Causal machine learning for predicting treatment outcomes.

Causal machine learning (ML) offers flexible, data-driven methods for predicting treatment outcomes including efficacy and toxicity, thereby supporting the assessment and safety of drugs. A key benefit of causal ML is that it allows for estimating individualized treatment effects, so that clinical decision-making can be personalized to individual patient profiles. Causal ML can be used in combination with both clinical trial data and real-world data, such as clinical registries and electronic health records, but caution is needed to avoid biased or incorrect predictions. In this Perspective, we discuss the benefits of causal ML (relative to traditional statistical or ML approaches) and outline the key components and steps. Finally, we provide recommendations for the reliable use of causal ML and effective translation into the clinic.

A type I interferon regulatory network for human plasmacytoid dendritic cells based on heparin, membrane-bound and soluble BDCA-2.

Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll-like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation can cause adverse effects on the host and contributes to the pathogenesis of type I IFN-related autoimmune diseases. Here, we show that heparin interacts with the human pDCs-specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9-driven type I IFN production in primary human pDCs and the pDC-like cell line CAL-1. This inhibition is mediated by unfractionated and low-molecular-weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-α in pDCs. Additionally, we identified an activation-dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9-driven IFN-α production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by Orientia tsutsugamushi) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane-bound and solBDCA-2 modulating TLR9-driven IFN-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases.

Humeral head size predicts baseplate lateralization in reverse shoulder arthroplasty: a comparative computer model study.

Background: In reverse shoulder arthroplasty (RSA), the ideal combination of baseplate lateralization (BL), glenosphere size (GS), and glenosphere overhang (GOH) with a commonly used 145° neck shaft angle (NSA) is unclear. This is the first study evaluating correlations of body height (BH), humeral head size (HS), glenoid height (GH), and association of gender with best glenoid configurations for range of motion (ROM) maintaining anatomic lateralization (aLAT) for optimized muscle length in 145° and less distalized 135° RSA. Methods: In this computer model study, 22 computed tomographies without joint narrowing were analyzed (11 male/female). A standardized semi-inlay 145° platform stem was combined with 20 glenoid configurations (baseplate [B] 25, 25 + 3/+6 lateralized [l], 29, 29 + 3/6l combined with glenosphere 36, 36 + 2 eccentric [e], 36 + 3l, 39, 39 + 3e, 39 + 3l , 42, 42 + 4e). Abduction-adduction, flexion-extension, external rotation-internal rotation, total ROM (TROM), and total notching relevant (TNR) ROM were computed, best TROM models respecting aLAT (-1 mm to +1 mm) and HS/GH recorded. Second, the 145° models (Ascend Flex stem; Stryker, Kalamazoo, MI, USA) were converted and compared to a 135° inlay RSA (New Perform stem; Stryker, Kalamazoo, MI, USA) maintaining GOH (6.5-7 mm) and aLAT. Results: Best 145° models had eccentric glenospheres (mean BL: 3.5 mm, GOH 8.8 mm, GS 38.1 mm, distalization 23 mm). The 135° models had concentric glenospheres, mean BL 3.8 mm, GOH 6.9 mm, GS 39.7 mm, and distalization 14.1 mm. HS showed the strongest positive correlation with BL in 145° and 135° models (0.65/0.79). Despite reduced GOH in smaller females with a 135° NSA, adduction, external rotation, extension, TNR ROM, and TROM were significantly increased (P = .02, P = .005, P = .005, P = .004, P = .003), abduction however reduced (P = .02). The same trends were seen for males. Conclusion: HS is a practical measure in surgery or preoperatively, and the strong positive correlation with BL is a useful planning aid. Despite reduction of GOH, conversion to a less distalized 135° NSAinlay design is powerful to maintain and even significantly increase all components of TNR ROM (extension/external rotation/adduction) in small females with the drawback of reduced abduction which may however be compensated by scapula motion. Lateralization with a less distalized 135° RSA optimizes muscle length, may facilitate subscapularis repair, and maintains highest rigid body motion.

T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms.

Endogenous retroviruses (ERVs) are an integral part of the mammalian genome. The role of immune control of ERVs in general is poorly defined as is their function as anti-cancer immune targets or drivers of autoimmune disease. Here, we generate mouse-strains where Moloney-Murine Leukemia Virus tagged with GFP (ERV-GFP) infected the mouse germline. This enables us to analyze the role of genetic, epigenetic and cell intrinsic restriction factors in ERV activation and control. We identify an autoreactive B cell response against the neo-self/ERV antigen GFP as a key mechanism of ERV control. Hallmarks of this response are spontaneous ERV-GFP+ germinal center formation, elevated serum IFN-γ levels and a dependency on Age-associated B cells (ABCs) a subclass of T-bet+ memory B cells. Impairment of IgM B cell receptor-signal in nucleic-acid sensing TLR-deficient mice contributes to defective ERV control. Although ERVs are a part of the genome they break immune tolerance, induce immune surveillance against ERV-derived self-antigens and shape the host immune response.

