Comparison of troponin and natriuretic peptides in Takotsubo syndrome and acute coronary syndrome: a meta-analysis.

OBJECTIVE: Takotsubo syndrome (TTS) is an acute heart failure syndrome which resembles acute coronary syndrome (ACS) at presentation. Differentiation requires coronary angiography, but where this does not occur immediately, cardiac biomarkers may provide additional utility. We performed a meta-analysis to compare troponin and natriuretic peptides (NPs) in TTS and ACS to determine if differences in biomarker profile can aid diagnosis. METHODS: We searched five literature databases for studies reporting NPs (Brain NP (BNP)/NT-pro-BNP) or troponin I/T in TTS and ACS, identifying 28 studies for troponin/NPs (5618 and 1145 patients, respectively). RESULTS: Troponin was significantly lower in TTS than ACS (standardised mean difference (SMD) -0.86; 95% CI, -1.08 to -0.64; p<0.00001), with an absolute difference of 75 times the upper limit of normal (×ULN) higher in ACS than TTS. Conversely, NPs were significantly higher in TTS (SMD 0.62; 95% CI, 0.44 to 0.80; p<0.00001) and 5.8×ULN greater absolutely. Area under the curve (AUC) for troponin in ACS versus TTS was 0.82 (95% CI, 0.70 to 0.93), and 0.92 (95% CI, 0.80 to 1.00) for ST-segment elevation myocardial infarction versus TTS. For NPs, AUC was 0.69 (95% CI, 0.48 to 0.89). Combination of troponin and NPs with logistic regression did not improve AUC. Recursive Partitioning and Regression Tree analysis calculated a troponin threshold ≥26×ULN that identified 95% cases as ACS where and specificity for ACS were 85.71% and 53.57%, respectively, with 94.32% positive predictive value and 29.40% negative predictive value. CONCLUSIONS: Troponin is lower and NPs higher in TTS versus ACS. Troponin had greater power than NPs at discriminating TTS and ACS, and with troponin ≥26×ULN patients are far more likely to have ACS.

3D printed porous membrane integrated devices to study the chemoattractant induced behavioural response of aquatic organisms.

Biological models with genetic similarities to humans are used for exploratory research to develop behavioral screening tools and understand sensory-motor interactions. Their small, often mm-sized appearance raises challenges in the straightforward quantification of their subtle behavioral responses and calls for new, customisable research tools. 3D printing provides an attractive approach for the manufacture of custom designs at low cost; however, challenges remain in the integration of functional materials like porous membranes. Nanoporous membranes have been integrated with resin exchange using purpose-designed resins by digital light projection 3D printing to yield functionally integrated devices using a simple, economical and semi-automated process. Here, the impact of the layer thickness and layer number on the porous properties - parameters unique for 3D printing - are investigated, showing decreases in mean pore diameter and porosity with increasing layer height and layer number. From the same resin formulation, materials with average pore size between 200 and 600 nm and porosity between 45% and 61% were printed. Membrane-integrated devices were used to study the chemoattractant induced behavioural response of zebrafish embryos and planarians, both demonstrating a predominant behavioral response towards the chemoattractant, spending >85% of experiment time in the attractant side of the observation chamber. The presented 3D printing method can be used for printing custom designed membrane-integrated devices using affordable 3D printers and enable fine-tuning of porous properties through adjustment of layer height and number. This accessible approach is expected to be adopted for applications including behavioural studies, early-stage pre-clinical drug discovery and (environmental) toxicology.

Patient and Caregiver Perception of Adenoidectomies: A Non-Real-World Social Media Analysis.

