Higher Initial Dose Research Articles

De Novo Psychiatric Disorders in a Woman With Giant Prolactinoma Treated With Cabergoline

Dopamine agonists are the first-line treatment of prolactinomas. The risk of developing de novo psychiatric symptoms during dopamine agonist therapy is low. Herein, we report the case of a 42-year-old woman with a giant prolactinoma who developed a psychiatric disorder after 1 day of cabergoline therapy initiation. She presented with amenorrhea, galactorrhea, headaches, and disturbed vision. Biological investigations revealed hyperprolactinemia (2975 ng/ml) with gonadotropin deficiency. Pituitary MRI showed a giant pituitary adenoma. The patient was treated with cabergoline at the dose of 1 mg twice weekly. One day after the treatment initiation, she developed acute delirium with temporospatial disorientation and compulsive medication use. These symptoms disappeared 1 week after the reduction of the dose of cabergoline. Patients with hyperprolactinemia receiving an initial high dose of cabergoline may develop changes in mood and behavior regardless of prior psychiatric history.

Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis

ObjectivesTo investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC ‘bridging’ in the initial treatment step and to identify factors that may affect this.MethodsData from 7...

High initial FSH dosage reduces the number of available cleavage-stage embryos in a GnRH-antagonist protocol: Real-world data of 8,772 IVF cycles from China.

To evaluate the relationship between the initial follicle stimulating hormone (FSH) dose and the number of available cleavage-stage embryos in in vitro fertilization (IVF) cycles.We included 8772 fresh IVF cycles using a GnRH antagonist protocol at the Genetic and Reproductive Institution of Chongqing, P. R. China, from January 2016 to June 2021.Univariate linear regression was used to evaluate the associations between the initial FSH dosage (≤ 150, 187.5-200, 225, 250, or 300 IU) with the number of available cleavage-stage embryos on day 3.A two-factor linear regression model was applied to calculate the threshold effect of the initial FSH dosage on the number of available cleavage-stage embryos based on a smoothing plot. The initial FSH dose was negatively correlated with the number of available cleavage-stage embryos, independent of female age, body mass index, infertility factors, duration of infertility, anti-Müllerian hormone and basal FSH levels, antral follicle count and the proportions of patients with poor ovarian response or polycystic ovarian syndrome. Using a two-factor linear regression model, we calculated the inflection point to be 200 IU of FSH. The relationship between the initial FSH dose and the number of available cleavage-stage embryos was nonlinear. The initial FSH dose was negatively associated with the number of available cleavage-stage embryos when the initial FSH dose was > 200 IU. Therefore, clinicians should try to avoid unnecessarily increasing the initial FSH dose.

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.

Effective antibiotic dosing in the presence of resistant strains.

Mathematical models can be very useful in determining efficient and successful antibiotic dosing regimens. In this study, we consider the problem of determining optimal antibiotic dosing when bacteria resistant to antibiotics are present in addition to susceptible bacteria. We consider two different models of resistance acquisition, both involve the horizontal transfer (HGT) of resistant genes from a resistant to a susceptible strain. Modeling studies on HGT and study of optimal antibiotic dosing protocols in the literature, have been mostly focused on transfer of resistant genes via conjugation, with few studies on HGT via transformation. We propose a deterministic ODE based model of resistance acquisition via transformation, followed by a model that takes into account resistance acquisition through conjugation. Using a numerical optimization algorithm to determine the 'best' antibiotic dosing strategy. To illustrate our optimization method, we first consider optimal dosing when all the bacteria are susceptible to the antibiotic. We then consider the case where resistant strains are present. We note that constant periodic dosing may not always succeed in eradicating the bacteria while an optimal dosing protocol is successful. We determine the optimal dosing strategy in two different scenarios: one where the total bacterial population is to be minimized, and the next where we want to minimize the bacterial population at the end of the dosing period. We observe that the optimal strategy in the first case involves high initial dosing with dose tapering as time goes on, while in the second case, the optimal dosing strategy is to increase the dosing at the beginning of the dose cycles followed by a possible dose tapering. As a follow up study we intend to look at models where 'persistent' bacteria may be present in additional to resistant and susceptible strain and determine the optimal dosing protocols in this case.

