Medical resource usage for COVID-19 evaluated using the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic exhibited several different waves threatening global health care. During this pandemic, medical resources were depleted. However, the kind of medical resources provided to each wave was not clarified. This study aimed to examine the characteristics of medical care provision at COVID-19 peaks in preparation for the next pandemic. METHODS: Using medical insurance claim records in Japan, we examined the presence or absence of COVID-19 infection and the use of medical resources for all patients monthly by age group. RESULTS: The wave around August 2021 with the Delta strain had the strongest impact on the working population in terms of hospital admission and respiratory support. For healthcare providers, this peak had the highest frequency of severely ill patients. In the subsequent wave, although the number of patients with COVID-19 remained high, they were predominantly older adults, with relatively fewer patients receiving intensive care. CONCLUSIONS: In future pandemics, we should refer to the wave around August 2021 as a situation of medical resource shortage resulting from the COVID-19 pandemic.

[A Case of Bacterial Meningitis in Which Occurrence of Ataxie Optique Led to Detection of a Small Subdural Abscess and Pialitis].

We report the case of a 69-year-old man with bacterial meningitis who presented with ataxie optique in the peripheral part of the left visual field in both hands. A detailed neurological examination with contrast-enhanced brain MRI in the early stage of the clinical course identified a small subdural abscess and pialitis in the right parietal area. A favorable outcome was obtained with antibiotic therapy alone. In a case with higher brain dysfunction of unknown cause in the clinical course of bacterial meningitis, a detailed neurological examination may be helpful to identify the causative site. (Received September 25, 2023; Accepted October 31, 2023; Published March 1, 2024).

Remarkable remission of symptomatic dermatomyositis after curative breast cancer surgery.

Dermatomyositis (DM) is an autoimmune disease that causes proximal muscle weakness in the extremities leading to severe immobility and dysphagia. Approximately 20% of patients with DM are positive for anti-TIF-1γ antibody and frequently accompanied by malignant tumors. Although DM remission after tumor resection has been reported, the indications for surgery in patients with severe DM are unknown. Herein, we report a case of a 79-year-old Japanese woman who presented with breast cancer and anti-TIF-1γ antibody-positive DM. She became bedridden shortly after DM onset. Although pulsed steroid therapy, intravenous immunoglobulin, tacrolimus, and endocrine therapy with fulvestrant did not improve her symptoms, tumor resection with axillary lymph node dissection resulted in complete remission of the DM after 8 months. Immunohistochemistry revealed high expression of TIF-1γ in cancer cells, both in the primary tumor and axillary lymph nodes. Since the serum levels of anti-TIF-1γ antibody decreased after the surgery, the existence of breast cancer with TIF-1γ expression may have contributed to the worsening of DM. The present case suggests that curative surgery should be considered as a treatment option even if the patient has severe symptoms, such as immobility and dysphagia. Careful discussions with patients and multidisciplinary collaboration are essential to make surgery feasible, particularly for those with severe symptomatic DM.

Quantitative analysis of the effect of docetaxel-induced edema on quality of life in patients with breast cancer and related factors: a prospective cohort study.