Objective: To survey the social media outlets Twitter and Instagram for public posts related to adenoidectomy surgery. This study aims to investigate the attitudes and perceptions of patients and caregivers on social media, through thematic content-analysis of social media posts regarding adenoidectomy. Study Design: Non-real world qualitative study. Setting: Twitter and Instagram social media platforms. Methods: Public posts uploaded between February, 2021 and February, 2023 using the hashtags "#adenoidectomy," and "#adenoidectomyrecovery" were searched. Posts were excluded if they were unrelated to adenoidectomy or were in a non-English language. Relevant posts were stratified demographically as patient or caregiver and pre- or postoperative, and categorized into relevant themes for analysis. Outcomes were measured as the total number of posts. Results: A total of 394 relevant posts were analyzed. A significance threshold of P < 0.05 was used. Patients posted significantly more posts regarding procedure pain (P = 0.002) and concern for appearance (P = 0.048) compared to caregivers. Caregivers posted significantly (P < 0.001) more posts regarding condition awareness and were significantly (P < 0.001) more likely to spread positivity in their posts compared to patients themselves. Posts made by female caregivers were more likely to reference fear, while those made by male caregivers were more likely to provide education (P = 0.002). Conclusion: Patients may worry about appearance and mental health while caregivers are more likely to spread information and positivity. Male and female caregivers may also use social media differently. A better understanding of patient and caregiver concerns may optimize physician interaction and involvement.

Vascular Loop of the Anterior Inferior Cerebellar Artery (AICA) as a Cause of Sensorineural Hearing Loss (SNHL): A Case Report.

Sensorineural hearing loss (SNHL) is one of the most common causes of hearing loss worldwide. Although highly prevalent, many patients often present with SNHL of unknown cause. Related to SNHL is tinnitus, which often presents with SNHL and can have debilitating effects on patients. The idiopathic nature of SNHL and tinnitus often makes treatment difficult, however, a relatively new etiology has been suggested as a cause of SNHL and tinnitus -- vascular loops within the internal auditory canal (IAC). This report presents the case of a 36-year-old male with bilateral SNHL and tinnitus treated with oral steroids. The patient reported subjective improvement of hearing loss and tinnitus, and the audiogram demonstrated hearing improvement, except in higher frequencies. After initial treatment, MRI revealed a vascular loop of the anterior inferior cerebral artery (AICA) in the right IAC, in contact with the vestibulocochlear nerve. Thus, this case report seeks to present a conservative strategy for SNHL and tinnitus in the presence of a vascular loop of the AICA. As a controversial cause of SNHL and tinnitus, there is no standard of treatment for AICA loops of the IAC which are often treated surgically. This case highlights the importance of an initial conservative prior to surgical intervention. Thus, we seek to contribute to the growing body of literature by further elucidating the relationship between SNHL, tinnitus, and vascular loops and discussing potential pathophysiological mechanisms to guide optimal management strategies.

3D printed integrated nanoporous membranes for electroextraction of DNA.

3D printing is established as an alternative microfabrication approach, and while printer resolution limits the direct 3D printing of pore features in the micron/submicron range, the use of nanoporous materials allows for the integration of porous membranes in 3D printed devices. Here, nanoporous membranes were formed by digital light projection (DLP) 3D printing using a polymerization-induced phase separation (PIPS) resin formulation. A functionally integrated device was fabricated using resin exchange following a simple, semi-automated manufacturing process. Printing of porous materials from a PIPS resin formulations based on polyethylene glycol diacrylate 250 as monomer was investigated by varying exposure time, photoinitiator concentration, and porogen content to yield materials with average pore size varying from 30-800 nm. Aiming for printing a size-mobility trap for electrophoretic extraction of deoxyribonucleic acid (DNA), conditions for printing materials with a mean pore size of 346 nm and 30 nm were selected for integration in a fluidic device using a resin exchange approach. Under optimized conditions (12.5 V for 20 min), cell concentrations as low as 103 cells per mL were detected following amplification of the extract by quantitative polymerase chain reaction (qPCR) at a Cq of 29. The efficacy of the size/mobility trap formed by the two membranes is demonstrated by detecting DNA concentrations equivalent to the input detected in the extract while removing 73% of the protein in the lysate. The DNA extraction yield was not statistically different from that obtained using a spin column, but manual handling and equipment needs were significantly reduced. This study demonstrates that nanoporous membranes with tailored properties can be integrated into fluidic devices using a simple manufacturing process based on resin exchange DLP. The process was used to manufacture a size-mobility trap and applied for the electroextraction and purification of DNA from E. coli lysate with reduced processing time, manual handling, and equipment needs compared with a commercially sourced DNA extraction kit. Combining manufacturability and portability with ease of use, the approach has demonstrated potential for manufacturing and using devices used in point-of-need testing for diagnostic nucleic acid amplification testing.