RAPIDLY PROGRESSING DERMATOMYOSITIS-ASSOCIATED RESPIRATORY FAILURE SUCCESSFULLY STABILIZED WITH EXTRACORPOREAL MEMBRANE OXYGENATION

RAPIDLY PROGRESSING DERMATOMYOSITIS-ASSOCIATED RESPIRATORY FAILURE SUCCESSFULLY STABILIZED WITH EXTRACORPOREAL MEMBRANE OXYGENATION

OA06 A complex case of thigh pain in Granulomatosis with Polyangiitis (GPA)

OA06 A complex case of thigh pain in Granulomatosis with Polyangiitis (GPA)

Management of Subacute Thyroiditis - A Systematic Review of Current Treatment Protocols.

PurposeThis systematic review endeavors to find an effective treatment protocol for subacute thyroiditis (SAT) to minimize side effects, recurrence and long-term hypothyroidism.Materials and MethodsWe analyzed available original studies on treatment protocols for SAT. A thorough literature search was performed on the following online databases PubMed, Cochrane library nd Google Scholar using appropriate keywords for choosing relevant articles. Two reviewers assessed the methodological quality of selected articles independently using a critical appraisal instrument. The results were analyzed and synthesized qualitatively using the level of evidence method.ResultsThe literature search retrieved a total of 460 publications after abstract screening; out of which 36 articles met the inclusion criteria. After full text screening, 23 articles were further excluded as they were focusing on aspects of SAT other than management, the remaining 15 articles were investigated for both reliability and validity. Thirteen studies provided low-quality evidence, and two randomized control trials (RCT) provided a high quality of evidence. Steroid therapy was found to be the most effective for moderate to severe SAT and provided relief from acute symptoms but was found to not be a risk factor for recurrence. Low initial doses of steroid (15 mg) were preferred over high initial dosage (30–40 mg). Furthermore, a look into the mode of steroid delivery (RCT) revealed that intrathyroidal steroid therapy can potentially become a safer and faster mode of therapy. The duration of tapering was found to be of significance as a short tapering period was linked with greater recurrence rates.ConclusionLow initial doses of steroid along with an extended tapering period may help lower recurrence rates; also, intrathyroidal steroid injections are potentially a better alternative to oral prednisone (PSN) with regard to safety and speed of action. However, the evidence is of moderate quality and further investigation is required.

Allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: Signal detection and preventability from Vietnam National pharmacovigilance database.

Allopurinol, the first-line medication for hyperuricemia is well-known for its association with severe cutaneous adverse reactions, especially Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In the current study, we analysed the Vietnamese spontaneous reporting database to identify signals and preventability of allopurinol-induced SJS/TEN in Vietnam from 2010 to 2019. Signal generation was assessed using the case/non-case method. Reporting odds ratios (RORs) and 95% confidence intervals (95% CI) were calculated. Among 72,822 spontaneous ADR reports submitted to the Vietnam National Drug Information and Adverse Drug Reaction Monitoring Centre, 392 reports were on SJS/TEN, of which, 65 cases (16.6%) were related to allopurinol. The signals of allopurinol-induced SJS/TEN in Vietnam started in 2014 (ROR of 3.531, 95% CI: 1.830-6.810) and annually increased until 2019 (ROR of 11.923, 95% CI: 8.508-16.710). The preventability assessment showed that no allopurinol-induced SJS/TEN case was definitely unpreventable. 61.6% of the SJS/TEN cases were avoidable because they were associated with inappropriate prescribing such as unapproved indications, too high initial dose and even rechallenging in patients with a history of allopurinol allergy. The signals of allopurinol-induced SJS/TEN in Vietnam started in 2014 and annually increased until 2019. Our first report specifically focusing on the ADR preventability of allopurinol showed that correction of medical errors relating to prescription could prevent more than 60% of SJS/TEN cases in Vietnamese allopurinol users. This is a feasible and practical solution, provided that there would be a systematic change in both healthcare systems and public awareness.

Neuromyelitis optica spectrum disorders and anti-myelin oligodendrocyte glycoprotein positive optic neuropathies.

