert scale (1 [strongly disagree] to 5 [strongly agree]) to inquire about patient satisfaction, general pharmacy experience, medication ordering/access/dispensing, and clinical services for both pharmacy settings. In this section, the respondents were asked to score each attribute separately for both pharmacy settings . The second section asked participants to rank the following pharmacy service attributes in order of importance: trust in and relationship with the pharmacy staff, ease of ordering medication refills, additional adherence services, expedited medication delivery (couriered or overnight), and access to the pharmacist when needed. The last section assessed overall pharmacy preference, whether participants had ever been mandated to use a specific mail-order pharmacy, and whether they believed the mandate negatively affected their medical care.All eligible participants were contacted in-person during a scheduled clinic visit or through electronic communication through the electronic health record, Epic . Surveys were disseminated via two methods: REDCap ,23 or viThe University of Nebraska Medical Center’s Institutional Review Board (IRB #741-21-EP) approved this study. Participants provided written informed consent prior to survey initiation.Descriptive statistics were used to summarize patient demographics and baseline characteristics. Counts and percentages were used for categorical data with median (range) or mean (standard deviation [SD]) used for continuous data. The Mann-Whitney test was used to compare the median value of agreement questions based on preference  and requirement (no mail-order pharmacy mandate vs. mail-order pharmacy mandate). Fisher’s exact test was used to evaluate the association demographic characteristics and preference. All analyses were done using SAS Version 9.4, SAS Institute Inc., Cary, NC. A p-value of less than 0.05 was considered statistically significant.Table 1 summarizes baseline characteristics.Sixty patients  responded to the survey. The median age was 52  years. Most of participants were male (93%), White (83%), not Hispanic (95%), and commercially insured (83%). Six respondents (10%) were on ART for PrEP. Mean adherence, by percentage of days covered, to ART was high overall at 91%. Among PWH, 50 (93%) and 54 (100%) respondents had HIV RNA <50 and <200 copies/mL, respectively. At the time of survey completion, 58% were receiving prescription service from a mail-order pharmacy. Fig 1.Respondents were asked 16 questions regarding their perspectives on pharmacy services for both local and mail-order pharmacy settings. Specific focuses included general pharmacy experience, pharmacy settings, and medication ordering/access/dispensing and clinical services. Agreement scores were consistently significantly higher for the local pharmacy setting . A descriptive summary of mean pharmacy attribute scoring for both local and mail-order pharmacy settings is described in Fig 2).Respondents ranked five components: trust in pharmacy, ease of refilling, additional services provided, delivery methods and pharmacist accessibility. Respondents ranked “ease of ordering medication refills” as the most important attribute; whereas, “additional services to help me take my medications as prescribed” was ranked least important . However, no significant differences were observed when comparing respondent pharmacy preference based on whether they had experienced a mail-order pharmacy mandate (p = 0.2604) or by baseline characteristics (S1 Table). No significant differences in pharmacy preference was observed based on respondent demographics.Forty-seven participants (78%) reported their insurance had mandated use of a specific pharmacy for their ART. Further, 43% (20/47) of these respondents believed being mandated to use a specific mail-order pharmacy impacted their medical care. More respondents preferred a local pharmacy  (Table 2). When comparing attribute scores for the local pharmacy setting, significant higher differences were observed for respondents preferring a local pharmacy compared to mail-order pharmacy for refill ordering ease (p = 0.0098), pharmacy delivery services (p = 0.0292), on-time refills (p = 0.0004), prescription counseling offered (p = 0.0134), and pharmacy knowledge of health condition (p = 0.0107). Only attribute scoring for pharmacy delivery services (p = 0.0233) was significantly higher when comparing local pharmacy attribute scores among respondents who had experienced a mail-order pharmacy mandate vs not.Mean scores for pharmacy attributes for both pharmacy settings were individually compared by respondent pharmacy preference and whether they had experienced a mail-order pharmacy mandate , pharmacy cares about my health/wellbeing (p = 0.0010), privacy (p = 0.0441), refill ordering ease (p = 0.0002), pharmacy delivery services (p = 0.0251), on-time refills (p = 0.0208), offering urgent prescription delivery (p = 0.0004), ease of pharmacist access (p = 0.0238), trust in pharmacist (p = 0. 