Effect of Interbody Composition on the Development of Pseudarthrosis Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Retrospective cohort study. PURPOSE: To determine if polyetheretherketone (PEEK) or titanium alloy cages increase the rate of pseudarthrosis development or revision surgery rate compared with structural allograft following anterior cervical discectomy and fusion (ACDF) and identify if the cage type results in differences in patient-reported outcome measures (PROMs) versus structural allograft. OVERVIEW OF LITERATURE: PEEK and titanium alloy cages have become popular options for ACDF intervertebral spacers. However, while data is beginning to emerge on how cage types affect arthrodesis rates, the effect of their composition on PROMs is less clear. METHODS: All patients aged >18 years who underwent primary one- to four-level ACDF at a single institution were retrospectively identified. Propensity matching was performed to compare patients' PEEK or titanium alloy cages with structural allograft. Multivariate logistic regression analysis was performed to measure the effect of interbody spacer composition on the likelihood of pseudarthrosis development. RESULTS: Of the 502 patients who received structural allograft and had 1-year postoperative dynamic radiographs, 96 patients were propensity matched to 32 patients who received a PEEK cage, and 162 patients were propensity matched to 54 patients who received a titanium alloy cage. Multivariate logistic regression analysis identified that PEEK cage implants (odds ratio [OR], 3.34; p =0.007) predicted pseudarthrosis development compared with structural allograft implantation. Titanium alloy cage (OR, 1.64; p =0.156) implantation was not predictive of pseudarthrosis. One-year postoperative PROMs were not significantly different between patients who received PEEK or titanium alloy cages and those who received structural allograft (all p >0.05). CONCLUSIONS: Compared with structural allograft, receiving a PEEK cage increased the risk of pseudarthrosis development following ACDF, whereas receiving a titanium alloy cage had no significant effect on pseudarthrosis development. One-year postoperative patient-reported outcomes were similar between patients who received structural allograft, PEEK, and titanium alloy interbody spacers.

Effect of Drain Duration and Output on Perioperative Outcomes and Readmissions after Lumbar Spine Surgery.

STUDY DESIGN: Single-center retrospective cohort. PURPOSE: To compare surgical outcomes of patients based on lumbar drain variables relating to output and duration. OVERVIEW OF LITERATURE: The use of drains following lumbar spine surgery, specifically with respect to hospital readmission, postoperative hematoma, postoperative anemia, and surgical site infections, has been controversial. METHODS: Patients aged ≥18 years who underwent lumbar fusion with a postoperative drain between 2017 and 2020 were included and grouped based on hospital readmission status, last 8-hour drain output (<40 mL cutoff), or drain duration (2 days cutoff). Total output of all drains, total output of the primary drain, drain duration in days, drain output per day, last 8-hour output, penultimate 8-hour output, and last 8-hour delta (last 8-hour output subtracted by penultimate 8-hour output) were collected. Continuous and categorical data were compared between groups. Multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis were performed to determine whether drain variables can predict hospital readmission, postoperative blood transfusions, and postoperative anemia. Alpha was 0.05. RESULTS: Our cohort consisted of 1,166 patients with 111 (9.5%) hospital readmissions. Results of regression analysis did not identify any of the drain variables as independent predictors of hospital readmission, postoperative blood transfusion, or postoperative anemia. ROC analysis demonstrated the drain variables to be poor predictors of hospital readmission, with the highest area under curve of 0.524 (drain duration), corresponding to a sensitivity of 61.3% and specificity of 49.9%. CONCLUSIONS: Drain output or duration did not affect readmission rates following lumbar spine surgery.

