Pharmacogenomic Clinical Support Tools for the Treatment of Depression.

OBJECTIVE: In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression. METHODS: The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized. RESULTS: Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results. CONCLUSIONS: The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response.

Ligand-Assisted Direct Lithography of Upconverting and Avalanching Nanoparticles for Nonlinear Photonics.

Upconverting nanoparticles (UCNPs) exhibit unique nonlinear optical properties that can be harnessed in microscopy, sensing, and photonics. However, forming high-resolution nano- and micropatterns of UCNPs with large packing fractions is still challenging. Additionally, there is limited understanding of how nanoparticle patterning chemistries are affected by the particle size. Here, we explore direct patterning chemistries for 6-18 nm Tm3+-, Yb3+/Tm3+-, and Yb3+/Er3+-based UCNPs using ligands that form either new ionic linkages or covalent bonds between UCNPs under ultraviolet (UV), electron-beam (e-beam), and near-infrared (NIR) exposure. We study the effect of UCNP size on these patterning approaches and find that 6 nm UCNPs can be patterned with compact ionic-based ligands. In contrast, patterning larger UCNPs requires long-chain, cross-linkable ligands that provide sufficient interparticle spacing to prevent irreversible aggregation upon film casting. Compared to approaches that use a cross-linkable liquid monomer, our patterning method limits the cross-linking reaction to the ligands bound on UCNPs deposited as a thin film. This highly localized photo-/electron-initiated chemistry enables the fabrication of densely packed UCNP patterns with high resolutions (∼1 µm with UV and NIR exposure; <100 nm with e-beam). Our upconversion NIR lithography approach demonstrates the potential to use inexpensive continuous-wave lasers for high-resolution 2D and 3D lithography of colloidal materials. The deposited UCNP patterns retain their upconverting, avalanching, and photoswitching behaviors, which can be exploited in patterned optical devices for next-generation UCNP applications.

Quantum Dot Fluorescent Imaging: Using Atomic Structure Correlation Studies to Improve Photophysical Properties.

Efforts to study intricate, higher-order cellular functions have called for fluorescence imaging under physiologically relevant conditions such as tissue systems in simulated native buffers. This endeavor has presented novel challenges for fluorescent probes initially designed for use in simple buffers and monolayer cell culture. Among current fluorescent probes, semiconductor nanocrystals, or quantum dots (QDs), offer superior photophysical properties that are the products of their nanoscale architectures and chemical formulations. While their high brightness and photostability are ideal for these biological environments, even state of the art QDs can struggle under certain physiological conditions. A recent method correlating electron microscopy ultrastructure with single-QD fluorescence has begun to highlight subtle structural defects in QDs once believed to have no significant impact on photoluminescence (PL). Specific defects, such as exposed core facets, have been shown to quench QD PL in physiologically accurate conditions. For QD-based imaging in complex cellular systems to be fully realized, mechanistic insight and structural optimization of size and PL should be established. Insight from single QD resolution atomic structure and photophysical correlative studies provides a direct course to synthetically tune QDs to match these challenging environments.

Sphingosine 1-phosphate receptor modulators in multiple sclerosis treatment: A practical review.

Four sphingosine 1-phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head-to-head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real-world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

Characterization of Fatigue in Primary Mitochondrial Myopathies: Findings From a Qualitative Interview Study.

Background and Objectives: Primary mitochondrial myopathies are genetic disorders that primarily affect peripheral skeletal muscles. Patients with primary mitochondrial myopathies often experience muscle weakness, fatigue, and other significant impacts on health-related quality of life. The aim of this noninterventional qualitative study was to collect the most bothersome fatigue-related symptoms and impacts reported by patients with primary mitochondrial myopathies and determine whether the questions included in an existing patient-reported outcome measure, the Modified Fatigue Impact Scale, are relevant and interpretable for this population. Methods: The interviews contained a concept elicitation exercise to understand the most bothersome primary mitochondrial myopathies symptoms and impacts and a cognitive debriefing section to review the questions included in the Modified Fatigue Impact Scale for relevance and interpretability. Transcripts were coded using ATLAS.ti software. Results: Interviews were conducted with 16 patients who were aged 16 years and older with a genetically confirmed and clinical diagnosis of symptomatic primary mitochondrial myopathies. Concept elicitation interviews established that while patients with mitochondrial myopathies reported a wide variety of symptoms and impacts, one of the most impactful symptoms discussed was fatigue. Cognitive debriefing interview results confirmed that the Modified Fatigue Impact Scale items were relevant, were interpretable, and largely captured patients' experience with fatigue. Discussion: Fatigue was one of the most widely discussed experiences discussed by participants and was considered the most important symptom/impact to treat by most of the participants. The Modified Fatigue Impact Scale could be used in future clinical trials to measure treatment benefit in fatigue-related impacts.