BACKGROUND: Systemic edema is an adverse effect of docetaxel chemotherapy and causes distress to patients, including those receiving this agent for breast cancer. However, its characteristics and factors related to its effect on quality of life (QoL) have not been adequately investigated. In this study, we assessed systemic edema quantitatively, explored related factors, and evaluated QoL in patients receiving docetaxel for breast cancer. METHODS: The study had a prospective cohort design and included 37 patients with no known history of swelling who were treated with docetaxel between September 2019 and April 2022. Patients were examined at the start, middle, and end of their course of treatment and 1 and 2 months later. Body water content, body mass, fat mass, and muscle mass were quantified using bioelectrical impedance analysis. Systemic edema was evaluated with reference to the Common Terminology Criteria for Adverse Events. The timing of development of systemic edema at any anatomical site that was grade 2 or worse was recorded. QoL was assessed using the Quality of Life-Anti Cancer Drug scale. Nutrition was evaluated using the Brief-type self-administered diet history questionnaire. Multivariable logistic regression analysis was performed to identify related factors. QoL was also compared between patients with edema and those without edema. RESULTS: Systemic edema developed in 67% of the study participants and was most prevalent at the end of treatment. Body fat mass (adjusted odds ratio [aOR] 0.802, 95% confidence interval [CI] 0.651-0.988, p = 0.038), disease stage (aOR 3.279, 95% CI 0.493-21.793, p = 0.219), and history of alcohol consumption (aOR 0.141, 95% CI 0.013-1.521, p = 0.106) were identified as risk factors for docetaxel-induced edema. Participants who developed systemic edema experienced more physical, vital, and emotional distress 1 month after treatment than those who did not. There was no association between systemic edema and nutrition. CONCLUSIONS: Systemic edema may develop after treatment with docetaxel and increase distress in patients with a high body fat mass. Patients at risk of systemic edema should be informed in advance about the potential frequency, location, and timing of its onset and encouraged to self-manage this condition.

Pregnancy-related issues from the perspective of patients with inflammatory rheumatic diseases - Results from a survey of the members of the National Association for Inflammatory Rheumatic Diseases.

OBJECTIVES: This study aimed to clarify the issues related to pregnancy in patients with inflammatory rheumatic diseases (RDs) and to provide useful information for developing medical services from patients' perspectives. METHODS: A survey involving approximately 5,000 members of the Patients Association for Collagen Vascular Diseases Japan was conducted using a questionnaire that was sent and returned by mail. The questionnaire items included age at the time of the survey, types of RDs, association of RDs with pregnancy/childbirth outcomes, and pregnancy-related supports and hindrances. RESULTS: We received 491 completed questionnaires. The most common RD was systemic lupus erythematosus (n=309). Approximately 60% of participants had a history of childbirth. Approximately 60% of participants had previously experienced pregnancy-related challenges due to RDs. These included concerns about the influence of drugs on babies, genetic transmission, and active disease. Patients with active disease at the time of conception were more likely to experience disease exacerbation during pregnancy, but this did not correlate with whether the pregnancy was planned. CONCLUSION: This study revealed that many patients with RDs experienced pregnancy-related challenges and needed appropriate support based on appropriate information. The findings here should help rheumatologists, health care providers, and public agencies provide counseling and information.

Individual Activity Anomaly Estimation in Operating Rooms Based on Time-Sequential Prediction.

Surveillance videos of operating rooms have potential to benefit post-operative analysis and study. However, there is currently no effective method to extract useful information from the long and massive videos. As a step towards tackling this issue, we propose a novel method to recognize and evaluate individual activities using an anomaly estimation model based on time-sequential prediction. We verified the effectiveness of our method by comparing two time-sequential features: individual bounding boxes and body key points. Experiment results using actual surgery videos show that the bounding boxes are suitable for predicting and detecting regional movements, while the anomaly scores using key points can hardly be used to detect activities. As future work, we will be proceeding with extending our activity prediction for detecting unexpected and urgent events.

Medical care costs according to the stage and subtype of breast cancer in a municipal setting: a case study of Hachioji City, Japan.