Serotonin Reuptake Inhibitor Increases Pseudarthrosis Rates in Anterior Cervical Discectomy and Fusions.

STUDY DESIGN: Retrospective cohort. PURPOSE: To determine (1) the effects of serotonin reuptake inhibitors in pseudarthrosis rates after anterior cervical decompression and fusion (ACDF) and (2) to identify patient-reported outcome measures in patients taking serotonin reuptake inhibitors. OVERVIEW OF LITERATURE: Recent literature suggests that selective serotonin reuptake inhibitors (SSRIs) may inhibit fracture healing via downregulation of osteoblast differentiation. Spinal fusion supplementation with osteoblast-rich substances enhances spinal fusion, thus SSRIs may be detrimental. METHODS: Patients with 1-year postoperative dynamic cervical spine radiographs following ACDF were grouped into serotonin reuptake inhibitor prescriptions (SSRI, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant [TCA]) and no prescription (atypical antidepressant or no antidepressant). Pseudarthrosis was defined as ≥1 mm interspinous process motion on dynamic radiographs. Logistic regression models were controlled for confounding to analyze pseudarthrosis rates. Alpha was set at p - values of <0.05. RESULTS: Of the 523 patients who meet the inclusion criteria, 137 (26.2%) were prescribed an SSRI, SNRI, or TCA. Patients with these prescriptions were more likely to have pseudarthrosis (p =0.008) but not a revision surgery due to pseudarthrosis (p =0.219). Additionally, these patients had worse 1-year postoperative mental component summary (MCS)-12 (p =0.015) and Neck Disability Index (NDI) (p =0.006). The multivariate logistic regression analysis identified SSRI/SNRI/TCA use (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.11-2.99; p =0.018) and construct length (OR, 1.91; 95% CI, 1.50-2.44; p <0.001) as pseudarthrosis predictors. A SSRI/SNRI/TCA prescription was a revision surgery predictor due to adjacent segment disease on univariate analysis (OR, 2.51; p =0.035) but not on multivariate logistic regression analysis (OR, 2.24; p =0.10). CONCLUSIONS: Patients taking serotonin reuptake-inhibiting antidepressants are at increased risk of worse postoperative outcome scores, including NDI and MCS-12, likely due to their underlying depression. This may contribute to their greater likelihood of having adjacent segment surgery. Additionally, preoperative use of serotonin reuptake inhibitors in patients undergoing an ACDF is a predictor of radiographic pseudarthrosis but not pseudarthrosis revision.

Metabolic reprogramming underlies cavefish muscular endurance despite loss of muscle mass and contractility.

Physical inactivity is a scourge to human health, promoting metabolic disease and muscle wasting. Interestingly, multiple ecological niches have relaxed investment into physical activity, providing an evolutionary perspective into the effect of adaptive physical inactivity on tissue homeostasis. One such example, the Mexican cavefish Astyanax mexicanus, has lost moderate-to-vigorous activity following cave colonization, reaching basal swim speeds ~3.7-fold slower than their river-dwelling counterpart. This change in behavior is accompanied by a marked shift in body composition, decreasing total muscle mass and increasing fat mass. This shift persisted at the single muscle fiber level via increased lipid and sugar accumulation at the expense of myofibrillar volume. Transcriptomic analysis of laboratory-reared and wild-caught cavefish indicated that this shift is driven by increased expression of pparγ-the master regulator of adipogenesis-with a simultaneous decrease in fast myosin heavy chain expression. Ex vivo and in vivo analysis confirmed that these investment strategies come with a functional trade-off, decreasing cavefish muscle fiber shortening velocity, time to maximal force, and ultimately maximal swimming speed. Despite this, cavefish displayed a striking degree of muscular endurance, reaching maximal swim speeds ~3.5-fold faster than their basal swim speeds. Multi-omic analysis suggested metabolic reprogramming, specifically phosphorylation of Pgm1-Threonine 19, as a key component enhancing cavefish glycogen metabolism and sustained muscle contraction. Collectively, we reveal broad skeletal muscle changes following cave colonization, displaying an adaptive skeletal muscle phenotype reminiscent to mammalian disuse and high-fat models while simultaneously maintaining a unique capacity for sustained muscle contraction via enhanced glycogen metabolism.