Prospective Clinical and Computed Tomography Evaluation of Calcaneus Fractures Treated Through Sinus Tarsi Approach.

Background: The traditional lateral extensile approach to the calcaneus allows for excellent visualization but is associated with high wound complication rates. The sinus tarsi approach has been shown to produce similar radiographic outcomes with much lower rates of wound complications. The purpose of this study is to prospectively determine clinical and radiographic outcomes in calcaneus fractures treated with a sinus tarsi approach. Methods: Twenty-nine patients with 30 calcaneus fractures underwent operative fixation through a sinus tarsi approach and were prospectively evaluated. Routine pre- and postoperative radiographs were obtained, in addition to computed tomography (CT) scans at 6 weeks and 12 months after surgery. Patient-reported outcomes including American Orthopaedic Foot & Ankle Society (AOFAS) score, visual analog scale (VAS) pain score, Veterans Rand 12-Item Health Survey (VR-12), and Foot Functional Index (FFI) were recorded. Patients were followed for a minimum of 1 year postoperation. Results: Twenty-one patients with 22 calcaneus fractures completed 1 year of follow-up. At 12 months postoperation, 20 of 22 patients (91%) had 0 to 2 mm of fracture displacement at the posterior facet on CT scans whereas 2 of 22 patients had 2 to 4 mm of fracture displacement. There was no significant change in posterior facet fracture displacement comparing 6-week and 12-month postoperative CT scans (P > .99). Mean postoperative Bohler angle was 26.1 degrees compared to 13.2 degrees preoperatively. All patients had complete union of fracture site. There were no major wound complications. Four of 22 patients (18.2%) had minor wound complications. AOFAS, FFI, and VAS pain scores improved postoperatively but were not found to correlate with Bohler angle or critical angle of Gissane. Conclusion: We found that in select patients excellent anatomic alignment and good clinical outcomes with low wound complication rates can be achieved when fixing calcaneus fractures through the sinus tarsi approach. Level of Evidence: Level II, prospective cohort study.

Cerebellar transcranial magnetic stimulation in psychotic disorders: intermittent, continuous, and sham theta-burst stimulation on time perception and symptom severity.

Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms. Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive. Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons. Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029.

Differential Diagnosis of Tumor-like Brain Lesions.

Purpose of Review: Tumor-like brain lesions are rare and commonly suggest a neoplastic etiology. Failure to rapidly identify non-neoplastic causes can lead to increased morbidity and mortality. In this review, we describe 10 patients who presented with atypical, non-neoplastic tumor-like brain lesions in which brain biopsy was essential for a correct diagnosis and treatment. Recent Findings: There has been increasing recognition of autoimmune conditions affecting the nervous system, and many of those diseases can cause tumor-like brain lesions. Currently available reports of non-neoplastic tumor-like brain lesions are scarce. Most case series focus on tumefactive demyelinating lesions, and a comprehensive review including other neuroimmunological conditions such as CNS vasculitis, neurosarcoidosis, histiocytic and infectious etiologies is lacking. Summary: We review the literature on tumor-like brain lesions intending to increase the awareness and differential diagnosis of non-neoplastic brain tumor mimics. We advocate for earlier brain biopsies, which, in our case series, significantly changed diagnosis, management, and outcomes.

Advanced techniques in automated high-resolution scanning transmission electron microscopy.

Scanning transmission electron microscopy is a common tool used to study the atomic structure of materials. It is an inherently multimodal tool allowing for the simultaneous acquisition of multiple information channels. Despite its versatility, however, experimental workflows currently rely heavily on experienced human operators and can only acquire data from small regions of a sample at a time. Here, we demonstrate a flexible pipeline-based system for high-throughput acquisition of atomic-resolution structural data using an all-piezo sample stage applied to large-scale imaging of nanoparticles and multimodal data acquisition. The system is available as part of the user program of the Molecular Foundry at Lawrence Berkeley National Laboratory.