BACKGROUND: It is important to assess whether the early detection of breast cancer affects medical care costs. However, research remains scant on the actual medical care costs associated with breast cancer treatment in Japan. This study aimed to determine the medical care costs of breast cancer treatment based on its stage using national health insurance claims data. METHODS: This was an observational study including patients with breast cancer who had undergone breast cancer treatment, as defined by the disease name and related treatment codes. Between August 2013 and June 2016, patients who underwent surgical treatment without axillary lymph node dissection and other radical treatment were classified as the curable group, while those who underwent palliative treatment were classified as the non-curable group. Patients were further stratified by subtype. The total and treatment-specific medical care costs for the five years were calculated using the national health insurance claims data of Hachioji City between August 2013 and May 2021. RESULTS: The mean total medical care costs for the curable and non-curable groups for the 5 years were JPY 3958 thousand (standard deviation 2664) and JPY 8289 thousand (8482), respectively. The mean medical care costs for specific breast cancer treatment for the curable and non-curable groups were JPY 1142 (728) thousand and JPY 3651 thousand (5337), respectively. Further, human epidermal growth factor receptor 2 + , Hormone + patients had the highest mean cost over the 5 years. CONCLUSIONS: The results suggest that the early detection of breast cancer may reduce medical care costs at the patient level.

Variation in Utilization of Postoperative Rehabilitation After Total Hip Arthroplasty in Japan.

OBJECTIVE: The use of rehabilitation after arthroplasty in Japan is unknown. We aimed to identify utilization of postoperative rehabilitation after total hip arthroplasty (THA) and to explore the factors associated with rehabilitation usage. DESIGN: A retrospective cohort study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB). SETTING: Hospitals nationwide. PARTICIPANTS: Patients aged >40 years who underwent primary THA between 2017 and 2018 (N=51,332). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The proportion of patients who underwent postoperative rehabilitation and the number of rehabilitation days were also calculated. Patient demographic characteristics, hospital case volumes, and regions associated with continuing postoperative rehabilitation were analyzed using a Cox proportional hazards model. RESULTS: Eligible patients were selected from 3033 hospitals, of whom 41,192 (80%) were women. Of these, 94% used inpatient rehabilitation, and 20% received outpatient rehabilitation. The mean durations of rehabilitation were 47±72 days for inpatient and 195±109 days for outpatient, respectively. Large-scale hospitals performing more than 200 procedures annually had the shortest duration of inpatient rehabilitation (36-65 days) and the longest duration of outpatient rehabilitation (220-109 days) compared with smaller hospitals. The regression model consistently showed that rehabilitation continued longer at hospitals with over 200 patients per year (HR 0.96, 95% CI 0.93-0.99, P<.007). CONCLUSION: The Japanese health care system provided higher access to inpatient rehabilitation after THA than other countries. One limitation of this study is that long-term care insurance data were not analyzed. However, outpatient rehabilitation vary according to hospital case volume. Further research is needed to determine the causes of variation in rehabilitation use and the effect of variation on patient outcomes.

Steroids May Be Associated With Extensive Skeletal Muscle Uptake of 18 F-FDG.

PURPOSE: The possibility of steroid administration inducing the extensive skeletal muscle uptake (ESMU) of FDG in PET scans was investigated. METHODS: From 8923 consecutive 18 F-FDG PET/CT scans taken at our hospital, 23 scans (15 patients) met adult age and ESMU-positive inclusion criteria. Among the 15 patients, 13 with both ESMU-positive and -negative scans were examined for association with steroid administration. RESULTS: Extensive skeletal muscle uptake was associated with a history of steroid administration ( χ2 test: P = 0.001). Notably, 20 ESMU-positive scans and 11 ESMU-negative scans were significantly different, with 0 to 95 days (median, 18.5 days) and 0 to 708 days (median, 319.0 days) since the last steroid administration, respectively (Mann-Whitney U test, P = 0.003). A significant correlation was observed between mean skeletal muscle SUV max and the number of days since the last steroid administration (Spearman rank correlation coefficient, ρ = -0.501, P = 0.004). Specifically, the degree of ESMU tended to decrease over time, after steroid administration. From multiple regression analysis, the number of days since the last steroid administration was significantly associated with mean SUV max ( P = 0.007), but the blood glucose level was not significant ( P = 0.204), revealing that the number of days since the last steroid administration was an independent risk factor. Multicollinearity was low (the variance inflation factor was 1.007 for both the number of days since the last steroid administration and blood glucose levels). CONCLUSIONS: Steroid administration within months before PET may be one cause of ESMU.