Effect of Interbody Composition on the Development of Pseudarthrosis Following Anterior Cervical Discectomy and Fusion

Methods@#All patients aged >18 years who underwent primary one- to four-level ACDF at a single institution were retrospectively identified. Propensity matching was performed to compare patients’ PEEK or titanium alloy cages with structural allograft. Multivariate logistic regression analysis was performed to measure the effect of interbody spacer composition on the likelihood of pseudarthrosis development. @*Results@#Of the 502 patients who received structural allograft and had 1-year postoperative dynamic radiographs, 96 patients were propensity matched to 32 patients who received a PEEK cage, and 162 patients were propensity matched to 54 patients who received a titanium alloy cage. Multivariate logistic regression analysis identified that PEEK cage implants (odds ratio [OR], 3.34; p =0.007) predicted pseudarthrosis development compared with structural allograft implantation. Titanium alloy cage (OR, 1.64; p =0.156) implantation was not predictive of pseudarthrosis. One-year postoperative PROMs were not significantly different between patients who received PEEK or titanium alloy cages and those who received structural allograft (all p >0.05). @*Conclusions@#Compared with structural allograft, receiving a PEEK cage increased the risk of pseudarthrosis development following ACDF, whereas receiving a titanium alloy cage had no significant effect on pseudarthrosis development. One-year postoperative patient-reported outcomes were similar between patients who received structural allograft, PEEK, and titanium alloy interbody spacers.

Effect of Drain Duration and Output on Perioperative Outcomes and Readmissions after Lumbar Spine Surgery

Methods@#Patients aged ≥18 years who underwent lumbar fusion with a postoperative drain between 2017 and 2020 were included and grouped based on hospital readmission status, last 8-hour drain output (<40 mL cutoff), or drain duration (2 days cutoff). Total output of all drains, total output of the primary drain, drain duration in days, drain output per day, last 8-hour output, penultimate 8-hour output, and last 8-hour delta (last 8-hour output subtracted by penultimate 8-hour output) were collected. Continuous and categorical data were compared between groups. Multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis were performed to determine whether drain variables can predict hospital readmission, postoperative blood transfusions, and postoperative anemia. Alpha was 0.05. @*Results@#Our cohort consisted of 1,166 patients with 111 (9.5%) hospital readmissions. Results of regression analysis did not identify any of the drain variables as independent predictors of hospital readmission, postoperative blood transfusion, or postoperative anemia. ROC analysis demonstrated the drain variables to be poor predictors of hospital readmission, with the highest area under curve of 0.524 (drain duration), corresponding to a sensitivity of 61.3% and specificity of 49.9%. @*Conclusions@#Drain output or duration did not affect readmission rates following lumbar spine surgery.

Serotonin Reuptake Inhibitor Increases Pseudarthrosis Rates in Anterior Cervical Discectomy and Fusions