To describe the clinical characteristics and treatments associated with antibody positive optic neuropathies including anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin 4 (AQP4), alongside diagnostic modalities, investigations, and outcomes. A cross-sectional single-centre retrospective case series consisting of 16 patients including 12 anti-MOG positive patients and 4 anti-AQP4 positive patients. Each of these patients had clinical signs and symptoms of optic neuritis and consisted of all patients who had a positive blood antibody result in our centre. Clinical findings including presence of a relative afferent pupillary defect, colour vision and disc assessment were recorded. Structured clinical exam and multimodal imaging was undertaken sequentially on each. Optical coherence tomography (OCT) scanning was preformed to examine the correlation between ganglion cell layer (GCL) thickness and visual acuity (VA) at presentation and as a determinant of final visual outcome in both groups. Initial and long-term treatment is also summarised. A total of 16 patients were included in the study consisting of 12 anti-MOG and 4 anti-AQP4 positive patients. Nine of the 16 patients were female and the average age of onset was 29.2y in the MOG group and 42y in the AQP4 group. There was no statistically significant correlation (Pearson correlation) between GCL thickness and presenting and final VA [r(10)=0.081, P=0.08 and r(10)=0.089, P=0.34 respectively]. The same statistical analysis was performed for the correlation between retinal nerve fibre layer (RNFL) and VA and similar outcomes were observed [r(10)=0.04, P=0.22 and r(10)=0.09, P=0.04]. No correlation was seen for initial RNFL thickness and final visual outcome in this group either [r(2)=0.19, P=0.38]. Visual field testing and radiological findings for each group are described. No correlation between initial VA or RNFL and final visual outcome is identified. A broad range of visual field and radiographic findings are identified, a consensus on treatment of neuromyelitis optica spectrum disorders and anti-MOG positive optic neuropathies has yet to be accepted but initial high dose immunosuppression followed by low dose maintenance therapy is favoured.

A growing heart: a literary review on clozapine-induced Myocarditis

IntroductionClozapine, a unique antipsychotics, is well known for its adverse effects. Myocarditis is a rare but life-threatening complication, however not monitored at a global scale.ObjectivesThis work aims to review the literature on clozapine-induced myocarditis.MethodsPubmed and Google Scholar search using Mesh terms clozapine, myocarditis, clozapine-induced myocarditis.ResultsClozapine-induced Myocarditis (CIM) is potentially fatal, with mortality rates environ 21%. According to the World Health Organization Monitoring Program, notification rate is 0,93%, nonetheless incidence found in literature varies dramatically. Highest rates are reported in Australia, where this relationship was first established and a complete monitoring protocol is compulsory in all patients starting clozapine, which causes some authors to defend this condition is generally undernotified. Underlying mechanisms are not fully understood, but an imunomediated hypersensitive reaction occurring in the first 3-4 weeks after treatment is suggested. CIM is rare after 6 weeks. Risk factors include age, cardiac disease, initial high dose, rapid titration and simultaneous valproate or other antipsychotics use. The most common symptoms, fever, tachycardia, dyspnea and malaise, are non-specific and can be indistinguishable from other clozapine benign adverse effects. Analytically, C-reactive protein and Troponine elevation are the most specific diagnostic markers, therefore the most suitable for monitoring. Prompt cardiological observation for further evaluation should be seeked whenever CIM is suspected.ConclusionsDiagnosis of CIM can be challenging. Systematic monitoring is not consensual but may increase detection, prevent severe outcomes and help clinicians decide whether to keep or suspend therapy. Clozapine is beneficial and shouldn’t be avoided or unjustifiably discontinued.DisclosureNo significant relationships.

Establishing combination PAC‐1 and TRAIL regimens for treating ovarian cancer based on patient‐specific pharmacokinetic profiles using in silico clinical trials

AbstractOvarian cancer is commonly diagnosed in its late stages, and new treatment modalities are needed to improve patient outcomes and survival. We have recently established the synergistic effects of combination tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and procaspase activating compound (PAC‐1) therapies in granulosa cell tumors (GCT) of the ovary, a rare form of ovarian cancer, using a mathematical model of the effects of both drugs in a GCT cell line. Here, to understand the mechanisms of combined TRAIL and PAC‐1 therapy, study the viability of this treatment strategy, and accelerate preclinical translation, we leveraged our mathematical model in combination with population pharmacokinetics (PKs) models of both TRAIL and PAC‐1 to expand a realistic heterogeneous cohort of virtual patients and optimize treatment schedules. Using this approach, we investigated treatment responses in this virtual cohort and determined optimal therapeutic schedules based on patient‐specific PK characteristics. Our results showed that schedules with high initial doses of PAC‐1 were required for therapeutic efficacy. Further analysis of individualized regimens revealed two distinct groups of virtual patients within our cohort: one with high PAC‐1 elimination and one with normal PAC‐1 elimination. In the high elimination group, high weekly doses of both PAC‐1 and TRAIL were necessary for therapeutic efficacy; however, virtual patients in this group were predicted to have a worse prognosis when compared to those in the normal elimination group. Thus, PAC‐1 PK characteristics, particularly clearance, can be used to identify patients most likely to respond to combined PAC‐1 and TRAIL therapy. This work underlines the importance of quantitative approaches in preclinical oncology.