IgG index of cerebrospinal fluid can reflect pathophysiology associated with Lewy bodies in Parkinson's disease.

BACKGROUND: Neuroinflammation is one of the pathophysiologies of Parkinson's disease (PD). Lewy bodies, the pathological hallmark of PD, emerge as a consequence of α-synuclein aggregation, and neuroinflammation is induced concurrently with this aggregation. Imaging and cerebrospinal fluid (CSF) biomarkers that reflect PD pathophysiology have been developed or are under investigation. The IgG index of CSF is a marker of inflammation, and may also reflect the pathophysiology of PD. AIM: We examined if the IgG index reflects the pathophysiology of PD in drug-naïve PD patients. METHOD: The subjects were 20 consecutive PD patients who underwent 123I-MIBG scintigraphy for assessment of the heart to mediastinum (H/M) ratio and wash out rate, 123I-Ioflupane SPECT for examination of the specific binding ratio in the striatum, and lumbar puncture before treatment. The CSF IgG index and levels of pathogenic proteins (total α-synuclein, oligomeric α-synuclein, total tau, phosphorylated tau and amyloid Aß1-42) were determined. The IgG index was compared with the other parameters using Spearman correlation analysis. RESULTS: The IgG index showed a significant correlation with the H/M ratio in early (r = -0.563, p = 0.010) and delayed (r = -0.466, p = 0.038) images in 123I-MIBG scintigraphy and with the CSF total tau level (r = -0.513, p = 0.021). CONCLUSION: Neuroinflammation is involved in PD pathophysiology in some patients, and a higher IgG index indicates the presence of neuroinflammation accompanied by emergence of Lewy bodies.

De-differentiation in cultures of organoids from luminal-type breast cancer is restored by inhibition of NOTCH signaling.

Estrogen receptor (ER) expression in breast cancer can change during progression and the treatment, but the mechanism has not been well studied. In this study, we successfully prepared organoids from samples obtained from 33 luminal-type breast cancer patients and studied their ER expression. The expression status was well maintained in primary organoids, whereas it decreased after passaging in most of the cases. In fact, the studied organoid lines were classified into those that retained a high level of ER expression (9%), those that completely lost it (9%), and those that repressed it to varying degrees (82%). In some cases, the ER expression was suddenly and drastically decreased after passaging. Marker protein immunohistochemistry revealed that after passaging, the differentiation status shifted from a luminal- to a basal-like status. Differentially expressed genes suggested the activation of NOTCH signaling in the passaged organoids, wherein a NOTCH inhibitor was able to substantially rescue the decreased ER expression and alter the differentiation status. Our findings suggest that the differentiation status of luminal-type cancer cells is quite flexible, and that by inhibiting the NOTCH signaling we can preserve the differentiation status of luminal-type breast cancer organoids.

Development of Photoredox Cross-Electrophile Coupling of Strained Heterocycles with Aryl Bromides Using High-Throughput Experimentation for Library Construction.

Microscale high-throughput experimentation was used to develop a photoredox-assisted reductive cross-coupling reaction of aryl halides with strained aliphatic heterocycles facilitated via a ring-opening reaction. This methodology was found to be applicable to medicinally relevant substrates including Boc-protected strained aliphatic heterocycles and (hetero)aryl bromides and was used for compound library construction via parallel medicinal chemistry. Furthermore, the coupling reactions were shown to be scalable to the gram scale by continuous flow reaction. A possible reaction mechanism is also discussed.

Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

Plasma amyloid-ß biomarkers are associated with Alzheimer's disease comorbidity in Lewy body disease.

No blood biomarkers which can identify Alzheimer's disease pathology in Lewy body disease (LBD) have ever been established. We showed that the plasma amyloid-ß (Aß) 1-42/Aß1-40 ratio was significantly decreased in patients with Aß+ LBD compared with those with Aß- LBD and it might be a useful biomarker.