Methods@#Patients with 1-year postoperative dynamic cervical spine radiographs following ACDF were grouped into serotonin reuptake inhibitor prescriptions (SSRI, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant [TCA]) and no prescription (atypical antidepressant or no antidepressant). Pseudarthrosis was defined as ≥1 mm interspinous process motion on dynamic radiographs. Logistic regression models were controlled for confounding to analyze pseudarthrosis rates. Alpha was set at p - values of <0.05. @*Results@#Of the 523 patients who meet the inclusion criteria, 137 (26.2%) were prescribed an SSRI, SNRI, or TCA. Patients with these prescriptions were more likely to have pseudarthrosis (p =0.008) but not a revision surgery due to pseudarthrosis (p =0.219). Additionally, these patients had worse 1-year postoperative mental component summary (MCS)-12 (p =0.015) and Neck Disability Index (NDI) (p =0.006). The multivariate logistic regression analysis identified SSRI/SNRI/TCA use (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.11–2.99; p =0.018) and construct length (OR, 1.91; 95% CI, 1.50–2.44; p <0.001) as pseudarthrosis predictors. A SSRI/SNRI/TCA prescription was a revision surgery predictor due to adjacent segment disease on univariate analysis (OR, 2.51; p =0.035) but not on multivariate logistic regression analysis (OR, 2.24; p =0.10). @*Conclusions@#Patients taking serotonin reuptake-inhibiting antidepressants are at increased risk of worse postoperative outcome scores, including NDI and MCS-12, likely due to their underlying depression. This may contribute to their greater likelihood of having adjacent segment surgery. Additionally, preoperative use of serotonin reuptake inhibitors in patients undergoing an ACDF is a predictor of radiographic pseudarthrosis but not pseudarthrosis revision.

Discovery of JNJ-64264681: A Potent and Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (13), a covalent, irreversible BTK inhibitor with potent whole blood activity and exceptional kinome selectivity. JNJ-64264681 demonstrated excellent oral efficacy in both cancer and autoimmune models with sustained in vivo target coverage amenable to once daily dosing and has advanced into human clinical studies to investigate safety and pharmacokinetics.

Reinterpreting the Fate of Iridium(III) Photocatalysts─Screening a Combinatorial Library to Explore Light-Driven Side-Reactions.

Photoredox catalysts are primarily selected based on ground and excited state properties, but their activity is also intrinsically tied to the nature of their reduced (or oxidized) intermediates. Catalyst reactivity often necessitates an inherent instability, thus these intermediates represent a mechanistic turning point that affords either product formation or side-reactions. In this work, we explore the scope of a previously demonstrated side-reaction that partially saturates one pyridine ring of the ancillary ligand in heteroleptic iridium(III) complexes. Using high-throughput synthesis and screening under photochemical conditions, we identified different chemical pathways, ultimately governed by ligand composition. The ancillary ligand was the key factor that determined photochemical stability. Following photoinitiated electron transfer from a sacrificial tertiary amine, the reduced intermediate of complexes containing 1,10-phenanthroline derivatives exhibited long-term stability. In contrast, complexes containing 2,2'-bipyridines were highly susceptible to hydrogen atom transfer and ancillary ligand modification. Detailed characterization of selected complexes before and after transformation showed differing effects on the ground and excited state reduction potentials dependent on the nature of the cyclometalating ligands and excited states. The implications of catalyst stability and reactivity in chemical synthesis was demonstrated in a model photoredox reaction.

Dental management of a patient with systemic mastocytosis.

Mastocytosis is a term encompassing a group of clinical disorders characterised by clonal proliferation of abnormal mast cells (MCs) in organ systems of the body. Mastocytosis can be systemic (with or without skin involvement) or cutaneous, and can affect organs including bone marrow, liver, spleen, lymph nodes and mucosal surfaces. Patients with systemic mastocytosis (SM) are susceptible to triggers that could cause activation of abnormal MCs, resulting in multiorgan dysfunction and life-threatening anaphylactic reactions. Mastocytosis has a number of ramifications for the dental management of a patient with the condition. Patients are at increased risk of complications due to a number of risk factors for MC activation present within the dental context, including stress, certain prescribed drugs, oral hygiene products and dental materials. This report presents the oral management of an adult with SM, discussing the implications of the condition within the context of the limited existing literature on the subject.

JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.

The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid ß lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.

Identification of a new class of HBV capsid assembly modulator.

The HBV core protein is a druggable target of interest due to the multiple essential functions in the HBV life cycle to enable chronic HBV infection. The core protein oligomerizes to form the viral capsid, and modulation of the HBV capsid assembly has shown efficacy in clinical trials. Herein is described the identification and hit to lead SAR of a novel series of pyrazolo piperidine HBV capsid assembly modulators.