1496-PUB: Augmenting Clinical Trial Data with In-Silico Evidence to Evaluate Initial Conversion Dose Changes for Technosphere Insulin (TI)

Background: TI is an inhaled mealtime insulin with ultra-rapid onset and short duration of action closely mimicking physiologic insulin. Clinical studies demonstrated a higher initial dose could result in faster titration to overcome a perceived lack of effect. The aim was to develop an in silico model to augment results of a study (NCT04849845) evaluating an increased initial conversion of TI from injected insulin vs. the current label in 20 adults with diabetes that showed significantly improved post-prandial control after 45 minutes. Methods: The in silico model characterizes blood glucose trends and outcomes utilizing published equations and distributions derived from real-world data sources. Inputs with the largest effects on glucose outcomes were combined to match study parameters to generate one million meal boluses. The model was validated using common modeling and simulation recommendations. Results: Model inputs were constrained to match clinical study parameters; in silico results substantiated and complemented in vivo safety and efficacy results with similar predictive values and acceptable hypoglycemia distributions. Conclusions: Clinical data augmented by in silico data support that an increased initial dose is not associated with any new safety concerns. Leveraging in silico data generates high quality evidence faster and with less risk to patients. Disclosure L.Desborough: Consultant; Luna, MannKind Corporation, Roche Diabetes Care, Securecell AG, Tandem Diabetes Care, Inc., Employee; Nudge BG, Inc. K.B.Kaiserman: Advisory Panel; Medtronic, Consultant; Medtronic, Employee; MannKind Corporation, Research Support; Medtronic, Speaker's Bureau; Medtronic, Stock/Shareholder; MannKind Corporation. J.Hanna: Employee; MannKind Corporation, Medtronic. K.Jaffe: None. J.Ulloa: Employee; MannKind Corporation, Medtronic, Stock/Shareholder; MannKind Corporation, Medtronic.

Medium Versus High Initial Prednisone Dose for Remission Induction in Lupus Nephritis: A Propensity Score-Matched Analysis.

The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1.0 mg/kg/day. However, recent studies reported noninferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30 mg/day or ≥40 mg/day. Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30 mg/day) and high prednisone groups (≥40 mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria <0.5 gm/day and no worsening in renal function. Glucocorticoid-related damage was also assessed. High-dose prednisone patients (n = 103; mean ± SD dose 48.6 ± 12.3 mg/day) achieved better rates of complete response compared to the medium group (n = 103; mean ± SD dose 24.2 ± 4.6 mg/day) (61.8% versus 38.2%; P = 0.024) at 12 months. The difference in response rates was reproduced for several subgroups (concomitant immunosuppressive treatment, proliferative/nonproliferative LN). Complete remission rates were higher at 2 years (67.8% versus 39%; P = 0.002) and 3 years (64.9% versus 49.1%; P = 0.025) after LN diagnosis. Cumulative glucocorticoid dose was comparable at 2 and 3 years. Glucocorticoid-related damage was accelerated in both groups for the same period. Higher initial prednisone doses (median 45 mg/day) achieved significantly better rates of complete renal response at 12 months in new-onset LN. Cumulative glucocorticoid dose and damage accrual were not different at 2 and 3 years after LN. Damage was more prominent in the late phases of LN in both groups, underlining the importance of rapid tapering and the need to implement alternative strategies.

The Use of High Initial Doses of Botulinum Toxin Therapy for Cervical Dystonia Is a Risk Factor for Neutralizing Antibody Formation-A Monocentric Cross-Sectional Pilot Study.

Background and Objectives: The present study aims to analyze the complex patient/treating physician interaction at onset of botulinum toxin (BoNT) therapy in patients with idiopathic cervical dystonia (CD) and the influence of high initial doses on long-term outcomes. Materials and Methods: A total of 74 CD patients with well-documented courses of BoNT treatment were consecutively recruited after written informed consent. Patients had to rate the amount of improvement of CD in percent of severity of CD at onset of BoNT therapy. They had to draw the course of disease severity (CoD) of CD from the onset of symptoms until the onset of BoNT therapy and from the onset of BoNT therapy until recruitment. The remaining severity of CD was estimated by the treating physician using the TSUI score. Demographic- and treatment-related data were extracted from the charts of the patients. Seventeen patients with suspected secondary treatment failure (STF) were tested for the presence of antibodies. Results: Depending on the CoD before BoNT therapy, three patient subgroups could be distinguished: rapid onset, continuous onset and delayed onset groups. Time to BoNT therapy, increase in dose and improvement were significantly different between these three groups. In the rapid onset group, with the highest initial doses, the best improvement was reported, but the highest number of patients with an STF and with neutralizing antibodies was also observed. Conclusion: The use of high initial doses in the BoNT therapy of CD is associated with a rapid response and quick success; however, it leads to an elevated risk for the development of a secondary treatment failure and induction of neutralizing antibodies.