Reduction in X-ray Retake Rate Using the Token Economy Method.

Excessive retakes of X-ray images increase labor and material costs, as well as result in excess radiation exposure for patients and a long waiting time. In this study, we evaluated the effectiveness of the token economy method as a management method for reducing X-ray retake rate among radiology technicians. The results showed a 2.5% reduction in retake rate, indicating the effectiveness of our method. In addition, we suggest that the token-economy-based approach can be applied to other hospital management problems.

Hospital-Level Variation in Cardiac Rehabilitation After Myocardial Infarction in Japan During Fiscal Years 2014-2015 Using the National Database.

Background: Cardiac rehabilitation (CR) is an evidence-based medical service for patients with acute myocardial infarction (AMI); however, its implementation is inadequate. We investigated the provision status and equality of CR by hospitals in Japan using a comprehensive nationwide claims database. Methods and Results: We analyzed data from the National Database of Health Insurance Claims and Specific Health Checkups in Japan for the period April 2014-March 2016. We identified patients aged ≥20 years with postintervention AMI. We calculated hospital-level proportions of inpatient and outpatient CR participation. The equality of hospital-level proportions of inpatient and outpatient CR participation was evaluated using the Gini coefficient. We included 35,298 patients from 813 hospitals for the analysis of inpatients and 33,328 patients from 799 hospitals for the analysis of outpatients. The median hospital-level proportions of inpatient and outpatient CR participation were 73.3% and 1.8%, respectively. The distribution of inpatient CR participation was bimodal; the Gini coefficients of inpatient and outpatient CR participation were 0.37 and 0.73, respectively. Although there were statistically significant differences in the hospital-level proportion of CR participation for several hospital factors, CR certification status for reimbursement was the only visually evident factor affecting the distribution of CR participation. Conclusions: The distributions of inpatient and outpatient CR participation by hospitals were suboptimal. Further research is warranted to determine future strategies.

Cerebral white matter lesions and regional blood flow are associated with reduced cognitive function in early-stage cognitive impairment.

Background: Differences in the extent of cerebral white matter lesions (WML) and regional cerebral blood flow (rCBF) in early-stage cognitive impairment (ESCI) contribute to the prognosis of cognitive decline; however, it is unclear precisely how WML and rCBF affect cognitive decline in ESCI. Objective: We examined the association between WML, rCBF, and cognitive impairment in the ESCI, using path analysis to clarify how these variables affect each other. Methods: Eighty-three patients who consulted our memory clinic regarding memory loss were included in this study based on the Clinical Dementia Rating. Participants underwent the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging (MRI) for voxel-based morphometry analysis, and brain perfusion single-photon emission computed tomography (SPECT) for rCBF evaluation in cortical regions, using 3D stereotactic surface projection (3D-SSP) analysis. Results: Path analysis was performed on the MRI voxel-based morphometry and SPECT 3D-SSP data, showing a significant correlation between both and MMSE scores. In the most suitable model (GFI = 0.957), correlations were observed between lateral ventricular (LV-V) and periventricular WML (PvWML-V) volumes [standardized coefficient (SC) = 0.326, p = 0.005], LV-V and rCBF of the anterior cingulate gyrus (ACG-rCBF; SC = 0.395, p < 0.0001), and ACG-rCBF and PvWML-V (SC = 0.231, p = 0.041). Furthermore, a direct relationship between PvWML-V and MMSE scores was identified (SC = -0.238, p = 0.026). Conclusion: Significant interrelationships were observed among the LV-V, PvWML-V, and ACG-rCBF that directly affected the MMSE score in the ESCI. The mechanisms behind these interactions and the impact of PvWML-V on cognitive function require further investigation.

Association between types of home healthcare and emergency house calls, hospitalization, and end-of-life care in Japan.