0019) and pharmacy collaboration with providers (p = 0.0067) for respondents preferring a local pharmacy vs mail-order pharmacy. Similarly, significantly lower differences were observed in pharmacy attribute score comparisons for the mail-order setting for general satisfaction (p = 0.0090), pharmacy cares about my health/wellbeing (p = 0.0037), refill ordering ease (p = 0.0055), offering urgent prescription delivery (p = 0.0167), ease of pharmacist access (p = 0.0013), pharmacy knowledge of health condition (p = 0.0169), and pharmacy collaboration with providers (p = 0.0290) among respondents who had experienced a mail-order pharmacy mandate vs not.In this cross-sectional, cohort study, we surveyed PWH and patients on PrEP regarding their perspectives/experience receiving pharmacy services from both local and mail-order pharmacy settings. Overall, significantly, higher scores were observed for the local pharmacy setting and the majority of respondents preferred the local pharmacy setting. Respondents believed ease of ordering ART refills was the most important pharmacy attribute regardless of pharmacy setting.Fig 1). This is consistent with a Veterans Affairs cohort study by Desai and colleagues, which found 47% of participants reporting prescription delivery delays leading to missed ART dosing while using mail-order service [While mail-order pharmacies are thought to improve access to medications and ultimately increase adherence –17, many service .S1 Table). Importantly, respondents ranked “ease of refills” as the most important pharmacy attribute and this was further evident in respondent mean scoring comparisons for both local and mail-order pharmacy settings (Table 2) based on preference . Similarly, “prescription delivery services” and “on-time refills” were notable for differences in scoring comparisons. Thus, ensuring a streamlined, easy ordering/refilling process and/or removing any associated barriers should be prioritized by pharmacies regardless of setting. Notably, respondents ranked “additional adherence services” least important and this was similarly evident in scoring comparisons with no significant differences observed. This is especially important given payers high prioritization of medication adherence for quality ratings [Most respondents (68%) reported a preference for the local pharmacy for prescription services. Respondents scoring generally followed their pharmacy setting preference. However, no significant differences in pharmacy preference was observed based on demographic characteristics or mail-order pharmacy mandate experience . These data portray negative patient perspectives and experiences concerning mail-order pharmacy mandates. This aspect further highlights that mail-order pharmacy mandates may themselves may be an adherence barrier, particularly with PWH, and emphasizes that patients prefer to choose which pharmacy setting works best for them individually. Insurance payers should consider the removal of mail-order pharmacy mandates for ART prescriptions to be more accommodative of all patients’ circumstances and to help with progression of the initiatives laid out by the Ending the HIV Epidemic [The majority of our respondents (78%) reported experiencing a mail-order pharmacy mandate and roughly, half believed the mandate negatively impacted their medical care. Respondents reporting a mail-order pharmacy mandate generally were less satisfied with pharmacy services, felt the pharmacy cared less about their health/wellbeing, collaborated less with medical providers, found the ease/urgency of refilling more challenged, and pharmacist access/knowledge were lacking based on scoring comparisons for mail-order pharmacy Click here for additional data file. 28 Apr 2023Patient Perspectives of Antiretroviral Pharmacy Services: A Cross-Sectional Cohort StudyPONE-D-23-02690Dear Dr. HavenWe’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********  5. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: The abstract is well written. The introduction is well written with reference to similar studies and knowledge gap was emphasize which gave fundamental reasons for this study to be carried out. The method is replicable and the results well presented. The authors have discussed the study well enough and made sound recommendations.Reviewer #2: A good work, Can be published without any changes.The work is good and very much appropriate.I recommend it for the publication without any modifications.It will provide a students and researchers some base.**********  6. 