Toksični megakolon posle iracionalne primene antibiotika u lečenju trudnice sa Covid-om 19 - prikaz slučaja

Introduction: Optimal management of toxic megacolon as a consequence of Cl. difficile colitis is still matter of controversy, as well as timing of available therapeutic modalities. In this article we report a case of severe C. difficile colitis associated with toxic megacolon in a pregnant patient with Covid 19, who was successfully treated conservatively. Case Report: A 33-years old pregnant woman contracted SARS-CoV-2 in the 32nd week of pregnancy. She was admitted to regional hospital and treated extensively by wide-spectrum antibiotics. After the delivery she developed severe form of Cl. difficile colitis with toxic megacolon. In spite of severe clinical picture, the patient was treated conservatively, with high initial oral doses of vancomycin, with subsequent tapering. The outcome of the treatment was complete recovery and colonic functions were regained completely. Conclusion: In conclusion, our case shows that in younger patients, who were fit before occurrence of Cl. difficile colitis and toxic megacolon, conservative therapy should be tried as long as possible before turning to colectomy, since chances for cure without surgery are considerable.

Prototyping a spinning adsorber submerged filter for continuous removal of wastewater contaminants

Adsorption process is widely used for the removal of wastewater contaminants. Classic adsorption units are fixed beds and membrane filtration systems. In this work a novel configuration of a bench scale spinning adsorber submerged filter is proposed. Different prototypes of cylindric, truncated cone or prismatic spinning adsorbers were studied using activated carbon of different particle sizes GAC (1.5 mm, Granulated), μGAC (0.475 mm, microGranulated), and cPAC (0.237 mm, coarse Powder) as adsorbent, and azorubine as model adsorbate. High maximum azorubine adsorptions per unit mass of adsorbent of 214, 225 and 275 mg/g for GAC, μGAC and cPAC, respectively, were obtained using the Langmuir isotherm adsorption model. Batch adsorption followed pseudo-second order kinetics, and adsorbate uptake rate increased with decreasing adsorbent particle size. Best adsorption unit was a tank equipped with a spinning rectangular prism adsorber prototype all made of stainless-steel woven wire filter of 180 mesh size. Running at 600 rpm and filled with a high cPAC concentration (25 g/L), adsorber can remove azorubine at similar rates that the use of free moving cPAC. Adsorber unit can run in continuous mode and works even better as a novel spinning submerged filter where filtered flow exits from a central pipe axis. This integrated adsorption-submerged filtration operation mode offer the possibility of adding a high initial dose or a continuous dosing of adsorbent in the tank, increasing the adsorbent concentration of the unit. This system can also offer novel opportunities for wastewater contaminants removal using different adsorbent materials located separately.

Investigating the impact of COVID-19 on performance and image enhancing drug use

BackgroundEmerging research has suggested that the COVID-19 pandemic has had some impact on substance use patterns. The aim of the study was to conduct a rapid survey to assess the impact of COVID-19 on performance and image enhancing drug (PIED) use and training, and any subsequent negative physical or mental health outcomes.MethodsDuring 2020, a convenience sample of 60 PIED consumers (mean age = 26.69; 68.3% located outside Australia) completed a quantitative anonymous online survey exploring how the coronavirus pandemic impacted patterns of PIED use and associated exercise habits. The survey was administered via the Qualtrics platform and distributed online through PIED forums as well as through the investigators’ networks. Participants were asked about their PIED use and exercise habits prior to and during restricted movement ‘lockdowns’.ResultsDuring pre-COVID, the majority of the sample opted to ‘blast-cruise’ (an initial high dose, followed by a lower maintenance dose; 71.7%, n = 43). During lockdown, 45% (n = 27) reported a change in PIED use as a result of the restrictions. In light of health concerns during COVID-19, a majority of men (60%, n = 36) did not take any extra precautions relating to their PIED use. A subgroup of men ceased using PIEDs completely (16.7%, n = 10) with the majority (80%, n = 8) of that subgroup following post-cycle therapy (PCT) of some kind. Only a small proportion of the sample reported negative mental health issues as a result of PCT access issues.ConclusionsThis study contributes to the emerging literature of the impact of the COVID-19 pandemic on substance use, specifically PIED use among men. The results suggest that the pandemic did influence the choice of PIEDs that participants consumed, although there was little disruption to patterns of exercise, an important aspect of PIED use. Of the men who did cease use completely, the majority reported little issue with PCT access; those who reported difficulty accessing PCT compounds indicated experience some mental health concerns related to ceasing their PIED use. Clinicians and those who come into contact with this group should be alert for any negative physical or mental health concerns resulting from disrupted or ceased PIED use.