Proposal and practicality of an alternative blue-light hazard risk assessment method for high-intensity white-light sources at workplaces.

Objectives. It is prescribed to determine blue-light hazard (BLH) weighted radiances, LB, for an assessment of spotlights with an angular subtense α≥11mrad. The BLH weighted irradiance, EB, can be used alternatively for smaller sources. Appropriate instruments are not common among persons commissioned with risk assessment (RA), and especially LB measurements may be challenging. Therefore, a practical BLH RA approach is proposed that is based on illuminance, Ev, pre-calculated blackbody BLH efficacies of luminous radiation, KB,vPlanck, and solid angle considerations. Methods. The practicality of this method was examined and compared against other RA approaches. Results. To ensure comparability of the applied instruments, measurements were performed close to a radiance standard, showing deviations within the lamp's expanded uncertainties (<4%), whereas the deviations were ±15% for longer distances. Focusing on a complex light-emitting diode (LED) spotlight, all detected values could be converted to LB by means of the RA methods within ±20%. Two field tests with several spotlights yielded maximum permissible exposure durations (MPED) obtained from the different RA approaches that agreed among each other within uncertainties largely below ±30%. Conclusion. The general practicality of the proposed Ev method can be concluded for a workplace BLH RA of white-light sources.

Correction: Bauer et al. Challenges for Optimization of Reverse Shoulder Arthroplasty Part II: Subacromial Space, Scapular Posture, Moment Arms and Muscle Tensioning. J. Clin. Med. 2023, 12, 1616.

In the original publication [...].

Quantitative three-dimensional imaging of chemical short-range order via machine learning enhanced atom probe tomography.

Chemical short-range order (CSRO) refers to atoms of specific elements self-organising within a disordered crystalline matrix to form particular atomic neighbourhoods. CSRO is typically characterized indirectly, using volume-averaged or through projection microscopy techniques that fail to capture the three-dimensional atomistic architectures. Here, we present a machine-learning enhanced approach to break the inherent resolution limits of atom probe tomography enabling three-dimensional imaging of multiple CSROs. We showcase our approach by addressing a long-standing question encountered in body-centred-cubic Fe-Al alloys that see anomalous property changes upon heat treatment. We use it to evidence non-statistical B2-CSRO instead of the generally-expected D03-CSRO. We introduce quantitative correlations among annealing temperature, CSRO, and nano-hardness and electrical resistivity. Our approach is further validated on modified D03-CSRO detected in Fe-Ga. The proposed strategy can be generally employed to investigate short/medium/long-range ordering phenomena in different materials and help design future high-performance materials.

Peroneus tertius revisited: The morphological variability of the bifurcated peroneus tertius insertion - An anatomical study.

BACKGROUND: The peroneus tertius muscle (PT) is one of the extensor muscles of the lower leg, often described as a variable separation from the extensor digitorum longus muscle (EDL). According to literature it has six different types of insertion, one of them (Olewnik Type IV) having two tendons inserting to the fifth metatarsal bone (FMTB). Morphometric data about this type of insertion is sparse, especially the relation between the two tendons, albeit the PT is suspected to contribute to stress fractures of the FMTB. Therefore, we examined this type of insertion to give detailed information on the tendons, the insertion points and the respective relations. METHODS: We examined 27 lower extremities of embalmed human bodies (12 paired, 15 single sided; 12 right and 15 left) with a distinguishable PT with two tendons inserting to the FMTB (Olewnik IV). The specimens were obtained of an undergrad dissection program, which in turn obtained them from a body donation program. After dissection of the PT and photo documentation in situ, resection and measurement of morphological properties of the tendons were performed with the PT attached to the fifth metatarsal bone. RESULTS: Results of the respective measurements yielded a wide range of variation, especially in the insertion point of the anterior tendon on the fifth metatarsal and the relation between the two tendons, but with no significant difference between sides or sex, except for the length of the posterior tendon between sex. The distance between the base of the FMTB and posterior tendon varies from 0 to 9 mm, with one outlier at 24 mm (mean = 3.9 ± 4.8 mm), the distance between the insertions from 0 to 15 mm (mean = 4.7 ± 4.7 mm), resulting in how far of the FMTB the anterior tendon reaches varying from 17 to 60 mm (mean = 39.6 ± 11.5 mm) or 22-98% (mean = 64 ± 19%). CONCLUSION: Our findings give a detailed overview of the morphological features the PTT can have, when attached with two tendons to the FMTB. Especially the varying relationship between those two insertions and varying point of the anterior insertion are of interest, as they might support its complex role in the occurrence of fractures of the fifth metatarsal by providing different amounts of torsional stress and its tendons can be used as tendon-grafts.

Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA).

PURPOSE: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). PATIENTS AND METHODS: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). RESULTS: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7-24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0-10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1-79.0]. For patients who received ribociclib + ET, grade 3-4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3-4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died - 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. CONCLUSION: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. TRIAL REGISTRATION: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.

The open Latarjet-Patte procedure for the treatment of anterior shoulder instability in professional handball players at a mean follow-up of 6.6 years.

BACKGROUND: The popularity of team handball is increasing, with >10 million children playing this overhead throwing and collision sport with highest demands on the shoulder joint. Because of the risk of recurrent instability, the Latarjet-Patte (LP) procedure has been recommended to treat young competitive players. This is the first LP outcome study in professional handball players. METHODS: We retrospectively included 20 shoulders (18 players [17 male patients]; mean age, 22.9 years [range, 17-35 years]; minimum follow-up period, 2 years; mean follow-up period, 6.6 years) operated on by 3 expert surgeons (2011-2020) with the Walch LP technique. We documented preoperative hyperlaxity (25%, n = 5), affected throwing arm (55%, n = 11), position (backcourt, winger, and goalkeeper, 22% each; full back and pivot, 17% each), >2 dislocations prior (20%, n = 4), >10 dislocations prior (5%, n = 1), previous failed Bankart or humeral avulsion of glenohumeral ligament (HAGL) repair (10%, n = 2), and large Hill-Sachs lesions (HSLs) (20%, n = 4). Clinical and radiographic outcomes, visual analog scale score, Subjective Shoulder Value, Walch-Duplay score, Rowe score, and return-to-sport (RTS) rate were recorded. RESULTS: The RTS rate was 85% (17 of 20 shoulders); rate of RTS at the same level, 80% (16 of 20); and rate of RTS with no throwing pain, 73% (8 of 11). The time to training with a ball was 3.2 months, and the time to competition was 4.9 months. The mean Rowe score, Walch-Duplay score, and Subjective Shoulder Value were 90 points, 88 points, and 89%, respectively. Shoulder symptoms led players to give up handball in 2 cases (10%), whereas 1 player (5%) stopped playing handball for other reasons. We recorded 1 recurrent dislocation (5%) (non-throwing arm, winger, no recurrence after rehabilitation). Persistent apprehension occurred in 1 goalkeeper (5%). Residual pain was seen in 4 shoulders (20%); this was relieved by screw removal in 1. Resistant pain (throwing shoulder) was seen in 2 backcourt players (10%, 1 of whom had a large HSL) and 1 goalkeeper (5%; large HSL with >10 dislocations prior), all 3 of whom were aged > 30 years. Bone block positioning was correct (no lateral overhang) in all shoulders. At final follow-up, 1 shoulder (5%) showed mild arthritic changes (>10 dislocations, large HSL). CONCLUSION: The open LP procedure is consistent in providing shoulder stability combined with return-to-throwing performance in professional handball players with a short time to RTS and high same-level RTS rate without increasing the risk of arthritic changes. Throwing shoulders of backcourt players, large HSLs, or age > 30 years may have an increased risk of persistent symptoms.

Current concepts in chronic traumatic anterior shoulder instability.

Chronic traumatic anterior shoulder instability can be defined as recurrent trauma-associated shoulder instability requiring the assessment of three anatomic lesions: a capsuloligamentous and/or labral lesion; anterior glenoid bone loss and a Hill-Sachs lesion. Surgical treatment is generally indicated. It remains controversial how risk factors should be evaluated to decide between a soft-tissue, free bone-block or Latarjet-type procedure. Patient risk factors for recurrence are age; hyperlaxity; competitive, contact and overhead sports. Trauma-related factors are soft tissue lesions and most importantly bone loss with implications for treatment. Different treatment options are discussed and compared for complications, return to sports parameters, short- and long-term outcomes and osteoarthritis. Arthroscopic Bankart and open Latarjet procedures have a serious learning curve. Osteoarthritis is associated with the number of previous dislocations as well as surgical techniques. Latarjet-type procedures have the lowest rate of dislocation recurrence and if performed correctly, do not seem to increase the risk of osteoarthritis.