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It is largely unknown how imatinib distributes within gastrointestinal stromal tumours (GISTs) and whether imatinib plasma concentrations correlate with tumour concentrations, whilst plasma concentrations are used to optimize treatment. In this exploratory study imatinib tumour concentrations were measured in different tumour regions after neoadjuvant treatment. The goal of this study was to reveal tumour distribution patterns and to investigate the possible correlation between plasma and tumour concentrations. Imatinib appears to accumulate in tumour tissue since tumour concentrations were higher compared to plasma concentrations. No clear distribution pattern within the tumour could be identified. Interpatient variability in tumour concentration was almost threefold higher than interindividual variability in plasma concentration. No correlation between tumour and plasma concentrations could be identified, nor with pathological treatment response.Imatinib plasma trough concentrations are associated with efficacy for patients treated for advanced or metastatic KIT-positive gastrointestinal stromal tumours (GISTs). This relationship has not been studied for patients treated in the neoadjuvant setting, let alone its correlation with tumour drug concentrations. In this exploratory study we aimed to determine the correlation between plasma and tumour imatinib concentrations in the neoadjuvant setting, investigate tumour imatinib distribution patterns within GISTs, and analyse its correlation with pathological response. Imatinib concentrations were measured in both plasma and in three regions of the resected primary tumour: the core, middle part, and periphery. Twenty-four tumour samples derived from the primary tumours of eight patients were included in the analyses. Imatinib tumour concentrations were higher compared to plasma concentrations. No correlation was observed between plasma and tumour concentrations. Interpatient variability in tumour concentrations was high compared to interindividual variability in plasma concentrations. Although imatinib accumulates in tumour tissue, no distribution pattern of imatinib in tumour tissue could be identified. There was no correlation between imatinib concentrations in tumour tissue and pathological treatment response. Gastrointestinal stromal tumours (GISTs) are the most common, though rare in occurrence, mesenchymal tumours that arise throughout the gastrointestinal tract, predominantly in the stomach (50–60%) or small intestines 20–30%) . The maj0–30% . TFor the treatment of advanced or metastatic GISTs, it has been demonstrated that imatinib trough plasma concentrations above 1100 μg/L at steady state conditions are associated with longer treatment benefit . NeverthHowever, even in patients with plasma concentrations exceeding the threshold, resistance is still unavoidable ,8. It haWe hypothesize that a wide range of factors may complicate imatinib tumour penetration, such as decreased tumour vascularity, treatment-induced necrosis, or differential expression of transporters ,14. To dIn this exploratory study, patients treated with imatinib for GIST in the neoadjuvant setting and candidates for tumour resection according to standard care were asked to participate. Patient and tumour characteristics were collected from the electronic patient records, as well as the imatinib starting dose, the imatinib dose prior to surgery, treatment duration, mutational status, and pathological treatment response defined as the percentage of tumour necrosis or hyalinization as determined by a sarcoma pathologist . In all The tumour tissue samples were weighed and homogenised with beads in 1 mL of DMSO. After homogenization, both an undiluted and 10-times-diluted sample were prepared. For the quantification of imatinib in plasma and tumour tissue, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was used in a similar manner to a previously described method, with minor modifications . Detailep-value < 0.05 was considered to be statistically significant.For each plasma sample, the date and time of the last imatinib intake and date and time of blood sampling were recorded. The plasma trough concentration was estimated using log-linear extrapolation based on the elimination half-life of imatinib and time after dose, as previously described . In ordet-test was performed. A tumour-to-plasma ratio was calculated for each patient using the average imatinib tumour tissue concentrations and the plasma trough concentration.Imatinib tumour concentrations in different tumour regions within the same tumour sample were evaluated to investigate the distribution pattern of imatinib within GISTs. Results below the lower limit of quantification (<LLOQ) were replaced by the value LLOQ/2 making it possible to handle these data in the analysis, which can be considered a common approach in clinical pharmacology studies ,19. BothBetween August 2019 and December 2022, eight patients with GIST who were treated with neoadjuvant imatinib, and for whom tumour resection was indicated, were included in this study. Patient and tumour characteristics are shown in Some patients used comedications for the treatment of comorbidities as listed in An overview of measured tumour imatinib concentrations as well as the plasma concentrations are presented in In two patients, imatinib concentrations were measured in both primary tumour and liver metastases. In patient 7 the average tumour concentrations in the primary tumour and the liver metastases were 2.8 and 6.8 ng imatinib per mg wet tissue, respectively. For patient 8, the average tumour concentrations in the primary tumour and the two liver metastases, liver segment 4a and 4b, were 1.0, 2.1, and 1.4 ng imatinib per mg wet tissue, respectively. Based on a CT scan two months prior to surgery, there appeared to be a recurrent vital