BACKGROUND: To meet the increasing demand for home healthcare in Japan, as part of the national healthcare system, home care support clinics/hospitals (HCSCs) and enhanced HCSCs were introduced in 2006 and 2012 respectively. This study aimed to evaluate whether HCSCs has succeeded in providing 24-h home care services through the end of life. METHODS: A retrospective cohort study was conducted using the national database in Japan. Participants were ≥ 65 years of age, had newly started regular home visits between July 2014 and September 2015, and used general clinics, conventional HCSCs, or enhanced HCSCs. Each patient was followed up for 6 months after the first visit. The outcome measures were (i) emergency house call(s), (ii) hospitalization(s), and (iii) end-of-life care defined as in-home death. Multivariable logistic regression analyses were performed for statistical analysis. RESULTS: The analysis included 160,674 patients, including 13,477, 64,616, and 82,581 patients receiving regular home visits by general clinics, conventional HCSCs, and enhanced HCSCs respectively. Compared to general clinics, the use of conventional and enhanced HCSCs was associated with an increased likelihood of emergency house calls (adjusted odds ratio [aOR] and 95% confidence intervals [CIs] of 1.62 [1.56-1.69] and 1.86 [1.79-1.93], respectively) and a decreased likelihood of hospitalizations (aOR [95% CIs] of 0.86 [0.82-0.90] and 0.88 [0.84-0.92] respectively). Among 39,082 patients who died during the follow-up period, conventional and enhanced HCSCs had more in-home deaths (aOR [95% CIs] of 1.46 [1.33-1.59] and 1.60 [1.46-1.74], respectively) compared to general clinics. CONCLUSIONS: HCSCs (especially enhanced HCSCs) provided more emergency house calls, reduced hospitalization, and enabled expected deaths at home, suggesting that further promotion of HCSCs (especially enhanced HSCSs) would be advantageous.

The Effect of Home Care Support Clinics on Hospital Readmission in Heart Failure Patients in Japan.

BACKGROUND: Heart failure is common and is associated with high rates of hospitalization. Home care support clinics/hospitals (HCSCs) and enhanced HCSCs were introduced in Japan in 2006 and 2012, respectively. OBJECTIVE: This study aimed to examine the effect of post-discharge care by conventional or enhanced HCSCs on readmission, compared with general clinics. DESIGN: Retrospective cohort study using the Japanese nationwide health insurance claims database. PARTICIPANTS: Participants were ≥65 years of age, admitted for heart failure and discharged between July 2014 and August 2015 and received a home visit within a month following the discharge (n=12,393). MAIN MEASURES: The exposure was the type of medical facility that provides post-discharge home healthcare: general clinics, conventional HCSCs, and enhanced HCSCs. The primary outcome was all-cause readmission for 6 months after the first visit; the incidence of emergency house calls was a secondary outcome. We used a competing risk regression using the Fine and Gray method, in which death was regarded as a competing event. KEY RESULTS: At 6 months, readmissions were lower in conventional (38%) or enhanced HCSCs (38%) than general clinics (43%). The adjusted subdistribution hazard ratio (sHR) of readmission was 0.87 (95% CI: 0.78-0.96) for conventional and 0.86 (0.78-0.96) for enhanced HCSCs. Emergency house calls increased with conventional (sHR: 1.77, 95% CI:1.57-2.00) and enhanced HCSCs (sHR: 1.93, 95% CI: 1.71-2.17). CONCLUSIONS: Older Japanese patients with heart failure receiving post-discharge home healthcare by conventional or enhanced HCSCs had lower readmission rates, possibly due to compensation with more emergency house calls. Conventional and enhanced HCSCs may be effective in reducing the risk of rehospitalization. Further studies are necessary to confirm the medical functions performed by HCSCs.

Fragment-Based Discovery of a Novel, Brain Penetrant, Orally Active HDAC2 Inhibitor.

Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-µM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.