Triplet-Induced Singlet Oxygen Photobleaches Near-Infrared Dye-Sensitized Upconversion Nanosystems.

The rapid photobleaching of near-infrared (NIR) dye-sensitized upconversion nanosystems is one of the crucial problems that has blocked their technological applications. Uncovering the photophysical and photochemical pathways of NIR dyes would help to elucidate the photobleaching mechanism and thereby improve the photostability of the system. Here we investigate the triplet dynamics of NIR dyes and their interaction with triplet oxygen in the typically investigated IR806-sensitized upconversion nanoparticle (UCNP) nanosystem. Low-temperature fluorescence at 77 K provides direct proof of the generation of singlet oxygen (1O2) under 808 nm laser irradiation. Mass spectrometry indicates that all three double bonds in the structure of IR806 can be broken in the photochemical process. Coupling IR806 to the surface of UCNPs can accelerate its triplet dynamics, thus producing more 1O2 to photocleave IR806. Importantly, we find that the addition of ß-carotene can scavenge the generated 1O2, thereby providing a simple method to effectively inhibit photobleaching.

Should Medical Insurance Review Serve the Patient's Best Interests? Examples and Considerations Illustrated by Behavioral Health Cases.

ABSTRACT: Physician medical directors working for health care insurance companies conduct utilization reviews, participate in quality-of-care reviews, and adjudicate appeals. As a result, they have access to substantial and important clinical information. The medical director may have both current and historical information that can assist the treatment team in providing care. Sharing this information with a patient's current health care provider(s) is problematic due to concerns about patient privacy and the insurer's goal of not assuming legal liability for patient care. While this paper considers legal issues, it predominantly addresses the ethical responsibilities of medical directors who have valuable information unavailable to or unrecognized by the treatment team. Although it is important to consider sharing general medical information, this paper emphasizes the sharing of behavioral health information, which can be highly sensitive but also pertinent to psychiatric and other medical treatment choices. We suggest that clinical information should flow from insurer to provider when the insurer has information that will benefit the patient or prove crucial to optimal care rather than just flow from provider to insurer for the purposes of claims payments. To support and secure that flow, the paper outlines procedures for determining the need to share information, the means of providing that information, ways to separate liability, and processes for protecting privacy.

An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models.

The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson's disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1's transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD.

A Generalized Approach to Photon Avalanche Upconversion in Luminescent Nanocrystals.

Photon avalanching nanoparticles (ANPs) exhibit extremely nonlinear upconverted emission valuable for subdiffraction imaging, nanoscale sensing, and optical computing. Avalanching has been demonstrated with Tm3+-, Pr3+-, or Nd3+-doped nanocrystals, but their emission is limited to a few wavelengths and materials. Here, we utilize Gd3+-assisted energy migration to tune the emission wavelengths of Tm3+-sensitized ANPs and generate highly nonlinear emission from Eu3+, Tb3+, Ho3+, and Er3+ ions. The upconversion intensities of these spectrally discrete ANPs scale with nonlinearity factor s = 10-17 under 1064 nm excitation at power densities as low as 7 kW cm-2. This strategy for imprinting avalanche behavior on remote emitters can be extended to fluorophores adjacent to ANPs, as we demonstrate with CdS/CdSe/CdS core/shell/shell quantum dots. ANPs with rationally designed energy transfer networks provide the means to transform conventional linear emitters into a highly nonlinear ones, expanding the use of photon avalanching in biological, chemical, and photonic applications.

Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM. METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms. RESULTS: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity. DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated. TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017. CLINICALTRIALS: gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.

Indefinite and bidirectional near-infrared nanocrystal photoswitching.