Expression of TMPRSS2 is up-regulated by bacterial flagellin, LPS, and Pam3Cys in human airway cells.

Many viruses require proteolytic activation of their envelope proteins for infectivity, and relevant host proteases provide promising drug targets. The transmembrane serine protease 2 (TMPRSS2) has been identified as a major activating protease of influenza A virus (IAV) and various coronaviruses (CoV). Increased TMPRSS2 expression has been associated with a higher risk of severe influenza infection and enhanced susceptibility to SARS-CoV-2. Here, we found that Legionella pneumophila stimulates the increased expression of TMPRSS2-mRNA in Calu-3 human airway cells. We identified flagellin as the dominant structural component inducing TMPRSS2 expression. The flagellin-induced increase was not observed at this magnitude for other virus-activating host proteases. TMPRSS2-mRNA expression was also significantly increased by LPS, Pam3Cys, and Streptococcus pneumoniae, although less pronounced. Multicycle replication of H1N1pdm and H3N2 IAV but not SARS-CoV-2 and SARS-CoV was enhanced by flagellin treatment. Our data suggest that bacteria, particularly flagellated bacteria, up-regulate the expression of TMPRSS2 in human airway cells and, thereby, may support enhanced activation and replication of IAV upon co-infections. In addition, our data indicate a physiological role of TMPRSS2 in antimicrobial host response.

Resurfacing Hip Arthroplasty Is a Safe and Effective Alternative to Total Hip Arthroplasty in Young Patients: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed at comparing resurfacing hip arthroplasty (RHA) and total hip arthroplasty (THA) in terms of rate of complications, revisions, functional outcomes, blood loss, operative time and metal ions levels. The search was conducted on three databases (PubMed, Cochrane and Web of Science) updated until 13 October 2022. The inclusion criteria were RCTs) written in the English language, with no time limitation, comparing RHA and THA. Among the retrieved 4748 articles, 18 RCTs were eligible for a total of 776 patients (mean age 53.1 ± 5.0). A meta-analysis was performed. RHA reported significantly lower blood loss compared to THA (p < 0.001) but with longer operative time (p < 0.001). No statistically significant difference was found between RHA and THA in terms of complications (12.08% and 16.24%, respectively) and revisions (6.32% and 6.14%, respectively). Both RHA and THA provide excellent clinical results in a population of young and active patients. Functional outcomes were not significantly different between the groups. Moreover, no significant difference in metal ion levels was found. These findings provide evidence concerning the safety and clinical effectiveness of RHA. Because of its bone-preserving properties, the lack of drawbacks and good outcomes, RHA appears to be a valid alternative to THA in young and active patients.

Bacterial vesicles block viral replication in macrophages via TLR4-TRIF-axis.

Gram-negative bacteria naturally secrete nano-sized outer membrane vesicles (OMVs), which are important mediators of communication and pathogenesis. OMV uptake by host cells activates TLR signalling via transported PAMPs. As important resident immune cells, alveolar macrophages are located at the air-tissue interface where they comprise the first line of defence against inhaled microorganisms and particles. To date, little is known about the interplay between alveolar macrophages and OMVs from pathogenic bacteria. The immune response to OMVs and underlying mechanisms are still elusive. Here, we investigated the response of primary human macrophages to bacterial vesicles (Legionella pneumophila, Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, Streptococcus pneumoniae) and observed comparable NF-κB activation across all tested vesicles. In contrast, we describe differential type I IFN signalling with prolonged STAT1 phosphorylation and strong Mx1 induction, blocking influenza A virus replication only for Klebsiella, E.coli and Salmonella OMVs. OMV-induced antiviral effects were less pronounced for endotoxin-free Clear coli OMVs and Polymyxin-treated OMVs. LPS stimulation could not mimic this antiviral status, while TRIF knockout abrogated it. Importantly, supernatant from OMV-treated macrophages induced an antiviral response in alveolar epithelial cells (AEC), suggesting OMV-induced intercellular communication. Finally, results were validated in an ex vivo infection model with primary human lung tissue. In conclusion, Klebsiella, E.coli and Salmonella OMVs induce antiviral immunity in macrophages via TLR4-TRIF-signaling to reduce viral replication in macrophages, AECs and lung tissue. These gram-negative bacteria induce antiviral immunity in the lung through OMVs, with a potential decisive and tremendous impact on bacterial and viral coinfection outcome. Video Abstract.

Interventional versus Surgical Treatment of Degenerated Freestyle Prosthesis.