47-Year-Old Woman With Bilateral Flank Pain

47-Year-Old Woman With Bilateral Flank Pain

An Individualized Approach to Treating Pups with Severe Hemophilia a: Which Factors Correlate with the Low Rate of Inhibitor Development?

▪Introduction:Development of inhibitors to replacement factor VIII (FVIII) remains a significant challenge to the management of previously untreated patients (PUPs) with severe hemophilia A. Although several determinants have been associated with the risk of inhibitor development, the impact of treatment approach remains controversial. Here we report our experience with an individualized approach to managing PUPs at a single hemophilia treatment center (HTC) in Germany.Methods:PUPs with severe hemophilia A (FVIII:C <1%) treated at the Gerinnungszentrum Rhein-Ruhr (GZRR), Germany, between January 2013 and June 2021 were followed prospectively. Our treatment approach includes early prophylactic physiotherapy, pdFVIIIconcentrate for at least the first 50 exposure days (EDs), tailored prophylaxis with individualized dose escalation according to bleeding tendency, and avoidance of prolonged on-demand treatment by avoiding treatment of minor bleeds or hematomas. Potential bleeds were examined by a hemophilia specialist and a decision made as whether to treat with pdFVIII based on the bleed location and severity. Ultrasound was performed every 3-6 months to check for joint bleeds. Where on-demand treatment was necessary, we used a high initial dose of 60-80 IU/kg with the aim of reducing the need for subsequent doses. Non-urgent surgical procedures were postponed and venous access system implants were avoided within the first 100 EDs. Inhibitor levels were measured using the modified Bethesda assay every 3-4 EDs until ED 100, and every 3 months thereafter for 2 years.Results:Data from 28 consecutive caucasian PUPs were collected. Fourteen (50%) patients had a F8 gene mutation associated with a high risk for inhibitor development. At the time of data cut-off 23 patients had received over 50 EDs of FVIII treatment, with 21 patients having over 100 EDs; the remaining patients had up to 45 EDs.Of the 28 patients, 27 started prophylaxis within the first 10 EDs. The initial prophylaxis schedule was tailored to each patient and ranged from 21 IU/kg every 10 days up to 40 IU/kg twice per week. One patient was treated on-demand for an intracranial bleed from ED 1-100. Only 3 spontaneous bleeds in 3 patients were treated; 25 patients (89%) remained free of spontaneous bleeds during prophylaxis. All three spontaneous bleeds were treated successfully with FVIII ± tranexamic acid. None of the 28 patients developed inhibitors.Discussion:Our approach to managing PUPs includes treatment with pdFVIII for at least the first 50 EDs, during which we treat bleeds only where necessary and use high doses to minimize further infusions. We had no cases of inhibitor development in our prospective cohort of 28 patients. In contrast, between 2003 and 2012, four of nine (44%) PUPs treated at our center developed inhibitors during the first 20 EDs, with two patients developing low-titer and two high-titer inhibitors. At that time we used recombinant FVIII (rFVIII) for prophylaxis in most patients and were less selective about which bleeds to treat with FVIII. Our individualized management approach, choice of pdFVIII and restricted use of FVIII for on-demand treatment therefore appear to correlate with a reduction in inhibitor incidence at our center. We usually switch patients from pdFVIII to rFVIII after at least 50 EDs due to the lower administration volume. Given the low rate of inhibitor development reported for PUPs treated with human cell line-derived rFVIII, there is a rationale to consider starting PUPs on human cell line-derived rFVIII.Conclusion:Our data support the position, that the use of an individualized management approach minimizes the risk of inhibitor development and raise important questions about how different aspects of treatment approach could impact outcomes in PUPs with severe hemophilia A. DisclosuresNo relevant conflicts of interest to declare.