nodule (‘nodule within the mass’) present within the metastasis located in liver segment 4b . Therefop = 0.077). No correlation was found between imatinib tumour tissue concentrations and plasma concentrations  (p = 0.117) (The measured plasma concentration prior to surgery ranged from 700 to 2175 μg/L (median 954 μg/L). The calculated plasma density factor was 1009 g/L, resulting in a median plasma concentration of 0.9 (range 0.7–2.2) ng imatinib per mg plasma. A mean (±sd) tumour-to-plasma ratio of 7.4 ± 9.0 was found. There was no statistically significant difference between mean tumour imatinib concentrations and imatinib plasma concentrations (= 0.651) a, nor wi= 0.117) b. IntertIn this exploratory study, mean tumour imatinib concentrations were found to be higher compared to imatinib plasma concentrations. No correlation was found between plasma and tissue imatinib concentrations. Despite relatively low interpatient variability in plasma concentrations, high differences were observed in tumour imatinib concentrations between patients. No general distribution pattern of imatinib within primary GISTs could be identified. No correlation was found between imatinib tissue concentrations and pathological treatment response.The median plasma concentration of 954 μg/L prior to surgery seems to be comparable with plasma concentrations described in other real-life cohorts. In both TDM and non-TDM cohorts, median plasma concentrations of 756 to 1082 μg/L were reported ,22,23,24In all tumour lesions the mean imatinib concentration outweighed the corresponding plasma concentration with an overall mean tumour-to-plasma ratio of 7.4. Theou et al. found similar results in experiments with mice, as imatinib tissue concentrations were 6- to 8-fold higher compared to plasma . BerglunSurprisingly, no correlation was found between plasma and tumour concentrations, indicating that imatinib does not freely diffuse within the tumour and that other factors may play a role in the inequal distribution of imatinib over tumour tissue. We speculate that other factors, such as lysosomal sequestration and a reduction in tumour vascularization, may play a dominant role in the distribution of imatinib. Abu Sammour et al. confirmed the latter hypothesis with their findings, showing a decreased vasculature in GIST liver metastasis, mostly in the tumour core, compared to normal liver tissue after imatinib treatment . They shAlthough, to date, no standardized pathologic evaluation criteria of GISTs exist, the EORTC-STBSG has proposed a soft-tissue sarcoma response score based on the proportion of vital tumour cells . With thA limitation of our study is that it remains unknown where exactly in the tissue imatinib is located. The measurement of imatinib concentrations in homogenized tumour tissue is a sum of intra- and extracellular fluids. Imatinib might be unequally distributed in different cell compartments. It is unknown to which extent imatinib reached the target site intracellularly. Additionally, due to the heterogeneity of the tumours with regards to its size and shape, it is difficult to distinguish the different regions of the tumour. This is especially the case for small tumour samples. However, biopsies from tumour resections were taken by trained pathology analysts in a sarcoma centre, thereby also reducing sample errors. Nevertheless, the ability to sample three different regions of the tumour due to complete resection is also a strength of this study, as we were, thereby, able to explore imatinib tumour distribution. It is important to highlight that in the present study all patients were treated in the neoadjuvant setting. It is unknown if imatinib keeps accumulating in tumour tissue after prolonged treatment or if a plateau phase is reached. Since we only measured tissue concentrations at one time point it remains unknown if the imatinib tumour concentrations in the adjuvant and metastatic setting will be in the same range as in the neoadjuvant setting. Although the sample size of this study is relatively small, the sample size is deemed sufficient to conclude that a distribution pattern of imatinib in GISTs cannot be identified.This exploratory study revealed that imatinib concentrations in tumour tissue outweighed plasma concentrations and that no correlation was observed between plasma- and tumour concentrations. Interpatient variability in tumour concentrations was high compared to interindividual variability in plasma concentrations. Although imatinib accumulates in tumour tissue, no distribution pattern of imatinib in tumour tissue could be identified. We hypothesize that other factors such as lysosomal sequestration, tumour necrosis, and a reduction in tumour vascularization may be important factors involved in tumour distribution of imatinib. In the literature, imatinib plasma concentrations seem to be highly correlated with efficacy. However, the results of this study highlight that there is no correlation between imatinib tumour tissue concentrations and pathological treatment response. Based on the results of this study, measuring tumour imatinib concentrations in GISTs seems to be redundant.