BACKGROUND: Bioprosthetic stentless aortic valves may degenerate over time and will require replacement. This study aimed to evaluate early- and mid-term outcomes after isolated surgical redo aortic valve replacement (redo-SAVR) and transcatheter valve-in-valve implantation (TAVI-VIV) for degenerated stentless Freestyle bioprostheses. METHODS: We reviewed records of 56 patients at a single center. Overall, 37 patients (66.1%) received TAVI-VIV and 19 (33.9%) received redo-SAVR. RESULTS: Thirty-day survival was similar in both groups (100%). One-year survival was comparable between groups (97.3% in TAVI-VIV and 100% in redo-SAVR, p = 1.0). The difference in mid-term survival after adjusting for age and EuroScore II was not significant (p = 0.41). The incidence of pacemaker implantation after TAVI-VIV was higher than after redo-SAVR (19.4% vs. 0%, p = 0.08). CONCLUSION: The 30-day and 1-year survival rates after both procedures were outstanding, irrespective of baseline characteristics. Isolated redo-SAVR should be favored in young patients, as the pacemaker implantation rate is lower. TAVI-VIV for degenerated Freestyle prosthesis can be a method of choice in elderly patients and those with high operative risk.

Challenges for Optimization of Reverse Shoulder Arthroplasty Part I: External Rotation, Extension and Internal Rotation.

A detailed overview of the basic science and clinical literature reporting on the challenges for the optimization of reverse shoulder arthroplasty (RSA) is presented in two review articles. Part I looks at (I) external rotation and extension, (II) internal rotation and the analysis and discussion of the interplay of different factors influencing these challenges. In part II, we focus on (III) the conservation of sufficient subacromial and coracohumeral space, (IV) scapular posture and (V) moment arms and muscle tensioning. There is a need to define the criteria and algorithms for planning and execution of optimized, balanced RSA to improve the range of motion, function and longevity whilst minimizing complications. For an optimized RSA with the highest function, it is important not to overlook any of these challenges. This summary may be used as an aide memoire for RSA planning.

The Evolution of Reverse Total Shoulder Arthroplasty-Where Do We Stand and What Comes Next?

Over 35 years ago, the pioneer Paul Grammont from Lyon published his ideas of a reversed semi-constraint prosthesis improving the moment arm of the deltoid by medializing the center of rotation and lengthening of the arm and thus increasing deltoid muscle tension [...].

Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication.

Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces, called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S-adenosyl-l-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.

Challenges for Optimization of Reverse Shoulder Arthroplasty Part II: Subacromial Space, Scapular Posture, Moment Arms and Muscle Tensioning.

In part II of this comprehensive review on the optimization of reverse shoulder arthroplasty (RSA), we focus on three other challenges: 1. "Conservation of sufficient subacromial and coracohumeral space"; 2. "Scapular posture"; and 3. "Moment arms and muscle tensioning". This paper follows a detailed review of the basic science and clinical literature of the challenges in part I: 1. "External rotation and extension" and 2. "Internal rotation". "Conservation of sufficient subacromial and coracohumeral space" and "Scapular posture" may have a significant impact on the passive and active function of RSA. Understanding the implications of "Moment arms and muscle tensioning" is essential to optimize active force generation and RSA performance. An awareness and understanding of the challenges of the optimization of RSA help surgeons prevent complications and improve RSA function and raise further research questions for ongoing study.

Pyfectious: An individual-level simulator to discover optimal containment policies for epidemic diseases.

Simulating the spread of infectious diseases in human communities is critical for predicting the trajectory of an epidemic and verifying various policies to control the devastating impacts of the outbreak. Many existing simulators are based on compartment models that divide people into a few subsets and simulate the dynamics among those subsets using hypothesized differential equations. However, these models lack the requisite granularity to study the effect of intelligent policies that influence every individual in a particular way. In this work, we introduce a simulator software capable of modeling a population structure and controlling the disease's propagation at an individualistic level. In order to estimate the confidence of the conclusions drawn from the simulator, we employ a comprehensive probabilistic approach where the entire population is constructed as a hierarchical random variable. This approach makes the inferred conclusions more robust against sampling artifacts and gives confidence bounds for decisions based on the simulation results. To showcase potential applications, the simulator parameters are set based on the formal statistics of the COVID-19 pandemic, and the outcome of a wide range of control measures is investigated. Furthermore, the simulator is used as the environment of a reinforcement learning problem to find the optimal policies to control the pandemic. The obtained experimental results indicate the simulator's adaptability and capacity in making sound predictions and a successful policy derivation example based on real-world data. As an exemplary application, our results show that the proposed policy discovery method can lead to control measures that produce significantly fewer infected individuals in the population and protect the health system against saturation.