Materials whose luminescence can be switched by optical stimulation drive technologies ranging from superresolution imaging1-4, nanophotonics5, and optical data storage6,7, to targeted pharmacology, optogenetics, and chemical reactivity8. These photoswitchable probes, including organic fluorophores and proteins, can be prone to photodegradation and often operate in the ultraviolet or visible spectral regions. Colloidal inorganic nanoparticles6,9 can offer improved stability, but the ability to switch emission bidirectionally, particularly with near-infrared (NIR) light, has not, to our knowledge, been reported in such systems. Here, we present two-way, NIR photoswitching of avalanching nanoparticles (ANPs), showing full optical control of upconverted emission using phototriggers in the NIR-I and NIR-II spectral regions useful for subsurface imaging. Employing single-step photodarkening10-13 and photobrightening12,14-16, we demonstrate indefinite photoswitching of individual nanoparticles (more than 1,000 cycles over 7 h) in ambient or aqueous conditions without measurable photodegradation. Critical steps of the photoswitching mechanism are elucidated by modelling and by measuring the photon avalanche properties of single ANPs in both bright and dark states. Unlimited, reversible photoswitching of ANPs enables indefinitely rewritable two-dimensional and three-dimensional multilevel optical patterning of ANPs, as well as optical nanoscopy with sub-Å localization superresolution that allows us to distinguish individual ANPs within tightly packed clusters.

Preventing Osteoarthritis After an Anterior Cruciate Ligament Injury: An Osteoarthritis Action Alliance Consensus Statement.

After an anterior cruciate ligament (ACL) injury, people need secondary prevention strategies to identify osteoarthritis at its earliest stages so that interventions can be implemented to halt or slow the progression toward its long-term burden. The Osteoarthritis Action Alliance formed an interdisciplinary Secondary Prevention Task Group to develop a consensus on recommendations to provide clinicians with secondary prevention strategies that are intended to reduce the risk of osteoarthritis after a person has an ACL injury. The group achieved consensus on 15 out of 16 recommendations that address patient education, exercise and rehabilitation, psychological skills training, graded-exposure therapy, cognitive-behavioral counseling (lacked consensus), outcomes to monitor, secondary injury prevention, system-level social support, leveraging technology, and coordinated care models. We hope this statement raises awareness among clinicians and researchers on the importance of taking steps to mitigate the risk of osteoarthritis after an ACL injury.

Evidence Review for Preventing Osteoarthritis After an Anterior Cruciate Ligament Injury: An Osteoarthritis Action Alliance Consensus Statement.

CONTEXT: The Osteoarthritis Action Alliance formed a secondary prevention task group to develop a consensus on secondary prevention recommendations to reduce the risk of osteoarthritis after a knee injury. OBJECTIVE: Our goal was to provide clinicians with secondary prevention recommendations that are intended to reduce the risk of osteoarthritis after a person has sustained an anterior cruciate ligament injury. Specifically, this manuscript describes our methods, literature reviews, and dissenting opinions to elaborate on the rationale for our recommendations and to identify critical gaps. DESIGN: Consensus process. SETTING: Virtual video conference calls and online voting. PATIENTS OR OTHER PARTICIPANTS: The Secondary Prevention Task Group consisted of 29 members from various clinical backgrounds. MAIN OUTCOME MEASURE(S): The group initially convened online in August 2020 to discuss the target population, goals, and key topics. After a second call, the task group divided into 9 subgroups to draft the recommendations and supportive text for crucial content areas. Twenty-one members completed 2 rounds of voting and revising the recommendations and supportive text between February and April 2021. A virtual meeting was held to review the wording of the recommendations and obtain final votes. We defined consensus as >80% of voting members supporting a proposed recommendation. RESULTS: The group achieved consensus on 15 of 16 recommendations. The recommendations address patient education, exercise and rehabilitation, psychological skills training, graded-exposure therapy, cognitive-behavioral counseling (lacked consensus), outcomes to monitor, secondary injury prevention, system-level social support, leveraging technology, and coordinated care models. CONCLUSIONS: This consensus statement reflects information synthesized from an interdisciplinary group of experts based on the best available evidence from the literature or personal experience. We hope this document raises awareness among clinicians and researchers to take steps to mitigate the risk of osteoarthritis after an anterior cruciate ligament injury.

The Transformation of Documenting and Coding for Neurologic Hospital Inpatient and Observation Services.

ABSTRACT: Landmark changes to documenting and coding for office or other outpatient evaluation and management (E/M) codes were implemented on January 1, 2021. To decrease clinicians' administrative burden, many documentation requirements were eliminated. In addition, major changes were made in how medical decision making and time spent on the date of the encounter are used to determine the level of service. On January 1, 2023, these changes were extended to inpatient and observation E/M services. The level of service in both inpatient and outpatient settings can now be selected based on the total time dedicated to the patient's care on the day of the encounter or the new method of medical decision making. This article discusses the optimal ways to document and code for inpatient hospital and observation encounters after January 1, 2023.